Neurotoxicity induced by mephedrone: an up-to-date review

BACKGROUND: Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. OBJECTIVE: The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. MATERIALS AND METHODS: Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". RESULTS: Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-hydroxytryptamine (5-HT) and dopamine (DA) systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. CONCLUSIONS: Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health

Accounting for attitudes and perceptions influencing users' willingness to purchase Electric Vehicles through a Hybrid Choice Modeling approach based on Analytic Hierarchy Process

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scheduled synchronisation based on a mesoscopic flow model with speed dispersion

Abstract This paper proposes a method for netwok signal setting design, based on enhacements of an existing coordination method aiming: 1) to extend the existing approach in order to address the Traffic Control through Scheduled Synchronisation (i.e 'one step' optimisation of stage matrix, green timings, and node offsets ); 2) to extend the considered Mesoscopic Traffic Flow model (TRAFFMED) to the vehicle platoon speed dispersion; 3) to build up a solution method suitable for both off-line and on-line applications. The proposed optimisation method is an application of the Simulated Annealing meta-heuristic. Some numerical applications are proposed, specifically analysing 'two step' optimisation (synchronisation), and'one step' optimisation (scheduled synchronisation), for off-line (pre-timed strategy) and on-line applications (on-line computation strategy). A grid network was considered as case study and the effectiveness of the proposed strategies were evaluated by comparing the obtained results with those computed through commercial (benchmark) and in-house codes

Human herpesvirus 6A and 6B and NK cells

Human herpesvirus 6 (HHV-6) comprises two viral species, HHV-6A and HHV-6B, closely related but differing for pathogenic and biological characteristics. Both viral species are predominantly lymphotropic, infecting T lymphocytes and other lymphoid cells, including natural killer (NK) cells. The interactions between HHV-6 and NK cells have been scarcely studied, but it has become clear that NK cells are not only crucial in immune protection during the early phases of infection, but also that HHV-6 infection can affect NK cell functions. In this report, we shortly summarize the interactions between HHV-6 and NK cells

Estimating an Injury Crash Rate Prediction Model based on severity levels evaluation: The case study of single-vehicle run-off-road crashes on rural context

Abstract In general in case of crash situations the quality of collected data is very limited and several information are usually unreliable. Thus it is recognised that a significant effort is required in order to improve the quality of the crash prediction models moreover a crucial role is played by the identification of the factors influencing the crashes occurrence and the levels of severity estimation. In this paper two injury crash rate prediction models related to single-vehicle run-off-road crashes type are calibrated and in particular significant attributes estimated are identified not only with roadway geometric characteristics and surface conditions, but also with gender/number-of-drivers. To this aim a survey of injury crashes on two-lane rural roads collected in the Southern Italy was considered and analysed. Finally before the calibration step, a preliminary analysis of the data was provided through the estimation of the levels of severity by multinomial logit; in fact by this model only segments with highest values of severity are identified and involved in the calibration procedure

Identification of the zinc finger 216 (ZNF216) in human carcinoma cells. A potential regulator of EGFR activity

Epidermal Growth Factor Receptor (EGFR), a member of the ErbB family of receptor tyrosine kinase (RTK) proteins, is aberrantly expressed or deregulated in tumors and plays pivotal roles in cancer onset and metastatic progression. ZNF216 gene has been identified as one of Immediate Early Genes (IEGs) induced by RTKs. Overexpression of ZNF216 protein sensitizes 293 cell line to TNF-α induced apoptosis. However, ZNF216 overexpression has been reported in medulloblastomas and metastatic nasopharyngeal carcinomas. Thus, the role of this protein is still not clearly understood. In this study, the inverse correlation between EGFR and ZNF216 expression was confirmed in various human cancer cell lines differently expressing EGFR. EGF treatment of NIH3T3 cells overexpressing both EGFR and ZNF216 (NIH3T3-EGFR/ZNF216), induced a long lasting activation of EGFR in the cytosolic fraction and an accumulation of phosphorylated EGFR (pEGFR) more in the nuclear than in the cytosolic fraction compared to NIH3T3-EGFR cells. Moreover, EGF was able to stimulate an increased expression of ZNF216 in the cytosolic compartment and its nuclear translocation in a time-dependent manner in NIH3T3-EGFR/ZNF216. A similar trend was observed in A431 cells endogenously expressing the EGFR and transfected with Znf216. The increased levels of pEGFR and ZNF216 in the nuclear fraction of NIH3T3-EGFR/ZNF216 cells were paralleled by increased levels of phospho-MAPK and phospho-Akt. Surprisingly, EGF treatment of NIH3T3-EGFR/ZNF216 cells induced a significant increase of apoptosis thus indicating that ZNF216 could sensitize cells to EGF-induced apoptosis and suggesting that it may be involved in the regulation and effects of EGFR signaling

The possible prognostic role of histone deacetylase and transforming growth factor β/Smad signaling in high grade gliomas treated by radio-chemotherapy: a preliminary immunohistochemical study

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-β/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-β/Smad pathway, with high levels of IL-13, Smad2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in Smad 7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-β/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease

Biomarkers in Breast Cancer

Breast cancer is the most common cancer in women and its incidence experienced an important increase, thanks to the introduction of a systematic screening. The increased incidence of early breast cancer has led to debates on its over-treatment, which may cause unnecessary harm to patients with favorable prognosis. Therefore, modern research is in the quest of finding the perfect prognostic marker to avoid overtreatment in patients with a favorable prognosis. In this perspective, many molecular markers have been studied in the last decades in order to provide both a useful prognostic tool, able to determine whether the cancer is likely to be indolent or aggressive, and a possible therapeutic target. In this chapter, we review the current knowledge about the principal biomarkers, which are usually immunohistochemically tested on breast surgical specimens, including ER and PR, Mib1/Ki-67 and HER2/neu expression. Furthermore, we will analyze other possible prognostic markers which may have in the future a key role in breast cancer management, such as several multigene panels (OncotypeDX, Mammaprint, NanoString Prosigma). Finally, we will discuss the role of genetic tests for some know genetic mutations associated with higher breast cancer susceptibility (BRCA1 and 2 genes)