•iNOS, CD163 and ARG-I were investigated in GBM tumors and in the surrounding parenchyma from the same patients.•CD163 expression was higher within GBM specimens than in surrounding periphery in both ...male and female patients, and was inversely correlated with mean survival times.•A prevailing iNOS-like profile was present within the tumor, at variance with the peripheral parenchyma surrounding the tumor.•No significant association was found between ARG-I or iNOS expression and survival time.
Microglia and macrophages appear to be the most common cells in the GBM microenvironment. In the present study we investigated the status of macrophages/microglia activation in surgical specimens from 41 patients diagnosed with grade IV GBM. For each patient we analyzed both the center of tumor and the parenchyma surrounding the tumor. The specimens were stained for: i) IBA1, a 17-kDa EF hand protein specifically expressed in microglia/macrophages ii) CD163, a cell surface antigen associated with M2 phenotype; iii) iNOS, taken as a functional marker of M1 phenotype, and iv) ARG-I, taken as a functional marker of M2 phenotype. Staining was scored in a double-blinded score on a scale from 0 to 5. Our results suggest that CD163 expression is higher within the tumor than in surrounding periphery in both male and female patients; while iNOS is higher within the tumor in males, no significant difference was found for ARG-1. In addition, analyzing the data in TGCA database, we found that CD163 expression was significantly and inversely correlated with mean survival times, with average survival times ranging from 448days in patients having low expression, to 319 in mid, and 353 in patients with high CD163 expressing tumors. In contrast, no significant association was found between survival time and ARG-1 or iNOS expression.
Remifentanil (RF) is a potent short-acting μ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have ...shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF. Considering the role of microglia in the initiation and maintenance of brain inflammation and their different responses among species, we aimed at characterizing RF effects on human adult microglia in vitro.
RF was tested at clinically relevant concentrations on the human microglial C20 cell line. Expression and release of interleukin-6 (IL-6) and brain derived neurotrophic factor (BDNF) were assessed under basal and inflammatory conditions.
The expression and secretion of IL-6 significantly increased in C20 cells in response to pro-inflammatory cytokines. RF did not modify this response neither under basal nor under inflammatory conditions. No toxicity due to RF was detected. The drug displayed a modest stimulatory effect on the production of BDNF.
Although RF does not exert direct pro-inflammatory actions on human adult microglia, its effects on BDNF, a crucial mediator of pain transmission, suggest a possible role on neuroinflammation and pain perception.
A high-concentration of a multi-strain probiotic mixture, VSL#3® is widely used 'whenever it is useful to promote the balance of intestinal flora'. As a food supplement, VSL#3® has been so far ...scarcely investigated on the aspect of safety. To fill this gap, in this paper, we analyzed the adverse events (AEs) recorded during the conduct of three (3) double-blind, randomized, placebo-controlled trials carried out to explore the efficacy of VSL#3® in various clinical settings. Data from a large open-label observational trial were also considered.
All trials included in the analysis were carried out according to good clinical practice (GCP) rules. AEs were classified by System Organ Class (SOC), Preferred Term (PT) and frequency. Differences vs. placebo control were considered as statistically significant if the p-value was < 0.05.
A total of 120 patients were analyzed, 70 patients being included in the randomized controlled trials. In this population, 45 patients had at least one AE, 20 (64.5%) in the placebo group and 25 (64.1%) in the VSL#3® group. 29 patients had at least one related AE, 14 (45.2%) and 15 (38.5%) in the two treatment groups, respectively. Only one AE was assessed as serious, i.e., Foetal malformation, which occurred in the placebo group and was considered unrelated. No significant difference was found between VSL#3® and placebo for any of the SOC considered, with the exception of Injury, poisoning and procedural complications, which was in favor of VSL#3®.
Based on GCP-quality data from clinical trials, we conclude that VSL#3® is a safe and well-tolerated agent.
Background
Several classes of drugs are effective in prevention and treatment of migraine, although they may differ among each other in their mode of action and in indications. One such class is ...represented by antiepileptics. Lacosamide is an approved antiepileptic drug that also shows antinociceptive activity in animal models, including analgesic efficacy in central and trigeminal pain. Calcitonin gene‐related peptide (CGRP) is considered the main neuro‐mediator of trigeminal signalling, playing an essential role in headache, migraine in particular. Here, we investigated the effects of lacosamide on CGRP signalling in both in vitro and ex vivo/vitro models in the rat.
Methods
We assessed: (1) CGRP released from brainstem explants at baseline or after pharmacological challenges; and (2) CGRP levels in brain areas after in vivo treatments with test drugs.
Results
We found that: (1) lacosamide inhibits CGRP release from brainstem explants under basal conditions as well as after stimulation by 56 mM KCl, 10 μM veratridine or 1 μM capsaicin; and (2) the i.p. administration of nitroglycerine produces an increase in CGRP levels in the brainstem and trigeminal ganglia, which is inhibited by a pre‐treatment with lacosamide.
Conclusions
These findings provide preliminary evidence suggesting that lacosamide is able to control pain transmission under conditions affecting the trigeminal system, such as migraine.
Abstract Current treatments used in Multiple Sclerosis (MS) are partly effective in the early stages of the disease but display very limited benefits in patients affected by progressive MS. One ...possible explanation is that these therapies are unable to target the inflammatory component most active during the progressive phase of the disease, and compartmentalized behind the blood–brain barrier. Our findings show that Rapamycin ameliorates clinical and histological signs of chronic EAE when administered during ongoing disease. Moreover, Rapamycin significantly reduced the hyperalgesia observed before clinical development of EAE which, in turn, is completely abolished by the administration of the drug.
The effect of remifentanil on stress response to surgery is unclear. However, there are not clinical studies investigating the relationship between blood remifentanil concentrations and stress ...hormones. Therefore, the aim of the present study was to assess the association between blood remifentanil concentrations measured after pneumoperitoneum and cortisol (CORT) or prolactin (PRL) ratio (intraoperative/preoperative value), in patients undergoing laparoscopic cholecystectomy.
Patients did not receive any pre-anesthetic medication. Anesthesia induction was standardized. Anesthesia maintenance was performed with inhaled sevoflurane at age-adjusted 1.0 minimum alveolar concentration and intravenous remifentanil at infusion rate ranging from 0.1 to 0.4 mcg/kg/min. Blood samples were withdrawn before anesthesia induction and 5 min after achieving a pneumoperitoneum pressure of 12 mmHg. Correlation analyses were performed to evaluate the relationship between measured blood remifentanil concentrations, CORT or PRL ratio (intraoperative/preoperative value) and remifentanil dose delivered by the pump.
A significant inverse correlation was found between CORT ratio and measured blood remifentanil concentration (p=0.03) or planned remifentanil dose (p=0.04). No correlations were found between blood remifentanil concentration and PRL ratio (p=0.83).
Our data suggest that the CORT response to surgical stress is more efficiently counteracted by increased blood remifentanil concentration.
Summary
The aim of this study was to investigate whether auditory presentation of a story during general anaesthesia might influence stress hormone changes and thus affecting dream recall and/or ...implicit memory. One hundred and ten patients were randomly assigned either to hear a recording of a story through headphones or to have routine care with no auditory recording while undergoing laparoscopic cholecystectomy. Anaesthesia was standardised. Blood samples for cortisol and prolactin assays were collected 20 min before anaesthesia and 5 min after pneumoperitoneum. Dream recall and explicit/implicit memory were investigated upon awakening from anaesthesia and approximately 24 h after the end of the operation. Auditory presentation was associated with lower intra‐operative serum prolactin concentration compared with control (p = 0.0006). Twenty‐seven patients with recall of dreaming showed higher intra‐operative prolactin (p = 0.004) and lower cortisol (p = 0.03) concentrations compared with those without dream recall. The knowledge of this interaction might be useful in the quest to ensure postoperative amnesia.
In recent years, as multinational corporation (MNC) subsidiaries have become more closely linked to international networks, their knowledge intensity has risen, and some of their R&D has gained a ...more creative role. Simultaneously, and often connectedly, many subsidiaries have acquired considerable strategic independence in all aspects of their operations, and therefore are able to exercise considerable intra-firm bargaining power to influence the distribution of the firm's resources. In this context, we suggest that intra-MNC knowledge flows are a key determinant of subsidiary bargaining power. We argue that subsidiary managers can exploit such power to pursue their own ends. Such rent-seeking behavior is implicit in much of the literature on managerialism, but our analysis suggests that such behavior can now occur in headquarters-subsidiary and subsidiary-subsidiary relations. Thus subsidiary strategic independence, designed to enhance the competitiveness of outputs (market knowledge) and inputs (asset-seeking and learning), can be corroded when the pursuit of subsidiary objectives encourages rent-seeking. Empirical analysis of a sample of high-technology subsidiaries in the UK provides strong support for the theory. We examine several avenues whereby the incentives of units within the MNC can be aligned.
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► Integration of three simulators in a mine-to-mill application. ► Plant expansion feasibility linked to an ore storage bottleneck. ► Development of a 2D dynamic ore flow model of the ...ore storage 3D shape. ► Calculation of losses attributable to the ore storage bottleneck simulated on a yearly basis. ► Evaluation of three simulated scenarios for mitigating losses.
Stockpiling ore within a storage facility located between the mine and the concentrator can help damp production fluctuations originating from either the mining operation or the ore processing operation. To increase ore production rates, additional equipment is often installed within concentrators and mines. However, ore storage facilities may create bottlenecks in the production chain, if they are not properly redesigned. This paper proposes a mine-to-mill simulation method to determine the limitations of existing ore storage facilities and help their resizing in a context of production expansion. The modeling method combines three simulators to evaluate the production losses attributed to ore storage facilities: (1) a dynamic simulator of the 2D distribution of a storage facility filling profile, (2) a dynamic logistic model to simulate mine production and (3) a Monte Carlo simulator to emulate mine and concentrator equipment downtimes. The resulting overall simulator is able to provide answers to a very practical and critical industrial question: is an existing ore storage facility capable of handling increases in the production rate? Results of an application of this simulation technique to an iron ore processing plant helped reorient the plant expansion prefeasibility studies.
Purpose
The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of ...this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure.
Methods
The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography–ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1.
Results
A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%,
p
= 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels.
Conclusions
A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.
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