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Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A-G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays.

Background:Acute kidney injury (AKI) is associated with increased mortality and dialysis in hospitalized patients but has been little explored in the emergency department (ED) setting.Objective:The objective of this study was to describe the risk factors, prevalence, management, and outcomes in the ED population, and to identify the proportion of AKI patients who were discharged home with no renal-specific follow-up.Design:This is a retrospective cohort study using administrative and laboratory databases.Setting:Two urban EDs in Vancouver, British Columbia, Canada.Patients:We included all unique ED patients over a 1-week period.Methods:All patients had their described demographics, comorbidities, medications, laboratory values, and ED treatments collected. AKI was defined pragmatically, based upon accepted guidelines. The cohort was then probabilistically linked to the provincial renal database to ascertain renal replacement (transplant or dialysis) and the provincial vital statistics database to obtain mortality. The primary outcome was the prevalence of AKI; secondary outcomes included (1) the proportion of AKI patients who were discharged home with no renal-specific follow-up and (2) the combined 30-day rate of death or renal replacement among AKI patients.Results:There were 1651 ED unique patients, and 840 had at least one serum creatinine (SCr) obtained. Overall, 90 patients had AKI (10.7% of ED patients with at least one SCr, 95% confidence interval [CI], 8.7%-13.1%; 5.5% of all ED patients, 95% CI, 4.4%-6.7%) with a median age of 74 and 70% male. Of the 31 (34.4%) AKI patients discharged home, 4 (12.9%) had renal-specific follow-up arranged in the ED. Among the 90 AKI patients, 11 died and none required renal replacement at 30 days, for a combined outcome of 12.2% (95% CI, 6.5%-21.2%).Limitations:Sample sizes may be small. Nearly half of ED patients did not obtain an SCr. Many patients did not have sequential SCr testing, and a modified definition of AKI was used.

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