Carisbamate has powerful disease-modifying effects in the lithium-pilocarpine model of temporal lobe epilepsy

Lithium-pilocarpine, a relevant model of temporal lobe epilepsy was used to test the neuroprotective and antiepileptogenic effects of carisbamate. Status epilepticus (SE) was induced in adult rats by lithium and pilocarpine. Carisbamate (30, 60, 90, and 120?mg/kg) was injected at 1 and 9?h after SE onset and continued twice daily for 6 additional days. The reference groups received diazepam instead of carisbamate. Neuroprotection was assessed during the first 24?h of SE with Fluoro-Jade B and after 14 days with thionine staining. SE severity and epileptic outcome were assessed by video, and surface and depth electroencephalographic recordings. At the two highest doses, carisbamate treatment reduced SE severity; produced strong neuroprotection of hippocampus, ventral cortices, thalamus, and amygdala; prevented mossy fiber sprouting in the dentate gyrus of the hippocampus; and delayed or suppressed the occurrence of spontaneous motor seizures. Rats with no spontaneous motor seizures displayed spike-and-wave discharges that share all the characteristics of absence seizures. In conclusion, carisbamate is able to induce strong neuroprotection and affect the nature of epileptogenic events occurring during and after lithium-pilocarpine status epilepticus, reflecting marked insult- and disease-modifying effects.     

Peripheral immunization induces functional intrahepatic hepatitis C specific immunity following selective retention of vaccine-specific CD8 T cells by the liver

It is believed that an effective HCV vaccine must induce strong HCV-specific cytotoxic IFN-γ? CD8? T cells able to migrate into and become fully activated within the liver, an organ known to suppress T cell responses and induce tolerance. Given the importance of intrahepatic HCV-specific T cells in the clearance of acute infection, the goal of this present study was to determine if peripheral immunization was able to induce functional intrahepatic HCV-specific T cell based immunity both in the presence and absence of HCV antigen expression within the liver. Using a novel HCV NS3/NS4A DNA vaccine, we show that peripheral immunization of C57BL/6 mice results in the formation of a large pool of fully functional HCV-specific cytotoxic IFN-γ? CD8? T cells within the liver and that these cells were highly enriched within the liver as compared to the spleen. Following hepatic expression of cognate HCV antigen using a previously described liver transfection method, we show that this pool of vaccine-induced HCV-specific CD8? T cells retained its ability to become highly activated as shown by the upregulation of IFN-γ and CCR5 expression, as well as by the clearance of HCV NS3 expressing hepatocytes. Taken together, these findings suggest that T cell effector function is preserved within the liver and that selective recruitment of antigen-specific T cells to the liver may play a previously unappreciated role in the process of immune surveillance, which may be exploited for future T cell based HCV vaccines.     

Behavioral characterization of escalated aggression induced by GABAB receptor activation in the dorsal raphe nucleus

Rationale

Pharmacological activation of GABA_B receptors in the dorsal raphe nucleus (DRN) can escalate territorial aggression in male mice.

Objectives

We characterized this escalated aggression in terms of its behavioral and environmental determinants.

Methods

Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN 10 min before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment.

Results

Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts.

Conclusions

For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat.     

Maternal mirror syndrome after in utero aortic valve dilation. A case report

Fetal hydrops of various etiologies can be associated with maternal mirror syndrome. The exact pathophysiology of this rare disorder remains unclear, yet it can result in significant maternal and fetal morbidity. The recent advances in prenatal diagnosis and therapeutic interventions have focused on altering the course of pathologies associated with an expected poor prognosis. Severe fetal aortic valve stenosis with its potential for hypoplastic left heart fit this category. We report a case of maternal mirror syndrome in a parturient following intrauterine therapy for severe fetal aortic stenosis and hydrops. Despite a technically successful intervention, the mother required emergency cesarean section. We review the few reports of mirror syndrome as well as the current approaches to fetal aortic stenosis. This case reinforces the need for in depth risk analysis prior to fetal interventions. It also emphasizes the advantage of earlier detection and therapy with fetal aortic stenosis since fetal hydrops carries a somber prognosis.