Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro

Oxygen glucose deprivation (OGD) leads to rapid suppression of synaptic transmission. Here we describe an emergence of rhythmic activity at 8 to 20 Hz in the CA3 subfield of hippocampal slice cultures occurring for a few minutes prior to the OGD-induced cessation of evoked responses. These oscillations, dominated by inhibitory events, represent network activity, as they were abolished by tetrodotoxin. They were also completely blocked by the GABAergic antagonist picrotoxin, and strongly reduced by the glutamatergic antagonist NBQX. Applying CPP to block NMDA receptors had no effect and neither did UBP302, an antagonist of GluK1-containing kainate receptors. The gap junction blocker mefloquine disrupted rhythmicity. Simultaneous whole-cell voltage-clamp recordings from neighboring or distant CA3 pyramidal cells revealed strong cross-correlation of the incoming rhythmic activity. Interneurons in the CA3 area received similar correlated activity. Interestingly, oscillations were much less frequently observed in the CA1 area. These data, together with the observation that the recorded activity consists primarily of inhibitory events, suggest that CA3 interneurons are important for generating these oscillations. This transient increase in inhibitory network activity during OGD may represent a mechanism contributing to the lower vulnerability to ischemic insults of the CA3 area as compared to the CA1 area.     

Randomized comparison of prophylactic antidiarrheal treatment versus no prophylactic antidiarrheal treatment in patients receiving CPT-11 (irinotecan) for advanced 5-FU-resistant colorectal cancer: an open-label multicenter phase II study

Delayed diarrhea is the main toxicity of irinotecan at the currently recommended dose of 350 mg/m2 30-minute intravenous infusion, once every 3 weeks. This phase II, multicenter, open-label, randomized study was primarily designed to evaluate the effect of a 15-day Tiorfan (racecadotril) treatment on the incidence and severity of irinotecan-induced delayed diarrhea. One hundred thirty-six patients with metastatic colorectal cancer who failed to respond to a 5-fluorouracil-based treatment received 714 cycles of irinotecan. The patients were randomly allocated either to group A (68 patients) and received Tiorfan (300 mg/day) from D0 to D15 or to group B (68 patients) with no prophylactic treatment. Delayed diarrhea occurred in 197 of 355 cycles (55%) in Group A and 203 of 344 cycles (59%) in Group B. grade III-IV diarrhea was reported in 17 of 40 compliant patients (42%) in group A and 31 of 68 evaluable patients (45%) in group B. No difference was observed between the two groups for delayed diarrhea characteristics, incidence, or severity. The response rate in 99 evaluable patients was 12.1% (6.4%-20.2%). This study has shown that Tiorfan given prophylactically at 300 mg/day has no effect on delayed diarrhea.     

Entorhinal cortex involvement in human mesial temporal lobe epilepsy: an electrophysiologic and volumetric study

PURPOSE: Several studies have demonstrated diminution in the volume of entorhinal cortex (EC) ipsilateral to the pathologic side in patients with temporal lobe epilepsy (TLE). The relation between the degree of EC atrophy and the epileptogenicity of this structure has never been directly studied. The purpose of the study was to determine whether atrophy of the EC evaluated by the quantitative magnetic resonance imaging (MRI) method is correlated with the epileptogenicity of this structure in TLE. METHODS: Intracerebral recordings (SEEG method) of seizures from 11 patients with mesial TLE were analyzed. Seizures were classified according to patterns of onset: pattern 1 was the emergence of a low-frequency, high-amplitude rhythmic spiking followed by a tonic discharge, and pattern 2 was the emergence of a tonic discharge in the mesial structures. A nonlinear measure of SEEG signal interdependencies was used to evaluate the functional couplings occurring between hippocampus (Hip) and EC at seizure onset. MRI volumetric analysis was performed by using a T(1)-weighted three-dimensional gradient-echo sequence in TLE patients and 12 healthy subjects. RESULTS: Significant interactions between Hip and Ec were quantified at seizure onset. The EC was found to be the leader structure in most of the pattern 2 seizures. Volumetric measurements of EC demonstrated an atrophy in 63% of patients ipsilateral to the epileptic side. A significant correlation between the strength of EC-Hip coupling and the degree of atrophy was found. In addition, in those patients that had a normal EC volume, the EC was never the leader structure in Ec-Hip coupling. CONCLUSIONS: These results validate the potential role of volumetry to predict the epileptogenesis of the EC in patients with hippocampal sclerosis and MTLE.     

Spatio-temporal dynamics of neuronal networks in partial epilepsy

INTRODUCTION: The anatomo-functional organization of partial drug-resistant epilepsies is the subject of much current research aiming at better understanding these pathologies and improving their treatment. The work carried out by our team on the study of intracerebral recording falls within this category of research. The objectives are to identify the neural networks involved in the generation of paroxysmal activity and to understand their spatio-temporal dynamics, in order to be able in the long term to propose targeted therapeutic approaches likely to "control" these networks. STATE OF ART: The traditional concept of epileptic "focus" must nowadays be replaced by a more complex model taking into account potential interactions within the neural networks involved in the seizure. Indeed, during partial seizures, involved cerebral structures are the site of characteristic oscillations which may be synchronized or on the contrary transiently desynchronized. These epileptic rhythms may disturb the physiological rhythms underlying normal cognitive processes; these cognitive processes may thus be impaired in partial epilepsy, even those remote from the site of origin of the discharge. In this article we describe a model of organization of human partial seizures, through characterization of the relationships ("synchrony") between intracerebral signals recorded in the involved structures. We propose that seizures are generated in an initial network of highly epileptogenic brain structures (epileptogenic zone network, EZN) whose activity is synchronized; this activity is then transiently desynchronized with the appearance of fast oscillations. During a second ictal phase, other cortical and subcortical structures are the seat of slower rhythmic modifications that are synchronized (propagation network, PN). The emergence of a particular clinical semiology in the course of the seizure depends on these phenomena which can in certain cases "mimic" a normal cerebral process or on the contrary provoke a major rupture in normal cerebral functioning. CONCLUSIONS: These studies contribute to improvement in our knowledge of the neural networks involved in partial epilepsies. In the future, this type of research may contribute to the development of specific treatments that target certain pathophysiological mechanisms involved in seizure generation.