Impaired neurogenesis, learning and memory and low seizure threshold associated with loss of neural precursor cell survivin.

BACKGROUND: Survivin is a unique member of the inhibitor of apoptosis protein (IAP) family in that it exhibits antiapoptotic properties and also promotes the cell cycle and mediates mitosis as a chromosome passenger protein. Survivin is highly expressed in neural precursor cells in the brain, yet its function there has not been elucidated. RESULTS: To examine the role of neural precursor cell survivin, we first showed that survivin is normally expressed in periventricular neurogenic regions in the embryo, becoming restricted postnatally to proliferating and migrating NPCs in the key neurogenic sites, the subventricular zone (SVZ) and the subgranular zone (SGZ). We then used a conditional gene inactivation strategy to delete the survivin gene prenatally in those neurogenic regions. Lack of embryonic NPC survivin results in viable, fertile mice (SurvivinCamcre) with reduced numbers of SVZ NPCs, absent rostral migratory stream, and olfactory bulb hypoplasia. The phenotype can be partially rescued, as intracerebroventricular gene delivery of survivin during embryonic development increases olfactory bulb neurogenesis, detected postnatally. SurvivinCamcre brains have fewer cortical inhibitory interneurons, contributing to enhanced sensitivity to seizures, and profound deficits in memory and learning. CONCLUSIONS: The findings highlight the critical role that survivin plays during neural development, deficiencies of which dramatically impact on postnatal neural function.

Safety profile of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV).

Safety and reactogenicity data were reviewed following 10 years of experience with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in clinical development and from post-licensure settings. Analyses of pooled clinical trial data and post-marketing reports provided an overview of its safety profile and allowed assessment of rare adverse events that might not have been identified previously. The safety of PHiD-CV was also evaluated in children at higher risk for pneumococcal infection (preterm and HIV-infected or HIV-exposed infants), for different vaccination schedules and co-administered pediatric vaccines, and with a focus on special categories of adverse events (febrile convulsions, apnea, Kawasaki disease and sudden deaths). Following the distribution of over 235 million doses, PHiD-CV has been well tolerated when co-administered with other pediatric vaccines to children aged less than 5 years from diverse ethnic and geographic backgrounds. Detailed examination of various aspects has confirmed its favorable benefit: risk profile.