RESUMEN
Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain-Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of â¼5-10 µM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 µM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a "pre-open conformation", a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Serina Proteasas/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Virus Zika/efectos de los fármacos , Concentración 50 Inhibidora , Cinética , Conformación Proteica , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Resonancia por Plasmón de Superficie , Replicación Viral/efectos de los fármacos , Virus Zika/enzimologíaRESUMEN
BACKGROUND AND PURPOSE: ResolutionMD mobile application runs on a Smartphone and affords vascular neurologists access to radiological images of patients with stroke from remote sites in the context of a telemedicine evaluation. Although reliability studies using this technology have been conducted in a controlled environment, this study is the first to incorporate it into a real-world hub and spoke telestroke network. The study objective was to assess the level of agreement of brain CT scan interpretation in a telestroke network between hub vascular neurologists using ResolutionMD, spoke radiologists using a Picture Archiving and Communications System, and independent adjudicators. METHODS: Fifty-three patients with stroke at the spoke hospital consented to receive a telemedicine consultation and participate in a registry. Each CT was evaluated by a hub vascular neurologist, a spoke radiologist, and by blinded telestroke adjudicators, and agreement over clinically important radiological features was calculated. RESULTS: Agreement (κ and 95% CI) between hub vascular neurologists using ResolutionMD and (1) the spoke radiologist; and (2) independent adjudicators, respectively, were: identification of intracranial hemorrhage 1.0 (0.92-1.0), 1.0 (0.93-1.0), neoplasm 1.0 (0.92-1.0), 1.0 (0.93-1.0), any radiological contraindication to thrombolysis 1.0 (0.92-1.0), 0.85 (0.65-1.0), early ischemic changes 0.62 (0.28-0.96), 0.58 (0.30-0.86), and hyperdense artery sign 0.40 (0.01-0.80), 0.44 (0.06-0.81). CONCLUSIONS: CT head interpretations of telestroke network patients by vascular neurologists using ResolutionMD on Smartphones were in excellent agreement with interpretations by spoke radiologists using a Picture Archiving and Communications System and those of independent telestroke adjudicators using a desktop viewer. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov unique identifier NCT00829361.
Asunto(s)
Teléfono Celular , Accidente Cerebrovascular/diagnóstico por imagen , Telerradiología/instrumentación , Encéfalo/diagnóstico por imagen , Humanos , Radiografía , Telerradiología/métodosRESUMEN
This study was designed to characterize and compare the pulmonary effects in distal lung from a low-level exposure to jet propellant-8 fuel (JP-8) and a new synthetic-8 fuel (S-8). It is hypothesized that both fuels have different airway epithelial deposition and responses. Consequently, male C57BL/6 mice were nose-only exposed to S-8 and JP-8 at average concentrations of 53mg/m(3) for 1h/day for 7 days. A pulmonary function test performed 24h after the final exposure indicated that there was a significant increase in expiratory lung resistance in the S-8 mice, whereas JP-8 mice had significant increases in both inspiratory and expiratory lung resistance compared to control values. Neither significant S-8 nor JP-8 respiratory permeability changes were observed compared to controls, suggesting no loss of epithelial barrier integrity. Morphological examination and morphometric analysis of airway tissue demonstrated that both fuels showed different patterns of targeted epithelial cells: bronchioles in S-8 and alveoli/terminal bronchioles in JP-8. Collectively, our data suggest that both fuels may have partially different deposition patterns, which may possibly contribute to specific different adverse effects in lung ventilatory function.