Blockade of cholinergic neurotransmission by muscarinic receptor antagonists produces profound deficits in attention and memory. However, the antagonists used in previous studies bind to more than one of the five muscarinic receptor subtypes. Here we examined memory in mice with a null mutation of the gene coding the M1 receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain. In contrast with previous studies using nonselective pharmacological antagonists, the M1 receptor deletion produced a selective phenotype that included both enhancements and deficits in memory. Long-term potentiation (LTP) in response to theta burst stimulation in the hippocampus was also reduced in mutant mice. M1 null mutant mice showed normal or enhanced memory for tasks that involved matching-to-sample problems, but they were severely impaired in non-matching-to-sample working memory as well as consolidation. Our results suggest that the M1 receptor is specifically involved in memory processes for which the cortex and hippocampus interact.
Ondansetron, a 5HT3 antagonist, was given to 20 children aged 4 to 18 years who were undergoing treatment with the Australian and New Zealand Childhood Cancer Study Group Acute Lymphocytic Leukaemia (ALL) Study V Protocol. The study was open, dose ranging, and noncomparative, and designed to evaluate safety and efficacy of ondansetron in preventing nausea and vomiting caused by cyclophosphamide intravenous (IV) 1,000 mg/m2 day 1, and cytarabine IV subcutaneously (SC) 75 mg/m2 on days 2 to 5. Ten patients were given ondansetron 5 mg/m2 IV (group A) and subsequently another 10 patients were given ondansetron 3 mg/m2 IV (group B). Oral ondansetron was given for 14 doses, at the same dosage for both groups, commencing simultaneously with the IV infusion and continuing at 8 hourly intervals, ie, until day 5. The oral dose was based on surface area with the following schedule: 0.3 to 0.6 m2, 2 mg; 0.6 to 1 m2, 3 mg; and greater than 1 m2, 4 mg. Vomiting on the first day of chemotherapy was reported in group A by one patient and by one patient in group B. Vomiting during days 2 to 5 was reported by two group-A patients and by three group-B patients. Nausea was recorded on day 1 by one patient in group A, and two in group B, and on days 2 to 5 by three patients in group A, and by seven in group B. All patients were alert during treatment with ondansetron and there was no dystonia. There were no changes in renal function or hematology values that could be ascribed to the study drug. Transient elevations in bilirubin and liver enzymes were observed. We conclude that our results indicate that ondansetron is a safe and extremely effective single-agent antiemetic with minimal side effects, when administered both IV and orally.
The breakdown is a complex and dynamic facet of rugby union, often containing multiple players from each team. It is the responsibility of coaches and trainers to ensure players are prepared to comply with the World Rugby laws of the game to encourage safe and fair play between all participants. The aim of this study was to investigate player adherence and sanctioning of infringements at the breakdown during the knockout stages of the 2019 Rugby World Cup. Breakdown infringements according to World Rugby laws were identified using match video recordings of the 8 matches. Each breakdown was individually analysed by coding any infringement that had occurred and the sanctioning outcome of the breakdown. A total of 898 breakdowns were coded, of which 37.7% (n = 339) were deemed to involve illegal play. 79.9% of breakdowns involving illegal play were not penalised with the majority of infringements being “ head and shoulders below hips” (33.5%, n = 163), “ off feet” (13%, n = 63) and “ offside” (10.5%, n = 51). The attacking team were responsible for 70.0% (n = 340) of all breakdown infringements despite being penalised less than the defending team. A high number of infringements occurred at the breakdown and went unsanctioned in the knockout stages of the 2019 Rugby World Cup. Future work focused on technology, training or rule amendments may be required to improve player adherence and sanctioning of infringements at the breakdown, such that they protect players and are in keeping with the dynamics of the modern game.
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