RESUMEN
Salmonella enterica and Escherichia coli use the inner membrane transporter DctA to import the pyrimidine biosynthetic pathway intermediate orotate from the environment. To study the regulation of dctA expression, we used an S. enterica serovar Typhimurium pyrimidine auxotroph to select a mutant that could grow in an otherwise nonpermissive culture medium containing glucose and a low concentration of orotate. Whole genome sequencing revealed a point mutation upstream of dctA in the putative cyclic AMP receptor protein (CRP) binding site. The CâT transition converted the least favourable base to the most favourable base for CRP-DNA affinity. A dctA::lux transcriptional fusion confirmed that the mutant dctA promoter gained responsiveness to CRP even in the presence of glucose. Moreover, dctA expression was higher in the mutant than the wild type in the presence of alternative carbon sources that activate CRP.
Asunto(s)
Proteínas de Escherichia coli , Salmonella typhimurium , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Carbono/metabolismo , Proteína Receptora de AMP Cíclico/genética , Proteína Receptora de AMP Cíclico/metabolismo , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Glucosa/metabolismo , Proteínas de Transporte de Membrana/genética , Mutación , Pirimidinas/metabolismo , Salmonella typhimurium/genética , SerogrupoRESUMEN
Novel antiseizure medications are thought to be safer than their conventional counterparts, though no dedicated analysis of movement disorder risk among pediatric populations using novel antiseizure medications has been completed. We report a systematic review with meta-analysis describing the relationship between novel antiseizure medications and movement disorders in pediatrics.MEDLINE, EMBASE, and the World Health Organization's International Clinical Trials Registry Platform were searched up to October 2020 for randomized controlled trials investigating novel antiseizure medications in pediatric populations. Antiseizure medications included lacosamide, perampanel, eslicarbazepine, rufinamide, fenfluramine, cannabidiol, and brivaracetam. Outcomes were pooled using random effects models; risk difference (RD) and 95% confidence intervals (CIs) were calculated.Twenty-three studies were selected from 1690 nonredundant manuscripts (n = 1912 total). There was a significantly increased risk of movement disorders associated with perampanel (RD 0.07, 95% CI 0.01-0.13; n = 133), though only 1 relevant trial was found. No increased risk of movement disorders was found with other antiseizure medications.Our findings indicate most novel antiseizure medications are safe to use in pediatric populations with respect to movement disorders. However, findings were limited by quality of adverse event reporting.
Asunto(s)
Cannabidiol , Trastornos del Movimiento , Pediatría , Anticonvulsivantes/efectos adversos , Niño , Humanos , Lacosamida/uso terapéutico , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiologíaRESUMEN
The increasing need for remote and distributed methods to provide medical care for People with Parkinson Disease has increased the importance of additional tools to monitor symptoms of interest. We present data from a randomized trial of followup care delivered via traditional face to face visits with symptom diaries versus telehealth followup with wearable sensors.
Asunto(s)
Cuidados Posteriores , Evaluación de Procesos y Resultados en Atención de Salud , Enfermedad de Parkinson/terapia , Telemedicina , Dispositivos Electrónicos Vestibles , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Visita a Consultorio MédicoRESUMEN
Regional patient and physician density patterns pose problems to accessing care for people with Parkinson's disease, though telehealth may improve access. We surveyed and conducted a focus group for people with Parkinson's disease in Interior British Columbia regarding barriers to neurological care. Eighteen individuals completed the survey and seven parties joined the focus group. Perceived barriers include cost and difficulty of travel, wait times, and lack of specialized services outside large cities. 80% of participants (95% CI 64-96) would likely use telehealth for follow-up neurologist appointments. This sample of people with Parkinson's disease reports willingness to use telehealth to reduce travel and improve access to specialty care.
Asunto(s)
Enfermedad de Parkinson , Telemedicina , Accesibilidad a los Servicios de Salud , Humanos , Enfermedad de Parkinson/terapia , Percepción , Encuestas y CuestionariosRESUMEN
Fluoroquinolone antibiotics are prescribed for the treatment of Salmonella enterica infections, but resistance to this family of antibiotics is growing. Here we report that loss of the global regulatory protein cyclic AMP (cAMP) receptor protein (CRP) or its allosteric effector, cAMP, reduces susceptibility to fluoroquinolones. A Δcrp mutation was synergistic with the primary fluoroquinolone resistance allele gyrA83, thus able to contribute to clinically relevant resistance. Decreased susceptibility to fluoroquinolones could be partly explained by decreased expression of the outer membrane porin genes ompA and ompF with a concomitant increase in the expression of the ciprofloxacin resistance efflux pump gene acrB in Δcrp cells. Expression of gyrAB, which encode the DNA supercoiling enzyme GyrAB, which is blocked by fluoroquinolones, and expression of topA, which encodes the dominant supercoiling-relaxing enzyme topoisomerase I, were unchanged in Δcrp cells. Yet Δcrp cells maintained a more relaxed state of DNA supercoiling, correlating with an observed increase in topoisomerase IV (parCE) expression. Surprisingly, the Δcrp mutation had the unanticipated effect of enhancing fitness in the presence of fluoroquinolone antibiotics, which can be explained by the observation that exposure of Δcrp cells to ciprofloxacin had the counterintuitive effect of restoring wild-type levels of DNA supercoiling. Consistent with this, Δcrp cells did not become elongated or induce the SOS response when challenged with ciprofloxacin. These findings implicate the combined action of multiple drug resistance mechanisms in Δcrp cells: reduced permeability and elevated efflux of fluoroquinolones coupled with a relaxed DNA supercoiling state that buffers cells against GyrAB inhibition by fluoroquinolones.