Nobody wants it so why is it there? towards an understanding of low-level disruption

This article looks in some detail at the transcript of a mathematics lesson in exploring the nature of low-level disruption in schools. This is preceded by a brief theoretical overview of behavioural issues, aimed at giving a context for the consideration of low-level disruption. The discussion of the issues arising from the analysis of the transcript includes an argument for explicitly teaching aspects of classroom behaviour to children at the beginning of the secondary school years as a means of ensuring better access to classroom learning opportunities and greater autonomy for teachers to work with children in a proactive, rather than reactive, manner

Avis d’experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d’un trouble bipolaire traitées par valproate

National audienceINTRODUCTION: The perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. METHODS: A panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. RESULTS: First of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. CONCLUSION: Although the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant

Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS.Funding Agencies|Medical Faculty of Lund University [ALFSKANE-450751]; AFA Forsakring [140376]; Hjarnfonden [FO2019-0316]; Stiftelsen Olle Engkvist ByggmastareSwedish Research Council [189-290]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [07879]; Royal Physiographic Society, Lund Sweden; Clermont Auvergne University, INSERM; Agence Nationale de la Recherche of the French government through the program "Investissements dAvenir (I-Site CAP 20-25)French National Research Agency (ANR)</p