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Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood-brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20-25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 microM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 microM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography. We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model.

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Olfactory information processing is mediated by synaptic connections between the olfactory bulbs (OBs) and piriform-limbic cortices. Limited accessibility using common in vivo and in vitro preparations has hindered previous attempts to define these synaptic interactions. We utilized the isolated guinea-pig brain preparation to overcome these experimental limitations. Previous studies demonstrated extensive functional preservation in this preparation maintained in vitro by arterial perfusion. Field potential laminar profiles were performed with multi-channel probes in the OB following stimulation of both the lateral olfactory tract (LOT) and the anterior piriform cortex (APC). Current-source density analysis was carried out on laminar profiles to reconstruct current sinks/sources associated with intrinsic synaptic activities. LOT stimulation induced sequentially i) an antidromic population spike (at 2.66+/-0.39 ms) located in the mitral cell layer that was resistant to 100 Hz high-frequency stimulation (HFS) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM), ii) a component located in the external plexiform layer at 3.85+/-0.63 ms that was unaffected by HFS, iii) a large amplitude potential (peak amplitude at 5.84+/-0.58 ms) generated in the external plexiform layer, abolished by HFS and CNQX, but not by bicuculline (50 microM), iv) a late response (onset at 20.00+/-2.94 ms) abolished by CNQX and enhanced by bicuculline. Stimulation of the APC also induced a late potential abolished by HFS and CNQX. Both APC-evoked and late LOT-evoked responses were abolished by a transverse cut to separate OB from APC. These results demonstrate in an isolated mammalian brain preparation the presence of reciprocal synaptic interactions between the OB and piriform cortical structures.

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Mechanisms underlying epileptic activities recorded from entorhinal cortex (EC) were studied through a computational model based on review of cytoarchitectonic and neurobiological data about this structure. The purpose of this study is to describe and use this model to interpret epileptiform discharge patterns recorded in an experimental model of ictogenesis (guinea pig isolated brain perfused with bicuculline). A macroscopic modeling approach representing synaptic interactions between cells subpopulations in the EC was chosen for its adequacy to mimic field potentials reflecting overall dynamics rising from interconnected cells populations. Therefore intrinsic properties of neurons were not included in the modeling design. Model parameters were adjusted from an identification procedure based on quantitative comparison between real and simulated signals. For both EC deep and superficial layers, results show that the model generates very realistic signals regarding temporal dynamics, spectral features, and cross-correlation values. These simulations allowed us to infer information about the evolution of synaptic transmission between principal cell and interneuronal populations and about connectivity between deep and superficial layers during the transition from background to ictal activity. In the model, this transition was obtained for increased excitation in deep versus superficial layers. Transitions between epileptiform activities [interictal spikes, fast onset activity (25 Hz), ictal bursting activity] were explained by changes of parameters mainly related to GABAergic interactions. Notably, the model predicted an important role of GABAa,fast- and GABAb-receptor-mediated inhibition in the generation of ictal fast onset and burst activities, respectively. These findings are discussed with respect to experimental data.

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Interactions between olfactory cortices and the hippocampus support sensory discrimination and spatial learning functions. The olfactory input accesses the hippocampal formation via a polysynaptic pathway mediated by the lateral and rostral entorhinal cortex (EC). We recently demonstrated that following repetitive stimulation of the lateral olfactory tract (LOT) at 2-8 Hz, a delayed response (onset at circa 60 ms) was evoked in the caudal portion of the EC, identified as medial EC, that does not receive a direct olfactory input. By performing simultaneous laminar profile analysis in the EC and in different hippocampal subfields, we conclusively demonstrate that the delayed EC response evoked by repetitive ipsilateral LOT stimulation is headed by the sequential activation of the dentate gyrus and the CA3/CA1 subfields in the septal and temporal hippocampus. Repetitive stimulation of the contralateral LOT also induced an EC response that peaked at 76.28+/-2.42 ms (n=15). Current source density analysis and time-delay analysis of simultaneous field potential laminar profiles performed from the EC and from DG, CA3 and CA1 hippocampal subfields suggested that the contralateral EC response is mainly carried by an intrahippocampal CA3-CA3 commissural pathway. Contralateral LOT stimulation also induced a later EC component (delay >100 ms) generated in the superficial layers, mediated either by local associative interactions or by extrahippocampal circuits. The opportunity to activate the ipsi- and contralateral olfactory pathways in the same experiment and to record field potentials profiles simultaneously in different structures of both hemispheres in the isolated guinea-pig brain confirms that this preparation is unique and is particularly suitable for investigating the system physiology of the limbic region. The present study demonstrates that patterned stimulation of the olfactory input that mimics sniffing patterns during odor discrimination induces a diffuse activation of both ipsi- and contralateral hippocampi and ECs. The findings contribute to the understanding the physiological mechanisms that underlie associative interactions between olfactory and non-olfactory cortical inputs converging into the mesial temporal region.

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Anatomical studies demonstrated that neurons located in the superficial layers of the medial and lateral aspects of the rat entorhinal cortex (EC) project to temporal and septal portions of both the dentate gyrus (DG) and the CA1 region of the hippocampus, respectively. In the present study we investigated with electrophysiological techniques the propagation pattern of different EC subfields to the DG of the in vitro isolated brain of the guinea-pig. Laminar field potential profiles from different portions of the DG were recorded with multi-channel silicon probes following direct stimulation of the ipsilateral EC surface performed in different positions under direct visual control. Current source density analysis of laminar profiles demonstrated that i) stimulation of the rostral-medial EC induced monosynaptic responses exclusively in the temporal pole of the DG, ii) stimulation of both the lateral and the caudal portions of the EC determined a diffuse monosynaptic activation of both the intermediate and septal DG. The regions of the EC that project to different sectors of the DG in the guinea-pig do not correlate to the EC subfields identified on the basis of cytoarchitectonic criteria. The EC-evoked monosynaptic DG potentials were followed by disynaptic responses coupled with sinks located in the inner molecular layer, proximal to the EC-induced sink, where intra-DG associative synapses were demonstrated by anatomical studies. The present detailed topographical study of the EC connections with the DG in the guinea-pig demonstrates with an electrophysiological approach a projection pattern similar, even if not identical, to that described with tracer techniques in the rat. This report is essential for future studies of the dynamic parahippocampal-hippocampal interactions in the guinea-pig, and in particular in the isolated guinea-pig brain preparation.

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The perirhinal cortex is a key structure involved in memory consolidation and retrieval. In spite of the extensive anatomical studies that describe the intrinsic and extrinsic associative connections of the perirhinal cortex, the activity generated within such a network has been poorly investigated. We describe here the pattern of synaptic interactions that subtend the responses evoked in area 36 of the perirhinal cortex by neocortical and local stimulation. The experiments were carried out in the in vitro isolated guinea pig brain. The synaptic perirhinal circuit was reconstructed by integrating results obtained during intracellular recordings from layer II-III neurons with simultaneous current source density analysis of laminar profiles performed with 16-channel silicon probes. Both neocortical and local stimulation of area 36 determined a brief monosynaptic excitatory potential in layer II-III neurons, followed by a biphasic synaptic inhibitory potential possibly mediated by a feed-forward inhibitory circuit at sites close to the stimulation electrode and a late excitatory postsynaptic potential (EPSP) that propagated at distance within area 36 along the rhinal sulcus. During a paired-pulse stimulation test, the inhibitory postsynaptic potential (IPSP) and the late EPSP were abolished in the second conditioned response, suggesting that they are generated by poli-synaptic circuits. Current source density analysis of the field responses demonstrated that 1) the monosynaptic activity was generated in layers II-III and 2) the sink associated to the disynaptic responses was localized within the superficial layer of area 36. We conclude that the neocortical input induces a brief monosynaptic excitation in area 36 of the perirhinal cortex, that is curtailed by a prominent inhibition and generates a recurrent excitatory associative response that travels at distance within area 36 itself. The results suggest that the perirhinal cortex network has the potentials to integrate multimodal incoming neocortical information on its way to the hippocampus.

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Prolonged eosinophilia of unknown cause has generally been described as the hypereosinophilic syndrome, and is characterised by peripheral blood and bone marrow infiltration and frequent multisystem disease. The nature of this disorder has been questioned, and the clinical features are quite variable, suggesting its heterogeneity and probable neoplastic aetiology. A patient with severe eosinophilia, karyotype abnormalities, serum gammopathy and massive organ disease is reported. The clinical course was aggressive despite cytoreduction of eosinophils and terminated in multisystem failure. These findings are consistent with a diagnosis of eosinophilic leukaemia, and it is suggested that chromosome and cell culture studies might be useful in the early diagnosis of this controversial entity.

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Splenic lymphoma with villous lymphocytes is a new entity characterised by the presence of atypical lymphocytes in the peripheral blood and bone marrow, and splenic infiltration in the white and red pulp. Cell membrane markers are those of a B mature cell, and no particular chromosomal abnormalities have been associated with this disease. A case of this rare lymphoma occurred in two sisters. Histological examination of splenic tissue was identical in both cases, with the same immunological surface markers, although the clinical and laboratory features were different. Karyotype analysis showed an abnormal pattern in one case; no environmental causative factor could be detected. Familial cases of other lymphoproliferative disorders have been reported, but no consistent common link has been found. It is suggested that further reports of this lymphoma, including cytogenetic and molecular studies, may provide a better understanding of the aetiology.

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The first Portuguese cases of a combination of Hb D and B0 thalassaemia are reported. The structure of the Hb variant was identified as Hb D Los Angeles, Punjab, Chicago, Portugal. The cases reported belong to one family living in the south of the country: a woman and her two sons. Twice, in two different generations, women with a Hb D gene, married men with B0 thalassaemia trait. The hypochromic and microcytic red cell morphology in the propositi have been the first abnormalities for subsequent investigations.

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