Trichothecenes NIV and DON modulate the maturation of murinedendritic cells

Nivalenol (NIV) and Deoxynivalenol (DON), mycotoxins of the trichothecene family are considered very common food contaminants. In this work, we investigated whether the immunotoxic effects ascribed to these trichothecenes may be mediated by perturbations in the activity of dendritic cells (DCs). Murine bone marrow-derived DCs were used to evaluate the effects of NIV and DON on the LPS-induced maturation process.We found that the expression of the class II MHC and of the accessory CD11c molecules, but not of the costimulatory CD86 marker, was down-regulated by NIV and DON exposure in LPS-treated DCs, as well as nitric oxide (NO) production. Interestingly, NIV, but not DON, induced DC necrosis. Moreover, the analysis of the cytokine pattern showed that IL-12 and IL-10 expressions induced by LPS exposure were suppressed by both trichothecenes in a dose-dependent fashion. On the other hand, the secretion of the proinflammatory cytokine TNFa was increased as a direct consequence of DON and NIV exposure. Taken together, our data indicated that the immunotoxicity of NIV and DON was related to the capacity of both trichothecenes to interfere with phenotypic and functional features of maturing DCs

Preliminary report in treatment of proximal humeral fracture with closed reduction and DOS external fixation System: a multicentric study

Introduction: Proximal humerus fractures are the seventh most frequent fracture in adults, and the third in patients over 65 years old, 5.7% of whole diagnosed fractures. Most of these fractures can be treated conservatively and achieve good results. However, more and more frequently we are confronted with dislo-cated and multifragmentary fractures, and with elderly and high functional demanding patients. In patients with osteoporosis and poor general conditions external fixation can be performed as rapid and mininvasive procedure with good outcome and low complication rates. The authors investigated the use of external fixa-tion in the treatment of proximal humerus fractures. The objective is to demonstrate the effectiveness of this method as a valid alternative to other surgical techniques. Materials and Methods: A multicentre study was conducted at 7 hospitals in Italy from 2014 through 2018. We recruited all proximal humeral fractures (as classified with the Neer system) that are surgically treated with the same external fixator DOS, for a total of 110 patients, evaluated later with Oxford Shoulder Scale (OSS) and disability of the arm, shoulder and hand score (DASH) at 1, 2 and 6 months. Results:The patients have passed from a score of 75,37 in the first month to a score of 29,47in the sixth month at the DASH and from 47,02 to 27,71 at the OSS. The data further confirm the increased incidence of these fractures in women and in a mean age of about 65. Conclusions:Al-though it does not represent the golden standard in the treatment of fractures of the proximal humerus, in our experience the minimal osteosynthesis with external fixator turned out to be a very valid help especially for the simplicity and speed of the method, as well as for the exciting functional results. sometimes superior to other methods. The preliminary results from the different centers have confirmed this hypothesis. We hope this will be a good starting point for further in-depth studies

Dried blood spot UHPLC-MS/MS analysis of oseltamivir and oseltamivircarboxylate—a validated assay for the clinic

The neuraminidase inhibitor oseltamivir (Tamiflu®) is currently the first-line therapy for patients with influenza virus infection. Common analysis of the prodrug and its active metabolite oseltamivircarboxylate is determined via extraction from plasma. Compared with these assays, dried blood spot (DBS) analysis provides several advantages, including a minimum sample volume required for the measurement of drugs in whole blood. Samples can easily be obtained via a simple, non-invasive finger or heel prick. Mainly, these characteristics make DBS an ideal tool for pediatrics and to measure multiple time points such as those needed in therapeutic drug monitoring or pharmacokinetic studies. Additionally, DBS sample preparation, stability, and storage are usually most convenient. In the present work, we developed and fully validated a DBS assay for the simultaneous determination of oseltamivir and oseltamivircarboxylate concentrations in human whole blood. We demonstrate the simplicity of DBS sample preparation, and a fast, accurate and reproducible analysis using ultra high-performance liquid chromatography coupled to a triple quadrupole mass spectrometer. A thorough validation on the basis of the most recent FDA guidelines for bioanalytical method validation showed that the method is selective, precise, and accurate (≤15% RSD), and sensitive over the relevant clinical range of 5–1,500 ng/mL for oseltamivir and 20–1,500 ng/mL for the oseltamivircarboxylate metabolite. As a proof of concept, oseltamivir and oseltamivircarboxylate levels were determined in DBS obtained from healthy volunteers who received a single oral dose of Tamiflu®

Sol-gel derived mesoporous Pt and Cr-doped WO(3) thin films: the role played by mesoporosity and metal doping in enhancing the gas sensing properties

Mesoporous Cr or Pt-doped WO(3) thin films to be employed as ammonia gas sensors were prepared by a fast one-step sol-gel procedure, based on the use of triblock copolymer as templating agent. The obtained films were constituted by aggregates of interconnected WO(3) nanocrystals (20-50 nm) separated by mesopores with dimensions ranging between 2 and 15 nm. The doping metals, Pt and Cr, resulted differently hosted in the WO(3) mesoporous matrix. Chromium is homogeneously dispersed in the oxide matrix, mainly as Cr(III) and Cr(V) centers, as revealed by EPR spectroscopy; instead platinum segregated as Pt (0) nanoparticles (4 nm) mainly included inside the WO(3) nanocrystals. The semiconductor layers containing Pt nanoclusters revealed, upon exposure to NH(3), remarkable electrical responses, much higher than Cr-doped and undoped layers, particularly at low ammonia concentration (6.2 ppm). This behavior was attributed to the presence of Pt nanoparticles segregated inside the semiconductor matrix, which act as catalysts of the N-H bond cleavage, decreasing the activation barrier in the ammonia dissociation. The role of the mesoporous structure in influencing the chemisorption and the gas diffusion in the WO(3) matrix appeared less decisive than the electronic differences between the two examined doping metals. The overall results suggest that a careful combination between mesoporous architecture and metal doping can really promote the electrical response of WO(3) toward ammonia

Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Managing service level agreements in Premium IP networks: a business-oriented approach

This paper presents a market-enabling framework where users, content providers and network operators can interact in the seamless, transparent sale and delivery of a wide range of services. The framework allows for dynamic creation, configuration and delivery of services with quality assurance, via automated management of Service Level Agreements (SLAs). We propose an approach relying on a systemic treatment of business, service and network layer issues, which translates into a layered architecture where components belonging to different levels interact on the basis of a mediation paradigm. We use mediation as a generic term for a combination of negotiation, brokerage and state notification, jointly concurring to the realization of the entire life-cycle of a service

Optimal hysteresis control via a queueing system with two heterogeneous energy-consuming servers

A queueing system having two different servers is under study. Demands enter the system according to a Markov Arrival Process. Service times have phase-type distribution. Service of demands is possible only if the fixed number of energy units, probably different for two servers, is available in the system at the potential service beginning moment. Energy units arrive in the system also according to a Markov Arrival Process and are stored in a stock (battery) of a finite capacity. Leakage of energy units from the stock can occur. Demands waiting in the infinite buffer are impatient and can leave the buffer after an exponentially distributed waiting time. One server is the main one and permanently provides service when the buffer is not empty and the required number of energy units is available. The second server is the assistant server and is switched on or off depending on the availability of energy units and queue length according to the hysteresis strategy defined by two thresholds. The assistant server is switched on when the queue length is not less than the greater threshold and is switched off when the queue length becomes smaller than the smaller threshold. The use of the assistant server has to be paid. Thus, the problem of the optimal selection of the thresholds defining the control strategy naturally arises. To solve this problem, the study of the behavior of the system under any fixed values of the parameters of the control strategy is necessary. Such a study is given in this paper. Numerical results are presented. They illustrate the feasibility of computer realization of the developed algorithms for computation of the stationary distribution of the system states and the main key performance indicators as well as the result of solving one of the possible optimization tasks

Managing Service Level Agreements in Premium IP Networks: a Business-oriented Approach

This paper presents a market-enabling framework where users, content providers and network operators can interact in the seamless, transparent sale and delivery of a wide range of services. The framework allows for dynamic creation, configuration and delivery of services with quality assurance, via automated management of Service Level Agreements (SLAs). We propose an approach relying on a systemic treatment of business, service and network layer issues, which translates into a layered architecture where components belonging to different levels interact on the basis of a mediation paradigm. We use mediation as a generic term for a combination of negotiation, brokerage and state notification, jointly concurring to the realization of the entire life-cycle of a service