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1.
Emerg Infect Dis ; 28(9): 1814-1823, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35997366

RESUMO

We estimated costs of managing different forms of tuberculosis (TB) across Canada by conducting a retrospective chart review and cost assessment of patients treated for TB infection, drug-susceptible TB (DS TB), isoniazid-resistant TB, or multidrug-resistant TB (MDR TB) at 3 treatment centers. We included 90 patients each with TB infection and DS TB, 71 with isoniazid-resistant TB, and 62 with MDR TB. Median per-patient costs for TB infection (in 2020 Canadian dollars) were $804 (interquartile range [IQR] $587-$1,205), for DS TB $12,148 (IQR $4,388-$24,842), for isoniazid-resistant TB $19,319 (IQR $7,117-$41,318), and for MDR TB $119,014 (IQR $80,642-$164,015). Compared with costs for managing DS TB, costs were 11.1 (95% CI 9.1-14.3) times lower for TB infection, 1.7 (95% CI 1.3-2.1) times higher for isoniazid-resistant TB, and 8.1 (95% CI 6.1-10.6) times higher for MDR TB. Broadened TB infection treatment could avert high costs associated with managing TB disease.


Assuntos
Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/uso terapêutico , Canadá/epidemiologia , Humanos , Isoniazida/uso terapêutico , Tuberculose Latente/tratamento farmacológico , Estudos Retrospectivos , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
2.
Front Cell Neurosci ; 12: 127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867360

RESUMO

Neurotransmitter is released from presynaptic nerve terminals at fast-transmitting synapses by the action potential-gating of voltage dependent calcium channels (CaV), primarily of the CaV2.1 and CaV2.2 types. Entering Ca2+ diffuses to a nearby calcium sensor associated with a docked synaptic vesicle (SV) and initiates its fusion and discharge. Our previous findings that single CaVs can gate SV fusion argued for one or more tethers linking CaVs to docked SVs but the molecular nature of these tethers have not been established. We recently developed a cell-free, in vitro biochemical assay, termed SV pull-down (SV-PD), to test for SV binding proteins and used this to demonstrate that CaV2.2 or the distal third of its C-terminal can capture SVs. In subsequent reports we identified the binding site and characterized an SV binding motif. In this study, we set out to test if a similar SV-binding mechanism exists in the primary presynaptic channel type, CaV2.1. We cloned the chick variant of this channel and to our surprise found that it lacked the terminal third of the C-terminal, ruling out direct correlation with CaV2.2. We used SV-PD to identify an SV binding site in the distal half of the CaV2.1 C-terminal, a region that corresponds to the central third of the CaV2.2 C-terminal. Mutant fusion proteins combined with motif-blocking peptide strategies identified two domains that could account for SV binding; one in an alternatively spliced region (E44) and a second more distal site. Our findings provide a molecular basis for CaV2.1 SV binding that can account for recent evidence of C-terminal-dependent transmitter release modulation and that may contribute to SV tethering within the CaV2.1 single channel Ca2+ domain.

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