Neurons depend on afferent input for survival. Rats were given daily kanamycin injections from P8 to P16 to destroy hair cells, the sole afferent input to spiral ganglion neurons (SGNs). Most SGNs die over an approximately 14-week period after deafferentation. During this period, the SGN population is heterogeneous. At any given time, some SGNs exhibit apoptotic markers--TUNEL and cytochrome c loss--whereas others appear nonapoptotic. We asked whether differences among SGNs in intracellular signaling relevant to apoptotic regulation could account for this heterogeneity. cAMP response element binding protein (CREB) phosphorylation, which reflects neurotrophic signaling, is reduced in many SGNs at P16, P23, and P32, when SGNs begin to die. In particular, nearly all apoptotic SGNs exhibit reduced phospho-CREB, implying that apoptosis is due to insufficient neurotrophic support. However, >32% of SGNs maintain high phospho-CREB levels, implying access to neurotrophic support. By P60, when approximately 50% of the SGNs have died, phospho-CREB levels in surviving neurons are not reduced, and SGN death is no longer correlated with reduced phospho-CREB. Activity in the proapoptotic Jun N-terminal kinase (JNK)-Jun signaling pathway is elevated in SGNs during the cell death period. This too is heterogeneous: <42% of the SGNs exhibited high phospho-Jun levels, but nearly all SGNs undergoing apoptosis exhibited elevated phospho-Jun. Thus, heterogeneity among SGNs in prosurvival and proapoptotic signaling is correlated with apoptosis. SGN death following deafferentation has an early phase in which apoptosis is correlated with reduced phospho-CREB and a later phase in which it is not. Proapoptotic JNK-Jun signaling is tightly correlated with SGN apoptosis.

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These data suggest that the suppression of bcl-2 protein expression may lead to apoptosis-induced presbyacusis through activation of caspase-3 in the aged gerbil cochlea.

Acute effects of kanamycin and/or furosemide administration on the stria vascularis of the guinea pig cochlea were assessed by distortion product otoacoustic emission (DPOAE) and transmission electron microscopy. Kanamycin alone failed to affect the DPOAE levels and ultrastructural changes. Furosemide alone caused a rapid but reversible fall of the DPOAE levels. No remarkable pathological changes in the strial vascularis were observed after a complete recovery of the DPOAEs. On the other hand, furosemide injection following kanamycin with a 2 hour interval resulted in two patterns of significant changes in the DPOAEs, namely, a sudden drop in the DPOAE levels 2 to 3 hours after furosemide injection and a gradual fall in the DPOAE levels immediately after the incomplete recovery from the furosemide-induced decrease of the DPOAE levels. Ultrastructural changes in the stria vascularis included numerous vacuoles in the strial marginal cells and increased electron density of the intermediate and basal cells. These physiological and morphological changes in the stria vascularis may imply new ototoxic features induced by kanamycin potentiated by furosemide.

Vaccination is associated with the presence of both gp120-binding IgG in all compartments and plasma IgA but not with neutralizing activity. There is a role for the measurement of mucosal immunity in response to candidate vaccines and, in particular, for a determination of HIV-specific neutralizing antibodies.

Levetiracetam is a second-generation antiepileptic drug that is chemically unrelated to other antiepileptic drugs. Levetiracetam is a broad-spectrum antiseizure medication that is approved as an adjunctive therapy in the treatment of partial and generalized tonic-clonic seizures in children and adults with epilepsy. The mechanism by which Levetiracetam induces behavioral changes remains unknown. Its proposed mechanism of action involves binding to synaptic vesicle protein 2A (SV2A) and this leads to neuronal inhibition. Though, the drug has a convenient dosing regimen and is relatively well tolerated, neuropsychiatric side effects can emerge beyond the initial titration period and may be the most common reason for drug discontinuation. Levetiracetam has been reported to cause varying degrees of psychiatric adverse effects including behavioral disturbance such as agitation, hostility and psychosis, and mood symptoms and suicidality. It has been shown to induce psychiatric side effects in 13.3% of adults, with only 0.7% presenting with severe symptoms such as depression, agitation, or hostility. The prevalence rate of development of psychosis in these patients is estimated to be about 1.4%. A review of literature has demonstrated a relative correlation between Levetiracetam use and the development of neurobehavioral symptoms which is increased in predisposed individuals. This research describes the case of a 28-year-old woman with seizure disorder and a psychiatric history of schizoaffective disorder who developed aggressive behavior, paranoia, and severe hostility following administration of Levetiracetam 750 mg orally twice daily. She developed acute behavioral symptoms which were reversed with cessation of Levetiracetam. This report emphasizes the need for developing an appropriately high index of suspicion in promoting surveillance and prompt identification of behavioral adverse effects associated with Levetiracetam especially in high-risk patient population.

Adjuvants are crucial vaccine components for enhancing immune response to immunogens. Many potential adjuvant materials have been studied for their ability to augment the response to antigens while maintaining low toxicity. A US FDA approved adjuvant routinely used in humans is alum. The aim of this study was to comprehensively measure the ways in which innate immune signals induced by alum manifest in terms of the effect on the adaptive immune response to recombinant protective antigen (PA) from Bacillus anthracis. C57Bl/6 mice were given a single subcutaneous immunization with PA +/- alum at the base of each limb. Serum and draining lymph nodes were collected after immunization (days 1-70). On day 71, saline or PA only boost was administered, followed by additional serum and tissue collection (days 78-85). Using multi-color immunohistochemistry it was shown beginning day 10 that alum induces a rapid and strong germinal center response in the draining lymph node. This observation correlates with quantitative and qualitative changes in PA-specific antibody assessed by ELISA and Biacore (SPR). In addition, augmented antibody response to PA+alum resulted in increased antibody functionality, as determined by anthrax toxin neutralization assays. This study demonstrates a novel multi-parameter approach to evaluation of antigen-specific responses to immunization and the impact of adjuvants. This approach will be useful in the development and testing of novel adjuvants.