RESUMO
Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.
Assuntos
Antibacterianos/farmacologia , Macrófagos/microbiologia , Metergolina/farmacologia , Infecções por Salmonella/tratamento farmacológico , Salmonella typhimurium/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Membrana Celular/efeitos dos fármacos , Membrana Celular/genética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Deleção de Genes , Ensaios de Triagem em Larga Escala/métodos , Humanos , Macrófagos/imunologia , Macrófagos/ultraestrutura , Metergolina/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microscopia de Força Atômica , Células RAW 264.7 , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/mortalidade , Salmonella typhimurium/genética , Salmonella typhimurium/patogenicidade , Resultado do TratamentoRESUMO
OBJECTIVES: To summarize the clinical characteristics and outcomes of pediatric sports-related concussion (SRC) patients who were evaluated and managed at a multidisciplinary pediatric concussion program and examine the healthcare resources and personnel required to meet the needs of this patient population. METHODS: We conducted a retrospective review of all pediatric SRC patients referred to the Pan Am Concussion Program from September 1st, 2013 to May 25th, 2015. Initial assessments and diagnoses were carried out by a single neurosurgeon. Return-to-Play decision-making was carried out by the multidisciplinary team. RESULTS: 604 patients, including 423 pediatric SRC patients were evaluated at the Pan Am Concussion Program during the study period. The mean age of study patients was 14.30 years (SD: 2.32, range 7-19 years); 252 (59.57%) were males. Hockey (182; 43.03%) and soccer (60; 14.18%) were the most commonly played sports at the time of injury. Overall, 294 (69.50%) of SRC patients met the clinical criteria for concussion recovery, while 75 (17.73%) were lost to follow-up, and 53 (12.53%) remained in active treatment at the end of the study period. The median duration of symptoms among the 261 acute SRC patients with complete follow-up was 23 days (IQR: 15, 36). Overall, 25.30% of pediatric SRC patients underwent at least one diagnostic imaging test and 32.62% received referral to another member of our multidisciplinary clinical team. CONCLUSION: Comprehensive care of pediatric SRC patients requires access to appropriate diagnostic resources and the multidisciplinary collaboration of experts with national and provincially-recognized training in TBI.