The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, Jan 8, 2017
To assess the etiology of cerebrospinal fluid (CSF) pleocytosis in critical care patients with se... more To assess the etiology of cerebrospinal fluid (CSF) pleocytosis in critical care patients with seizure(s) or status epilepticus (SE). Many previous studies, some performed decades ago, concluded that CSF pleocytosis may be entirely attributable to seizure activity. We undertook a retrospective chart review of adult patients with an admitting or acquired diagnosis of seizure(s) or SE in critical care units at the Winnipeg Health Sciences Centre between 2009 and 2012. Patients were identified through a critical care information database at a tertiary care center. We limited our study to patients who had lumbar punctures at our center within 5 days of seizure(s) or SE. Of 426 patients with seizures in critical care units, 51 met the inclusion criteria. Seizure subtypes included focal seizures (5 or 10%), generalized seizures (14 or 27%), and SE (32 or 63%). Twelve (seven with SE) of the 51 (24%) were found to have CSF pleocytosis. A probable etiological cause for the CSF pleocytosis wa...
The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differenti... more The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differentially regulate these divergent actions are poorly understood. The hypoxia-inducible death factor Bnip3 is an E2F-1 target gene and integral component of the intrinsic mitochondrial death pathway. The mechanisms that govern Bnip3 gene activity remain cryptic. Herein we show that the transcription factor NF-κB provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. We show under basal nonapoptotic conditions that NF-κB constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-κB, or during hypoxia when NF-κB abundance is reduced, basal Bnip3 gene transcription is activated by the unrestricted binding of E2F-1 to the Bnip3 promoter. Genetic knock-down of E2F-1 or retinoblastoma gene product over-expression in cardiac and human pancreatic cancer cells deficient for NF-κB signaling abrogated basal and hypoxia-inducible Bnip3 transcription. The survival kinase PI3K/Akt inhibited Bnip3 expression levels in cells in a manner dependent upon NF-κB activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1-dependent Bnip3 expression by NF-κB highlights a survival pathway that overrides the E2F-1 tumor suppressor program. Our data may explain more fundamentally how cells, by selectively inhibiting E2F-1-dependent death gene transcription, avert apoptosis down-stream of the retinoblastoma/E2F-1 cell cycle pathway.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, Jan 8, 2017
To assess the etiology of cerebrospinal fluid (CSF) pleocytosis in critical care patients with se... more To assess the etiology of cerebrospinal fluid (CSF) pleocytosis in critical care patients with seizure(s) or status epilepticus (SE). Many previous studies, some performed decades ago, concluded that CSF pleocytosis may be entirely attributable to seizure activity. We undertook a retrospective chart review of adult patients with an admitting or acquired diagnosis of seizure(s) or SE in critical care units at the Winnipeg Health Sciences Centre between 2009 and 2012. Patients were identified through a critical care information database at a tertiary care center. We limited our study to patients who had lumbar punctures at our center within 5 days of seizure(s) or SE. Of 426 patients with seizures in critical care units, 51 met the inclusion criteria. Seizure subtypes included focal seizures (5 or 10%), generalized seizures (14 or 27%), and SE (32 or 63%). Twelve (seven with SE) of the 51 (24%) were found to have CSF pleocytosis. A probable etiological cause for the CSF pleocytosis wa...
The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differenti... more The transcription factor E2F-1 drives proliferation and death, but the mechanisms that differentially regulate these divergent actions are poorly understood. The hypoxia-inducible death factor Bnip3 is an E2F-1 target gene and integral component of the intrinsic mitochondrial death pathway. The mechanisms that govern Bnip3 gene activity remain cryptic. Herein we show that the transcription factor NF-κB provides a molecular switch that determines whether E2F-1 signals proliferation or death under physiological conditions. We show under basal nonapoptotic conditions that NF-κB constitutively occupies and transcriptionally silences Bnip3 gene transcription by competing with E2F-1 for Bnip3 promoter binding. Conversely, in the absence of NF-κB, or during hypoxia when NF-κB abundance is reduced, basal Bnip3 gene transcription is activated by the unrestricted binding of E2F-1 to the Bnip3 promoter. Genetic knock-down of E2F-1 or retinoblastoma gene product over-expression in cardiac and human pancreatic cancer cells deficient for NF-κB signaling abrogated basal and hypoxia-inducible Bnip3 transcription. The survival kinase PI3K/Akt inhibited Bnip3 expression levels in cells in a manner dependent upon NF-κB activation. Hence, by way of example, we show that the transcriptional inhibition of E2F-1-dependent Bnip3 expression by NF-κB highlights a survival pathway that overrides the E2F-1 tumor suppressor program. Our data may explain more fundamentally how cells, by selectively inhibiting E2F-1-dependent death gene transcription, avert apoptosis down-stream of the retinoblastoma/E2F-1 cell cycle pathway.
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