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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, with an average life expectancy of 12–15 months. GBM is highly infiltrated by microglial cells (MG) promoting tumor growth and invasiveness. Moreover, microglia activation and subsequent neuroinflammation seem to be involved in blood–brain barrier (BBB) dysfunction commonly observed in several central nervous system diseases, including brain tumors. Nevertheless, how the crosstalk between microglia and tumor cells interferes with BBB function is far from being clarified. Herein, we evaluated the effects of reciprocal interactions between MG and GBM cells in the barrier properties of brain endothelial cells (ECs), using an in vitro approach. The exposure of ECs to the inflammatory microenvironment mediated by MG‐GBM crosstalk induced a decrease in the transendothelial electric resistance and an increase in permeability across the ECs (macromolecular flux of 4 kDa‐fluorescein isothiocyanate and 70 kDa‐Rhodamine B isothiocyanate–Dextran). These effects were accompanied by a downregulation of the intercellular junction proteins, β‐catenin and zonula occludens. Moreover, the dynamic interaction between microglia and tumor cells triggered the release of interleukin‐6 (IL‐6) by microglia and subsequent activation of the downstream Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway. Interestingly, the depletion of IL‐6 or the blockade of the JAK/STAT3 signaling with AG490 were able to prevent the EC hyperpermeability. Overall, we demonstrated that IL‐6 released during MG‐GBM crosstalk leads to barrier dysfunction through the activation of the JAK/STAT3 pathway in ECs and downregulation of intercellular junction proteins. These results provide new insights into the mechanisms underlying the disruption of BBB permeability in GBM. [ABSTRACT FROM AUTHOR]

Background It would be important to better identify heart failure (HF) patients most likely to respond to cardiac resynchronization therapy (CRT). Because endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular endothelium integrity, we hypothesize that patients who have higher circulating EPCs levels have greater neovascularization potential and are more prone to be responders to CRT. Methods Prospective study of 30 consecutive patients, scheduled for CRT. Echocardiographic evaluation was performed before implant and 6 months after. Responders to CRT were defined as patients who were still alive, have not been hospitalized for HF management, and demonstrated ≥15% reduction in left ventricular end-systolic volume (LVESV) at the 6-month follow-up. EPCs were quantified before CRT, from peripheral blood, by flow cytometry using five different conjugated antibodies: anti-CD34, anti-KDR, anti-CD133, anti-CD45, and anti-CXCR4. We quantified five different populations of angiogenic cells: CD133+/CD34+ cells, CD133+/KDR+ cells, CD133+/CD34+/KDR+ cells, CD45dimCD34+/KDR+ cells, and CD45dimCD34+/KDR+/CXCR4+ cells. Results The proportion of responders to CRT at the 6-month follow-up was 46.7%. Responders to CRT presented higher baseline EPCs levels than nonresponders (0.0003 ± 0.0006% vs 0.0001 ± 0.0002%, P = 0.04, for CD34+/CD133+/KDR+ and 0.0006 ± 0.0005% vs 0.0003 ± 0.0003%, P = 0.009, for CD45dimCD34+/KDR+/CXCR4+ cells). In addition, baseline levels of CD45dimCD34+/KDR+/CXCR4+ cells were positively correlated with the reduction of LVESV verified 6 months after CRT (r = 0.497, P = 0.008). Conclusions High circulating EPCs levels may identify the subset of HF patients who are more likely to undergo reverse remodeling and benefit from CRT. Addition of EPCs levels assessment to current selection criteria may improve the ability to predict CRT response. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics which include the study on maximizing benefits and minimizing harms from drugs population pharmacokinetics of repaglinide in healthy Malaysian subjects and genetic polymorphisms of CYP3A4 and CYP2C8 , research on the effect of chronic mild stress 'CMS' on C1A2 enzyme activity and inducibility in wistar rats, and molecular to physiological function development of a P2X7 binding and ex vivo occupancy assay in rat brain.

The mechanisms by which methamphetamine (METH) causes neurotoxicity are not well understood. Recent studies have suggested that METH-induced neuropathology may result from a multicellular response in which glial cells play a prominent role, and so it is plausible to suggest that cytokines may participate in the toxic effects of METH. Therefore, in the present work we evaluated the effect of an acute administration of METH (30 mg/kg in a single intraperitoneal injection) on the interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA expression levels in the hippocampus, frontal cortex, and striatum of mice. We observed that METH did not induce changes in the IL-1β mRNA expression levels in both hippocampus and striatum, with immeasurable levels in the frontal cortex. Regarding IL-6, METH induced an increase in the expression levels of this cytokine in the hippocampus and striatum, 1 h and 30 min post injection, respectively. In the frontal cortex, the increase in IL-6 mRNA levels was more significant and remained high even after 2 h. Moreover, the expression levels of TNF-α were increased in both hippocampus and frontal cortex 30 min post METH administration, with immeasurable levels in the striatum. We conclude that the pro-inflammatory cytokines IL-6 and TNF-α rapidly increase after METH administration, providing a new insight for understanding the effect of this drug of abuse in the brain. [ABSTRACT FROM AUTHOR]

Purpose To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. Method Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. Results For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa = 0.26) and within the groups considered. Conclusion The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]