Selective blockade of mglu5 metabotropic glutamate receptors is protective against acetaminophen hepatotoxicity in mice

BACKGROUND/AIMS: mGlu5 metabotropic glutamate receptor antagonists protect rat hepatocytes against hypoxic death. Here, we have examined whether mGlu5 receptor antagonists are protective against liver damage induced by oxidative stress. METHODS: Toxicity of isolated hepatocytes was induced by tert-butylhydroperoxide (t-BuOOH) after pretreatment with the mGlu5 receptor antagonists, MPEP, SIB-1757 and SIB-1893. The effect of these drugs was also examined in mice challenged with toxic doses of acetaminophen. RESULTS: Addition of tBuOOH (0.5 mM) to isolated hepatocytes induced cell death (70+/-5% at 3 h). Addition of MPEP or SIB-1893 to hepatocytes reduced both the production of reactive oxygen species (ROS) and cell toxicity induced by t-BuOOH (tBuOOH=70+/-5%; tBuOOH+MPEP=57+/-6%; tBuOOH+SIB-1893=40+/-4%). In mice, a single injection of acetaminophen (300 mg/kg, i.p.) induced centrilobular liver necrosis, which was detectable after 24 h. MPEP (20 mg/kg, i.p.) substantially reduced liver necrosis and the production of ROS, although it did not affect the conversion of acetaminophen into the toxic metabolite, N-acetylbenzoquinoneimine. MPEP, SIB-1893 and SIB-1757 (all at 20 mg/kg, i.p.) also reduced the increased expression and activity of liver iNOS induced by acetaminophen. CONCLUSIONS: We conclude that pharmacological blockade of mGlu5 receptors might represent a novel target for the treatment of drug-induced liver damage

Exploring Social Sustainability and Economic Practices: Multi-Journal Compendium

In consideration of the three pillars of sustainability, alongside the environment, social and economic dimensions interplay valuable insight into how society is molded and what key components should be considered. In terms of social sustainability, there are processes and framework objectives that promote wellbeing integral to the balance of people, planet, and profit. Economic practices consider the system of production, resource allocation, and distribution of goods and services with respect to demand and supply between economic agents. As a result, an economic system is a variant of the social system in which it exists. At present, the forefront of social sustainability research partially encompasses the impact economic practices have on people and society—with notable emphasis centered on the urban environment. Specific interdisciplinary analyses within the scope of sustainability, social development, competitiveness, and motivational management as well as decision making within the urban landscape are considered. This book contains nine thoroughly refereed contributions that interconnect detailed research into the two pillars reviewed

Atypical mature T-cell neoplasms: The relevance of the role of flow cytometry

Lymphoproliferative disorders are a heterogeneous group of malignant clonal proliferations of lymphocytes whose diagnosis remains challenging, despite diagnostic criteria are now well established, due to their heterogeneity in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are more rarely seen than B-cell entities and more difficult to diagnose for the absence of a specific immunophenotypic signature. Flow cytometry is a useful tool in diagnosing T-cell lymphoproliferative disorders since it is not only able to better characterize T-cell neoplasms but also to resolve some very complicated cases, in particular those in which a small size population of neoplastic cells is available for the analysis. Here, we report three patients with mature T-cell neoplasms with atypical clinical and biological features in which analysis of peripheral blood and bone marrow specimens by means of multicolor flow cytometry was very useful to identify and characterize three rare T-cell lymphoproliferative disorders, such as angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and T-cell prolym-phocytic leukemia. The aim of this case series report is not only to describe three rare cases of lymphoproliferative neoplasms but also to raise awareness that a fast, highly sensitive, and reproducible procedure, such as flow cytometry immunophenotyping, can have a determinant diagnostic role in these patients

Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures

The chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. We examined the possibility that activation of G-protein-coupled metabotropic glutamate (mGlu) receptors regulates the formation of RANTES in glial cells. A 15 hr exposure of cultured astrocytes to tumor necrosis factor-alpha and interferon-gamma induced a substantial increase in both RANTES mRNA and extracellular RANTES levels. These increases were markedly reduced when astrocytes were coincubated with l-2-amino-4-phosphonobutanoate (l-AP-4), 4-phosphonophenylglycine, or l-serine-O-phosphate, which selectively activate group III mGlu receptor subtypes (i.e., mGlu4, -6, -7, and -8 receptors). Agonists of mGlu1/5 or mGlu2/3 receptors were virtually inactive. Inhibition of RANTES release produced by l-AP-4 was attenuated by the selective group III mGlu receptor antagonist (R,S)-alpha-methylserine-O-phosphate or by pretreatment of the cultures with pertussis toxin. Cultured astrocytes expressed mGlu4 receptors, and the ability of l-AP-4 to inhibit RANTES release was markedly reduced in cultures prepared from mGlu4 knock-out mice. This suggests that activation of mGlu4 receptors negatively modulates the production of RANTES in glial cells. We also examined the effect of l-AP-4 on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. l-AP-4 was subcutaneously infused for 28 d by an osmotic minipump that released 250 nl/hr of a solution of 250 mm of the drug. Detectable levels of l-AP-4 ( approximately 100 nm) were found in the brain dialysate of EAE rats. Infusion of l-AP-4 did not affect the time at onset and the severity of neurological symptoms but significantly increased the rate of recovery from EAE. In addition, lower levels of RANTES mRNA were found in the cerebellum and spinal cord of EAE rats infused with l-AP-4. These results suggest that pharmacological activation of group III mGlu receptors may be useful in the experimental treatment of neuroinflammatory CNS disorders

Steric sea level variability (1993-2010) in an ensemble of ocean reanalyses and objective analyses

Quantifying the effect of the seawater density changes on sea level variability is of crucial importance for climate change studies, as the sea level cumulative rise can be regarded as both an important climate change indicator and a possible danger for human activities in coastal areas. In this work, as part of the Ocean Reanalysis Intercomparison Project, the global and regional steric sea level changes are estimated and compared from an ensemble of 16 ocean reanalyses and 4 objective analyses. These estimates are initially compared with a satellite-derived (altimetry minus gravimetry) dataset for a short period (2003–2010). The ensemble mean exhibits a significant high correlation at both global and regional scale, and the ensemble of ocean reanalyses outperforms that of objective analyses, in particular in the Southern Ocean. The reanalysis ensemble mean thus represents a valuable tool for further analyses, although large uncertainties remain for the inter-annual trends. Within the extended intercomparison period that spans the altimetry era (1993–2010), we find that the ensemble of reanalyses and objective analyses are in good agreement, and both detect a trend of the global steric sea level of 1.0 and 1.1 ± 0.05 mm/year, respectively. However, the spread among the products of the halosteric component trend exceeds the mean trend itself, questioning the reliability of its estimate. This is related to the scarcity of salinity observations before the Argo era. Furthermore, the impact of deep ocean layers is non-negligible on the steric sea level variability (22 and 12 % for the layers below 700 and 1500 m of depth, respectively), although the small deep ocean trends are not significant with respect to the products spread

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

An ensemble of eddy-permitting global ocean reanalyses from the MyOcean project

A set of four eddy-permitting global ocean reanalyses produced in the framework of the MyOcean project have been compared over the altimetry period 1993–2011. The main differences among the reanalyses used here come from the data assimilation scheme implemented to control the ocean state by inserting reprocessed observations of sea surface temperature (SST), in situ temperature and salinity profiles, sea level anomaly and sea-ice concentration. A first objective of this work includes assessing the interannual variability and trends for a series of parameters, usually considered in the community as essential ocean variables: SST, sea surface salinity, temperature and salinity averaged over meaningful layers of the water column, sea level, transports across pre-defined sections, and sea ice parameters. The eddy-permitting nature of the global reanalyses allows also to estimate eddy kinetic energy. The results show that in general there is a good consistency between the different reanalyses. An intercomparison against experiments without data assimilation was done during the MyOcean project and we conclude that data assimilation is crucial for correctly simulating some quantities such as regional trends of sea level as well as the eddy kinetic energy. A second objective is to show that the ensemble mean of reanalyses can be evaluated as one single system regarding its reliability in reproducing the climate signals, where both variability and uncertainties are assessed through the ensemble spread and signal-to-noise ratio. The main advantage of having access to several reanalyses differing in the way data assimilation is performed is that it becomes possible to assess part of the total uncertainty. Given the fact that we use very similar ocean models and atmospheric forcing, we can conclude that the spread of the ensemble of reanalyses is mainly representative of our ability to gauge uncertainty in the assimilation methods. This uncertainty changes a lot from one ocean parameter to another, especially in global indices. However, despite several caveats in the design of the multi-system ensemble, the main conclusion from this study is that an eddy-permitting multi-system ensemble approach has become mature and our results provide a first step towards a systematic comparison of eddy-permitting global ocean reanalyses aimed at providing robust conclusions on the recent evolution of the oceanic state

The Ocean Reanalysis Intercomparison project (ORA-IP)

Uncertainty in ocean analysis methods and deficiencies in the observing system are major obstacles for the reliable reconstruction of the past ocean climate. The variety of existing ocean reanalyses is exploited in a multi-reanalysis ensemble to improve the ocean state estimation and to gauge uncertainty levels. The ensemble-based analysis of signal-to-noise ratio allows the identification of ocean characteristics for which the estimation is robust (such as tropical mixed-layer-depth, upper ocean heat content), and where large uncertainty exists (deep ocean, Southern Ocean, sea ice thickness, salinity), providing guidance for future enhancement of the observing and data assimilation systems

An assessment of upper ocean salinity content from the ocean reanalyses inter-comparison project (ORA-IP)

Many institutions worldwide have developed ocean reanalyses systems (ORAs) utilizing a variety of ocean models and assimilation techniques. However, the quality of salinity reanalyses arising from the various ORAs has not yet been comprehensively assessed. In this study, we assess the upper ocean salinity content (depth-averaged over 0–700 m) from 14 ORAs and 3 objective ocean analysis systems (OOAs) as part of the Ocean Reanalyses Intercomparison Project. Our results show that the best agreement between estimates of salinity from different ORAs is obtained in the tropical Pacific, likely due to relatively abundant atmospheric and oceanic observations in this region. The largest disagreement in salinity reanalyses is in the Southern Ocean along the Antarctic circumpolar current as a consequence of the sparseness of both atmospheric and oceanic observations in this region. The West Pacific warm pool is the largest region where the signal to noise ratio of reanalysed salinity anomalies is >1. Therefore, the current salinity reanalyses in the tropical Pacific Ocean may be more reliable than those in the Southern Ocean and regions along the western boundary currents. Moreover, we found that the assimilation of salinity in ocean regions with relatively strong ocean fronts is still a common problem as seen in most ORAs. The impact of the Argo data on the salinity reanalyses is visible, especially within the upper 500m, where the interannual variability is large. The increasing trend in global-averaged salinity anomalies can only be found within the top 0–300m layer, but with quite large diversity among different ORAs. Beneath the 300m depth, the global-averaged salinity anomalies from most ORAs switch their trends from a slightly growing trend before 2002 to a decreasing trend after 2002. The rapid switch in the trend is most likely an artefact of the dramatic change in the observing system due to the implementation of Argo