Metformin overdose: A serious iatrogenic complication-Western France Poison Control Centre Data Analysis

INTRODUCTION: The prevalence of type 2 diabetes (T2D) continues to rise across the world. Metformin is still considered the "gold standard" and is, therefore, increasingly prescribed. Monitoring of metformin continues to be debated because of its association with lactic acidosis (MALA), a rare but life-threatening complication. The aim of this study was to identify the main individual characteristics associated with severe poisoning in self-poisonings and therapeutic accidents reported at the Western France Poison Control Centre (PCC). METHODS: Retrospective study of metformin poisoning from September 1999 to September 2016 at the Western France PCC recorded in the French PCC\u27s database (SICAP). The end-point was clinically high severity (mortality and/or cardiovascular shock and/or GCS ≤ 7/15). RESULTS: Of the 382 cases included, 197 concerned acute accidental exposures, 127 self-poisonings and 58 therapeutic accidents. MALA concerned 63 patients: 44 therapeutic accidents and 19 self-poisonings. High severity concerned 59 patients: 47 therapeutic accidents and 12 self-poisonings. T2D and age > 60 significantly increase the risk of high severity (OR 7.7, CI [1.54-38.41]; P = 0.013; OR 3.5, CI [1.60-7.84]; P = 0.002, respectively). CONCLUSIONS: Metformin may lead to MALA and severe poisoning in therapeutic accidents but also in self-poisoning circumstances. Among reported cases, T2D history and age >60 increase the risk of serious poisoning. Monitoring of their treatment should be taken seriously especially in the event of digestive symptoms such as diarrhoea

Dephosphorylation of focal adhesion kinase (FAK) and loss of focal contacts precede caspase-mediated cleavage of FAK during apoptosis in renal epithelial cells

The relationship between focal adhesion protein (FAK) activity and loss of cell-matrix contact during apoptosis is not entirely clear nor has the role of FAK in chemically induced apoptosis been studied. We investigated the status of FAK phosphorylation and cleavage in renal epithelial cells during apoptosis caused by the nephrotoxicant dichlorovinylcysteine (DCVC). DCVC treatment caused a loss of cell-matrix contact which was preceded by a dissociation of FAK from the focal adhesions and tyrosine dephosphorylation of FAK. Paxillin was also dephosphorylated at tyrosine. DCVC treatment activated caspase-3 which was associated with cleavage of FAK. However, FAK cleavage occurred after cells had already lost focal adhesions indicating that cleavage of FAK by caspases is not responsible for loss of FAK from focal adhesions. Accordingly, although inhibition of caspase activity with zVAD-fmk blocked activation of caspase-3, FAK cleavage, and apoptosis, it neither affected dephosphorylation nor translocation of FAK or paxillin. However, zVAD-fmk completely blocked the cell detachment caused by DCVC treatment. Orthovanadate prevented DCVC-induced tyrosine dephosphorylation of both FAK and paxillin; however, it did not inhibit DCVC-induced apoptosis and actually potentiated focal adhesion disorganization and cell detachment. Thus, FAK dephosphorylation and loss of focal adhesions are not due to caspase activation; however, caspases are required for FAK proteolysis and cell detachment.Toxicolog

Microstructural and physical aspects of heat treated wood. Part 2. Hardwoods

Heat treatment of wood is an effective method to improve the dimensional stability and durability against biodegradation. Optimisation of a two-stage heat treatment process at relatively mild conditions (<200° C) and its effect on the anatomical structure of hardwoods were investigated by means of a light and scanning electron microscopic analysis. Hardwood species such as beech and poplar, were predominantly sensitive to collaps of the vessels and some deformation of the libriform fibres directly near the vessels. In treated beech and birch radial cracks were observed near the rays. Optimisation of the heat treatment process conditions including the application of a steam hydro thermolysis stage reduced such damages to a minimum. Broken cell walls perpendicular to the fibre direction resulting in transverse ruptures has been noticed in heat treated hardwood species. This contributes to abrupt fractures of treated wood as observed in bending tests which can lead to considerably different failure behavior after impact of mechanical stress. In some treated hardwood species maceration (small cracks between tracheids) was noticed after heat treatment. Heat treatment did not reveal damage to the ray parenchyma pit membranes, bordered pits and large window pit membranes; and the margo fibrils appeared without damage

Microstructural and physical aspects of heat treated wood. Part 1. Softwoods

Heat treatment of wood is an effective method to improve the dimensional stability and durability against biodegradation. Optimisation of a two-stage heat treatment process at relatively mild conditions (<200° C) and its effect on the anatomical structure of softwoods were investigated by means of a light and scanning electron microscopic analysis. Heat treatment did have an effect on the anatomical structure of wood, although this depends on the wood species considered and on the process method and conditions used. Softwood species with narrow annual rings and/or an abrupt transition from earlywood into latewood were sensitive to tangential cracks in the latewood section. Radial cracks occurred mainly in impermeable wood species such as Norway spruce, caused by large stresses in the wood structure during treatment. Sapwood of treated pine species revealed some damage to parenchyma cells in the rays and epithelial cells around resin canals, whereas this phenomenon has not been noticed in the heartwood section. Treated radiata pine resulted in a very open and permeable wood structure limiting the applications of this species. Broken cell walls perpendicular to the fibre direction resulting in transverse ruptures have been noticed in treated softwood species. This contributes to abrupt fractures of treated wood as observed in bending tests which can lead to considerably different failure behavior after impact or mechanical stress. In some treated softwood species maceration (small cracks between tracheids) was noticed after heat treatment. Heat treatment did not cause damage to the ray parenchyma pit membranes, bordered pits and large window pit membranes; the margo fibrils appeared without damage. Compared to the other softwood timbers tested European grown Douglas fir was the timber that stands heat treatment the best

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

Examining the Context of Strategy Instruction

The goal of literacy instruction is to teach reading and writing as tools to facilitate thinking and reasoning in a broad array of literacy events. An important difference in the disposition of children to participate in literacy experiences is the extent to which they engage in intentional self-regulated learning. The contexts attending six traditional models of strategy instruction are examined. An exploratory study, conducted with heterogeneous third graders, is reported, examining the implementation and outcomes of three models of strategy instruction—Direct Instruction, Reciprocal Teaching, and Collaborative Problem Solving—which manipulated teacher and student control of activity, as well as the instructional context.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69008/2/10.1177_074193259101200306.pd

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8 <sup>+</sup> T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy