Occurrence of seizures in hospitalized patients with a pre-existing seizure disorder

Objective. To assess the frequency of seizures in hospitalized patients with a pre-existing seizure disorder. Patients and Methods. A retrospective review was conducted on all patients with a documented seizure disorder who were hospitalized between January 1, 2002 and December 31, 2007. Children aged < 2 years and hospital admission for seizure control or surgical or obstetric indications were excluded. The first hospital admission of at least 24 hours was identified for each patient. Patient demographics, details of the seizure disorder, details of the hospital admission, and clinically-apparent seizure activity documented during the inpatient stay were recorded from the medical record. Results. During the 6-year study period, 720 patients with a documented seizure disorder were admitted for at least 24 hours. Thirty-nine patients experienced seizure activity for an overall frequency of 5.4% (95% CI: 3.8-7.1%). Younger age (p = 0.001), greater frequency of baseline seizure activity (p < 0.001), recent seizure activity (p < 0.001), greater number of chronic antiepileptic medications (p = 0.01), and admission for neurological (p = 0.03) conditions were associated with increased frequency of seizure activity during hospitalization. Conclusions. The majority of seizures occurring in hospitalized patients with a pre-existing seizure disorder appear related to the patient’s underlying seizure disorder. Because patients with frequent seizures on numerous anti-epileptic medications are likely to experience a seizure while hospitalized, it is essential to be prepared to treat seizure activity regardless of the reason for admission

Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML