A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses.

Arboviruses represent a group of pathogens that can spread efficiently throughout human populations by hematophagous arthropod vectors. The mosquito-borne (re)emerging Chikungunya and Dengue viruses belong to the alphavirus and flavivirus genus, respectively, with no approved therapeutics or safe vaccines for humans. Transmitted by the same vector Aedes spp., these viruses cause significant morbidity and mortality in endemic areas. Due to the increasing likelihood of co-circulation and co-infection with viruses, we aimed to identify a pharmacologically targetable host factor that can inhibit multiple viruses and show that a potent antagonist of prolyl tRNA synthetase (halofuginone) suppresses both Chikungunya and Dengue viruses. Host tRNA synthetase inhibition may signify an additional approach to combat present and future epidemic pathogens.

Rev-erb Agonist Inhibits Chikungunya and O'nyong'nyong Virus Replication.

Chikungunya virus (CHIKV), an alphavirus spread by Aedes spp. mosquitos, causes severe inflammation and joint pain, progressing to a chronic arthralgic state in a subset of patients. Due to recent global epidemics of CHIKV and the potential for related viruses to cause outbreaks, multiple approaches to combat these pathogens are of interest. We report that SR9009, a synthetic agonist of nuclear receptors Rev-erb α/ß, inhibits replication of multiple alphaviruses (CHIKV and O'nyong'nyong virus) mainly by suppressing structural protein synthesis, although viral RNA accumulation is relatively unimpeded. Furthermore, SR9009 reduces the inflammatory response in cultured murine macrophages exposed to alphavirus-infected cells.

Prevalence and risk factors of seizure clusters in adult patients with epilepsy.

PURPOSE: In the current study, we explored the prevalence of physician-confirmed seizure clusters. We also investigated potential clinical factors associated with the occurrence of seizure clusters overall and by epilepsy type. METHODS: We reviewed medical records of 4116 adult (≥16years old) outpatients with epilepsy at our centers for documentation of seizure clusters. Variables including patient demographics, epilepsy details, medical and psychiatric history, AED history, and epilepsy risk factors were then tested against history of seizure clusters. Patients were then divided into focal epilepsy, idiopathic generalized epilepsy (IGE), or symptomatic generalized epilepsy (SGE), and the same analysis was run. RESULTS: Overall, seizure clusters were independently associated with earlier age of seizure onset, symptomatic generalized epilepsy (SGE), central nervous system (CNS) infection, cortical dysplasia, status epilepticus, absence of 1-year seizure freedom, and having failed 2 or more AEDs (P<0.0026). Patients with SGE (27.1%) were more likely to develop seizure clusters than patients with focal epilepsy (16.3%) and IGE (7.4%; all P<0.001). Analysis by epilepsy type showed that absence of 1-year seizure freedom since starting treatment at one of our centers was associated with seizure clustering in patients across all 3 epilepsy types. In patients with SGE, clusters were associated with perinatal/congenital brain injury. In patients with focal epilepsy, clusters were associated with younger age of seizure onset, complex partial seizures, cortical dysplasia, status epilepticus, CNS infection, and having failed 2 or more AEDs. In patients with IGE, clusters were associated with presence of an aura. Only 43.5% of patients with seizure clusters were prescribed rescue medications. CONCLUSION: Patients with intractable epilepsy are at a higher risk of developing seizure clusters. Factors such as having SGE, CNS infection, cortical dysplasia, status epilepticus or an early seizure onset, can also independently increase one's chance of having seizure clusters.