Valproic acid mediates the synaptic excitatory/inhibitory balance through astrocytes--a preliminary study.

Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for the treatment of epilepsy and bipolar disorder. However, the underlying therapeutic mechanisms of the treatment of each disease remain unclear. Recently, the anti-epileptic effect of VPA has been found to lead to modulation of the synaptic excitatory/inhibitory balance. In addition, the therapeutic action of VPA has been linked to its effect on astrocytes by regulating gene expression at the molecular level, perhaps through an epigenetic mechanism as a histone deacetylase (HDAC) inhibitor. To provide insight into the mechanisms underlying the actions of VPA, this study investigated whether the synaptic excitatory/inhibitory (E/I) balance could be mediated by VPA through astrocytes. First, using the primary rat neuronal, astroglial, and neuro-glial mixed culture systems, we demonstrated that VPA treatment could regulate the mRNA levels of two post-synaptic cell adhesion molecules(neuroligin-1 and neuregulin-1) and two extracellular matrices (neuronal pentraxin-1and thrombospondin-3) in primary rat astrocyte cultures in a time- and concentration-dependent manner. Moreover, the up-regulation effect of VPA was noted in astrocytes, but not in neurons. In addition, these regulatory effects could be mimicked by sodium butyrate, a HDAC inhibitor, but not by lithium or two other glycogen synthase kinase-3 beta inhibitors. With the known role of these four proteins in regulating the synaptic E/I balance, we further demonstrated that VPA increased excitatory post-synaptic protein (postsynaptic density 95) and inhibitory post-synaptic protein (Gephyrin) in cortical neuro-glial mixed cultures. Our results suggested that VPA might affect the synaptic excitatory/inhibitory balance through its effect on astrocytes. This work provides the basis for future evaluation of the role of astroglial cell adhesion molecules and the extracellular matrix on the control of excitatory and inhibitory synapse formation.

The reporting completeness of a passive safety surveillance system for pandemic (H1N1) 2009 vaccines: a capture-recapture analysis.

Adverse events following pandemic (H1N1) 2009 vaccines ("2009 H1N1 vaccines") in Taiwan were passively reported to the National Adverse Drug Reaction Reporting System. To evaluate the completeness of spontaneous reporting, cases of death, Guillain-Barré syndrome (GBS), convulsion, Bell's palsy, and idiopathic thrombocytopenic purpura (ITP) after 2009 H1N1 vaccination that occurred between November 1, 2009 and August 31, 2010 were selected from the National Adverse Drug Reaction Reporting System (NADRRS) database and an additionally constructed nationwide large-linked database (LLDB), and matched on a unique personal identifier, date of vaccination (within ±7 days), and date of diagnosis (within ±7 days). Overall, matches occurred between the two data sources included 21 for death, 5 for GBS, 19 for convulsion, 22 for Bell's palsy, and 5 for ITP. The Chapman capture-recapture estimated spontaneous reporting completeness within 0-42 days of vaccination was 4% for death, 71% for GBS, 3% for convulsion, 9% for Bell's palsy, and 15% for ITP. For the interval ≥43 days after vaccination, reporting completeness was 0.1% for death, 14% for GBS, 0.1% for convulsion, <0.1% for Bell's palsy, and 0% for ITP. The estimated-to-expected ratio for Bell's palsy in the interval 0-42 days after vaccination was 1.48 (95% CI 1.11-1.98). Reporting completeness was higher for GBS than other adverse events after 2009 H1N1 vaccination. Linking the NADRRS to existing data sources in a capture-recapture analysis can be considered as an alternative to enhance Taiwan's postlicensure safety assessment of other routine vaccines. Nevertheless, the possibility of an increased risk for Bell's palsy detected by capture-recapture analyses needs further evaluation by controlled studies.

Adverse events following pandemic A (H1N1) 2009 monovalent vaccines in pregnant women--Taiwan, November 2009-August 2010.

BACKGROUND: During the 2009 H1N1 pandemic, pregnant women were prioritized to receive the unadjuvanted or MF59®-adjuvanted pandemic A (H1N1) 2009 monovalent vaccines ("2009 H1N1 vaccines") in Taiwan regardless of stage of pregnancy. Monitoring adverse events following 2009 H1N1 vaccination in pregnant women was a priority for the mass immunization campaign beginning November 2009. METHODS/FINDINGS: We characterized reports to the national passive surveillance from November 2009 through August 2010 involving adverse events following 2009 H1N1 vaccines among pregnant women. Reports from the passive surveillance were matched to a large-linked database on a unique identifier, date of vaccination, and date of diagnosis in a capture-recapture analysis to estimate the true number of spontaneous abortion after 2009 H1N1 vaccination. We verified 16 spontaneous abortions, 11 stillbirths, 4 neonatal deaths, 4 nonpregnancy-specific adverse events, and 2 inadvertent immunizations in recipients who were unaware of pregnancy at time of vaccination. The Chapman capture-recapture estimator of true number of spontaneous abortion after 2009 H1N1 vaccination was 329 (95% confidence interval [CI] 196-553). Of the 14,474 pregnant women who received the 2009 H1N1 vaccines, the estimated risk of spontaneous abortion was 2.3 (95% CI, 1.4-3.8) per 100 pregnancies, compared with a local background rate of 12.8 (95% CI, 12.8-12.9) per 100 pregnancies. CONCLUSIONS: The passive surveillance provided rapid initial assessment of adverse events after 2009 H1N1 vaccination among pregnant women. Its findings were reassuring for the safety of 2009 H1N1 vaccines in pregnancy.