Naloxone use by Aotearoa New Zealand emergency medical services, 2017-2021.

OBJECTIVE: Emergency medical services (EMS) use of naloxone in the prehospital setting is indicated in patients who have significantly impaired breathing or level of consciousness when opioid intoxication is suspected. The present study characterised naloxone use in a nationwide sample of Aotearoa New Zealand road EMS patients to establish a baseline for surveillance of any changes in the future. METHODS: A retrospective analysis of rates of patients with naloxone administrations was conducted using Hato Hone St John (2017-2021) and Wellington Free Ambulance (2018-2021) electronic patient report form datasets. Patient demographics, presenting complaints, naloxone dosing, and initial and last vital sign clinical observations were described. RESULTS: There were 2018 patients with an equal proportion of males and females, and patient median age was 47 years. There were between 8.0 (in 2018) and 9.0 (in 2020) naloxone administrations per 100 000 population-years, or approximately one administration per day for the whole country of 5 million people. Poisoning by unknown agent(s) was the most common presenting complaint (61%). The median dose of naloxone per patient was 0.4 mg; 85% was administered intravenously. The median observed change in Glasgow Coma Scale score was +1, and respiratory rate increased by +2 breaths/min. CONCLUSIONS: A national rate of EMS naloxone patients was established; measured clinical effects of naloxone were modest, suggesting many patients had reasons other than opioid toxicity contributing to their symptoms. Naloxone administration rates provide indirect surveillance information about suspected harmful opioid exposures but need to be interpreted with care.

Strong inhibition of neutrophil-sperm interaction in cattle by selective phosphatidylinositol 3-kinase inhibitors.

The vast majority of sperm are lost from the female reproductive tract in hours following natural mating or artificial insemination in mammals. Multiple complex processes including uterine contractions, mucus barriers, and phagocytosis of sperm by neutrophils have been reported to be involved in the sperm loss, although the contribution of each process is uncertain. If phagocytosis by neutrophils has a significant role in sperm loss, inhibition of neutrophil response to sperm could potentially reduce the dose of sperm required for artificial insemination. Through the development of a quantitative in vitro assay, we have screened 74 candidate compounds for their ability to inhibit the neutrophil-sperm interaction in cattle. Nine inhibitors (GSK2126458, wortmannin, ZSTK474, PIK294, CAL-101, GSK 1059615, GDC-0941, PIK 90 and PI103) active against phosphatidylinositol 3-kinase (PI3-kinase) were most potent, and strongly reduced neutrophil-sperm interaction with an IC50 of 10 nM or less. These inhibitors did not significantly modify sperm motility, and five of the inhibitors did not affect in vitro fertilization. Examination of neutrophil-sperm interaction by time-lapse video microscopy and cell tracking analysis revealed that GSK2126458 may prevent sperm phagocytosis through inhibition of neutrophil movement and/or attachment. Twenty-four other compounds exhibited weaker inhibition (IC50 < 115 µM), and the rest did not inhibit the neutrophil-sperm interaction. Strong PI3-kinase inhibitors identified in this study may be useful to determine the contribution of neutrophil phagocytosis in the clearance of sperm from the female reproductive tract.

Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels.

BACKGROUND: Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-beta peptide (Abeta) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Abeta42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Abeta40, the more prevalent Abeta peptide secreted by cells and a major component of cerebral Abeta deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Abeta42 and Abeta40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. RESULTS: Adeno-associated viral (AAV) vectors encoding BRI-Abeta cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Abeta peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Abeta40 and AAV-BRI-Abeta42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Abeta peptides. BRI-Abeta42 and the combination of BRI-Abeta40+42 overexpression resulted in elevated levels of detergent-insoluble Abeta. No significant increase in detergent-insoluble Abeta was seen in the rats expressing APPsw or BRI-Abeta40. No pathological features were noted in any rats, except the AAV-BRI-Abeta42 rats which showed focal, amorphous, Thioflavin-negative Abeta42 deposits. CONCLUSION: The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in vivo, and demonstrate that whilst expression of Abeta42 alone is sufficient to initiate Abeta deposition, both Abeta40 and Abeta42 may contribute to cognitive deficits.