Silver nanoparticles augment releasing of pyrogenic factors by blood cells stimulated with LPS

Silver nanoparticles (AgNPs) have cytotoxic properties via generation of reactive oxygen species which are involved in the generalized sickness behavior of the host including fever and lethargy among others. The aim of the present study was to investigate the impact of AgNPs on the ability of rat peripheral blood mononuclear cells (PBMCs) to release fever mediating factors after stimulation with lipopolysaccharide (LPS). Body temperature and motor activity of the Wistar rats were measured by biotelemetry system. Rat PBMCs were stimulated with LPS and after that, the cells were washed and incubated alone or with AgNPs. The final supernatants were injected intraperitoneally. The levels of endogenous pyrogens such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) released from the PBMCs into the final supernatants were also estimated. The results indicated that injection of the supernatants from the cells stimulated with LPS induced fever and inhibited motor activity. These effects were potentiated by the presence of AgNPs during the final incubation. The presence of the AgNPs also resulted in significant increases in levels of endogenous pyrogens. The augmentation of fever in the rats by the AgNPs treatment of the cultures seemed to be primarily associated with the changes in interleukin-1β levels

Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats

Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. It improves quality of the patients‟ life by decreasing pain, fatigue, loss of appetite, nausea, and vomiting. However, the effect of PSP on body temperature has not thus far been studied, although it is well known that treatment with other polysaccharide adjuvants, such as lipopolysaccharides, may induce fever. The aim of the present study, therefore, was to investigate the influence of PSP on temperature regulation in rats. We report that intraperitoneal injection of PSP provoked a dose-dependent decrease of temperature in male Wistar rats equipped with biotelemetry devices to monitor deep body temperature (Tb). The response was rapid (i.e., with latency of 15-20 minutes), transient (lasting up to 5 hours post-injection), and accompanied by a significant elevation of the blood tumor necrosis factor- α (TNF-α) level. Pretreatment of the rats with anti-TNF-α antibody prevented the PSP-induced drop in Tb. Based on these data, we conclude that rats may develop an anapyrexia-like response to the injection of peptidopolysaccharide rather than fever, and the response was TNF-α-dependent

The release of soluble forms of TRAIL and DR5 by neutrophils of oral cavity cancer patients.

In the present study we examined the release of the soluble form of TRAIL by neutrophils (PMN) derived from patients with oral cavity cancer. Simultaneously, we estimated the ability of PMNs of these patients to release the soluble form of DR5 receptor, a natural regulatory protein of TRAIL. The obtained results were confronted with the serum levels of sTRAIL and sDR5. The cells were isolated from 21 patients with squamous cell carcinoma of oral cavity at diagnosis and three weeks after surgery treatment. For comparative purposes we performed similar examinations in autologous peripheral blood mononuclear cells (PBMC). Cytoplasmic protein fractions of the cells were analyzed for the presence of TRAIL and DR5 by western blotting. Soluble TRAIL and soluble DR5 concentrations in the culture supernatants of cells were confronted with their serum levels using ELISA kit. PMN and PBMC of the whole cancer patient group expressed decreased TRAIL protein and unchanged expression of DR5 receptor in comparison with the control group. Unchanged release of sTRAIL by PMNs of patients in Stage II was accompanying the decrease of the ability of PBMC to secrete this protein. In patients in Stage IV the secretion of sTRAIL by PMNs and PBMC was impaired. In contrast to changes in sTRAIL secretion by PMN and PBMC of oral cavity cancer patients, the secretion of sDR5 by these cells was unchanged. The serum levels of sTRAIL were increased in patients in Stage II before treatment and decreased in the same patients after treatment. The altered ability of PMN of PBMC to secrete sTRAIL may have different implications for the immune response of patients with oral cavity cancer cells at different stages of disease

Immunomodulujące i przeciwnowotworowe właściwości polisacharydopeptydu (PSP)

Współczesna medycyna z powodzeniem wykorzystuje preparaty pochodzenia naturalnego o działaniu immunomodulującym, które mogą wpływać na reakcje biologiczne zachodzące w organizmie i wspomagać jego naturalne mechanizmy obronne, w tym skierowane przeciwko nowotworowi. Wśród nich liczną grupę stanowią produkty pozyskiwane z grzybów, m.in. schizofylan, lentinan, polisacharyd Krestin (PSK) i polisacharydopeptyd (PSP). W pracy przedstawiono właściwości polisacharydopeptydu, który ze względu na znikomą toksyczność staje się coraz powszechniej stosowany w Chinach i Japonii jako uzupełnienie terapii przeciwnowotworowych. PSP jest kompleksem białkowo-polisacharydowym o masie 100 kDa ekstrahowanym z grzyba Coriolus versicolor. Wyniki licznych badań i obserwacje kliniczne potwierdzają, że PSP hamuje wzrost komórek nowotworowych in vitro i in vivo. Łagodzi negatywne skutki leczenia z wykorzystaniem chemio- i radioterapii, takie jak zmęczenie, utrata apetytu, nudności, wymioty i ból. Zdolny jest odbudować osłabioną przez chemioterapię odpowiedź immunologiczną. U podłoża przeciwnowotworowego działania polisacharydopeptydu leżą jego właściwości immunomodulujące. PSP stymuluje komórki układu immunologicznego, indukuje syntezę cytokin, np. IL-1β, IL-6 i czynnika martwicy nowotworów-α (TNF-α), eikozanoidów, a w tym prostaglandyny E2 (PGE2), histaminy, reaktywnych form tlenu i mediatorów azotowych. Dokładne poznanie mechanizmów działania PSP wzbudza coraz większe zainteresowanie badaczy na całym świecie. Polisacharyd peptydowy, ze względu na swoje unikatowe właściwości i bezpieczeństwo stosowania może już w niedalekiej przyszłości stać się powszechnie stosowanym środkiem terapeutycznym.Modern medicine successfully uses multiple immunomodulators of natural origin, that can affect biological reactions and support body’s natural defense mechanisms including antitumor activities. Among them is a group of products derived from fungi, including schizophyllan, lentinan, polysaccharide Krestin (PSK), and polysaccharidepeptide (PSP). Present paper is focused on polysaccharidepeptide, which due to the negligible toxicity and numerous benefits for health, is increasingly used in China and Japan as an adjuvant in the treatment of cancer. PSP is a protein-polisaccharide complex with a molecular weight 100 kDa derived from Coriolus versicolor mushroom. The results of numerous studies and clinical trials confirm that it inhibits the growth of cancer cells in in vitro and in vivo settings as well as decreases cancer treatment-related adverse side effects such as fatigue, loss of appetite, nausea, vomiting, and pain. PSP is able to restore weakened immune response observed in patients with cancer during chemotherapy. Its anti-tumor effects seemed to be mediated through immunomodulatory regulation. PSP stimulates cells of the immune system, induces synthesis of cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), eicosanoids including prostaglandin E2 (PGE2), histamine, reactive oxygen species and nitrogen mediators. There is a growing interest in understanding the mechanisms of PSP action. Because of its unique properties and safety, PSP may become a widely used therapeutic agent in the near future

Antazoline for rapid termination of atrial fibrillation during ablation of accessory pathways

Background and aim: To assess safety and efficacy of antazoline for termination of atrial fibrillation (AF) occurring during ablation of accessory pathways (AP).Methods: We analyzed electrophysiological mechanism of antazoline (changes in A-A interval) and the percentage of pre-excited QRS complexes before and after antazoline administration. The total dose administered and the time from the start of injection to sinus rhythm restoration were also measured.Results: Out of consecutive 290 patients with Wolff-Parkinson-White syndrome undergoing radiofrequency (RF) ablation, 12 (4.1%) (4 females, mean age 36 ± 20 years) developed sustained AF which did not stop spontaneously within 10 min, and antazoline in 100 mg repeated boluses was administered. In all 12 patients the drug restored sinus rhythm after a mean of 425 ± 365 s (range 43–1245 s) using a mean cumulative dose of 176 ± 114 mg (range 25–400 mg). The drug slightly prolonged R-R intervals during AF (from 383 ± 106 to 410 ± 70 ms) and reduced the percentage of fully pre-excited QRS complexes (from 35% to 26%). Intracardiac recordings showed gradual increase in A-A intervals, as well as regularization and decreasing fractionation of atrial activity following drug injection (mean A-A interval of 162 ± 30 ms at baseline vs. 226 ± 26 ms shortly before sinus rhythm restoration, p < 0.001). AP was not completely blocked in any patient which enabled continuation of ablation.Conclusions: Antazoline safely and rapidly converts AF into sinus rhythm during ablation of AP. The drug does not block AP completely, enabling continuation of ablation. The drug converting AF into more organized atrial activity (atrial flutter/tachycardia) before sinus rhythm resumption.

Insanity as a Defense to the Civil Fraud Penalty

Most neurological diseases are associated with chronic inflammation initiated by the activation of microglia, which produce cytotoxic and inflammatory factors. Signal transducers and activators of transcription (STATs) are potent regulators of gene expression but contribution of particular STAT to inflammatory gene expression and STAT-dependent transcriptional networks underlying brain inflammation need to be identified. In the present study, we investigated the genomic distribution of Stat binding sites and the role of Stats in the gene expression in lipopolysaccharide (LPS)-activated primary microglial cultures. Integration of chromatin immunoprecipitation-promoter microarray data and transcriptome data revealed novel Stat-target genes including Jmjd3, Ccl5, Ezr, Ifih1, Irf7, Uba7, and Pim1. While knockdown of individual Stat had little effect on the expression of tested genes, knockdown of both Stat1 and Stat3 inhibited the expression of Jmjd3 and inflammatory genes. Transcriptional regulation of Jmjd3 by Stat1 and Stat3 is a novel mechanism crucial for launching inflammatory responses in microglia. The effects of Jmjd3 on inflammatory gene expression were independent of its H3K27me3 demethylase activity. Forced expression of constitutively activated Stat1 and Stat3 induced the expression of Jmjd3, inflammation-related genes, and the production of proinflammatory cytokines as potently as lipopolysacharide. Gene set enrichment and gene function analysis revealed categories linked to the inflammatory response in LPS and Stat1C + Stat3C groups. We defined upstream pathways that activate STATs in response to LPS and demonstrated contribution of Tlr4 and Il-6 and interferon-. signaling. Our findings define novel direct transcriptional targets of Stat1 and Stat3 and highlight their contribution to inflammatory gene expression

MizAR 60 for Mizar 50

As a present to Mizar on its 50th anniversary, we develop an AI/TP system that automatically proves about 60% of the Mizar theorems in the hammer setting. We also automatically prove 75% of the Mizar theorems when the automated provers are helped by using only the premises used in the human-written Mizar proofs. We describe the methods and large-scale experiments leading to these results. This includes in particular the E and Vampire provers, their ENIGMA and Deepire learning modifications, a number of learning-based premise selection methods, and the incremental loop that interleaves growing a corpus of millions of ATP proofs with training increasingly strong AI/TP systems on them. We also present a selection of Mizar problems that were proved automatically

ToFFi – Toolbox for frequency-based fingerprinting of brain signals

Spectral fingerprints (SFs) are unique power spectra signatures of human brain regions of interest (ROIs, Keitel & Gross, 2016). SFs allow for accurate ROI identification and can serve as biomarkers of differences exhibited by non-neurotypical groups. At present, there are no open-source, versatile tools to calculate spectral fingerprints. We have filled this gap by creating a modular, highly-configurable MATLAB Toolbox for Frequency-based Fingerprinting (ToFFi). It can transform magnetoencephalographic and electroencephalographic signals into unique spectral representations using ROIs provided by anatomical (AAL, Desikan-Killiany), functional (Schaefer), or other custom volumetric brain parcellations. Toolbox design supports reproducibility and parallel computations