The most fulminant course of the Marburg variant of multiple sclerosis-autopsy findings.

Multiple sclerosis (MS) is usually a chronic and disabling inflammatory disease. Marburg's type of MS is characterized by rapid progression and severe disease course that leads to death within one year after the onset of clinical signs. We describe a fulminant clinical presentation of this malignant subtype of MS and discuss the neuropathological hallmarks as well as differential diagnoses of other fulminant demyelinating diseases. To the best of our knowledge, this is the most fulminant course of this MS variant reported in the literature.

Side of pupillary mydriasis predicts the cognitive prognosis in patients with severe traumatic brain injury.

BACKGROUND: Pupils' abnormalities are associated to bad prognosis in traumatic brain injury. We investigated the association between the side of pupil mydriasis and the long-term cognitive performance of patients with severe traumatic brain injury (TBI). METHODS: We analyzed the cognitive performance of patients admitted at the intensive care unit with isochoric pupils (IP, n = 28), left mydriasis (LM, n = 10), right mydriasis (RM, n = 9) evaluated in mean 2.5 years after the severe TBI and controls (n = 26) matched for age, sex and education level. RESULTS: Patients and controls had similar scores in the four WAIS-III investigated subtests. In comparison with controls, LM patients had lower scores in Letters and Category Fluency and IP patients in Category Fluency. Among the 10 evaluated memory tests, LM patients had lower scores than controls in eight, RM patients in two and IP in three memory tests. IP and RM were 3.5 to nine times more associated to significant impairment (cognitive scores under the percentile 10 of controls) in six of 16 investigated cognitive tests. LM was six to 15 times more associated to significant impairment in 10 of 16 cognitive tests. The association among the pupil abnormalities and cognitive performances remained significant after the multiple linear regression analysis controlling for age, gender, admission coma Glasgow scale and serum glucose, presence of associated trauma, and cranial computed tomography abnormalities. CONCLUSION: Side of admission pupil abnormalities may be a useful variable to improve prognostic models for long-term cognitive performance in severe TBI patients.

Serum and cerebrospinal fluid S100B concentrations in patients with neurocysticercosis.

The clinical manifestations of neurocysticercosis (NC) are varied and depend on the number and location of cysts, as well as on the host immune response. Symptoms usually occur in NC when cysticerci enter a degenerative course associated with an inflammatory response. The expression of brain damage markers may be expected to increase during this phase. S100B is a calcium-binding protein produced and released predominantly by astrocytes that has been used as a marker of reactive gliosis and astrocytic death in many pathological conditions. The aim of the present study was to investigate the levels of S100B in patients in different phases of NC evolution. Cerebrospinal fluid and serum S100B concentrations were measured in 25 patients with NC: 14 patients with degenerative cysts (D), 8 patients with viable cysts (V) and 3 patients with inactive cysts. All NC patients, except 1, had five or less cysts. In most of them, symptoms had been present for at least 1 month before sample collection. Samples from 8 normal controls (C) were also assayed. The albumin quotient was used to estimate the blood-brain barrier permeability. There were no significant differences in serum (P = 0.5) or cerebrospinal fluid (P = 0.91) S100B levels among the V, D, and C groups. These findings suggest that parenchymal changes associated with a relatively small number of degenerating cysts probably have a negligible impact on glial tissue.

[Analgesia in intensive care medicine]. / Analgesie in der Intensivmedizin.

BACKGROUND: The administration of sedatives and analgesics on the intensive care unit (ICU) is routine daily practice. The correct discrimination between delirium, pain and anxiety or confusion is essential for the strategy and selection of medication. The correct pain therapy and sedation are essential for patient quality of life on the ICU and for the prognosis. OBJECTIVE: The aim of this article is to present state of the art recommendations on the classification of pain and pain therapy on the ICU. MATERIAL AND METHODS: An online search was carried out in PubMed for publications on the topics of "pain" and "ICU". RESULTS: Critical care patients are frequently subjected to many procedures and situations which can cause pain. The perception of pain is, among other things, influenced by the degree of orientation, anxiety and the degree of sedation. The administration of analgesics and non-pharmacological approaches are effective in reducing the stress perceived by patients. DISCUSSION: The main aim is improvement in the awareness of nursing and medical personnel for pain inducers and pain perception in ICU patients. The classification of pain must be made objectively. Therapeutic targets must be defined and in addition to the correct selection of pain medication, non-pharmacological approaches must also be consistently implemented.

A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system.

Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions.

Differential role of entorhinal and hippocampal nerve growth factor in short- and long-term memory modulation.

We studied the effects of infusion of nerve growth factor (NGF) into the hippocampus and entorhinal cortex of male Wistar rats (250-300 g, N = 11-13 per group) on inhibitory avoidance retention. In order to evaluate the modulation of entorhinal and hippocampal NGF in short- and long-term memory, animals were implanted with cannulae in the CA1 area of the dorsal hippocampus or entorhinal cortex and trained in one-trial step-down inhibitory avoidance (foot shock, 0.4 mA). Retention tests were carried out 1.5 h or 24 h after training to measure short- and long-term memory, respectively. Immediately after training, rats received 5 microl NGF (0.05, 0.5 or 5.0 ng) or saline per side into the CA1 area and entorhinal cortex. The correct position of the cannulae was confirmed by histological analysis. The highest dose of NGF (5.0 ng) into the hippocampus blocked short-term memory (P < 0.05), whereas the doses of 0.5 (P < 0.05) and 5.0 ng (P < 0.01) NGF enhanced long-term memory. NGF administration into the entorhinal cortex improved long-term memory at the dose of 5.0 ng (P < 0.05) and did not alter short-term memory. Taken as a whole, our results suggest a differential modulation by entorhinal and hippocampal NGF of short- and long-term memory.

Imbalance of antioxidant defense in mice lacking cellular prion protein.

Prion diseases are fatal neurodegenerative disorders resulting from conformational changes in the prion protein from its normal cellular isoform, PrPC, to the infectious scrapie isoform, PrP(Sc). In spite of many studies, the physiological function of PrPC remains unknown. Recent work shows that PrPC binds Cu2+, internalizing it into the cytoplasm. Since many antioxidant enzymes depend on Cu2+ (e.g., Cu/ZnSOD), their function could be affected in prion diseases. Here we investigate a possible relationship between PrP(C) and the cellular antioxidant systems in different structures isolated from PrPC knockout and wild-type mice by determining oxidative damage in protein and lipids and activity of antioxidant enzymes (CAT, SOD) and stress-adaptive enzymes (ODC). Our results show that, in the absence of PrPC, there is an increased oxidation of lipid and protein in all structures investigated. Decreased SOD activity and changes in CAT/ODC activities were also observed. Taking into account these results, we suggest that the physiological function of PrP(C) is related to cellular antioxidant defenses. Therefore, during development of prion diseases, the whole organism becomes more sensitive to ROS injury, leading to a progressive oxidative disruption of tissues and vital organs, especially the central nervous system.

Normal inhibitory avoidance learning and anxiety, but increased locomotor activity in mice devoid of PrP(C).

Prions are the causative agents of transmissible spongiform encephalopathies. The transmissible agent (PrP(Sc)) is an abnormal form of PrP(C), a normal neuronal protein. The physiological role of PrP(C) remains unclear. In the present report, we evaluated behavioral parameters in Prnp(0/0) mice devoid of PrP(C). Prnp(0/0) mice showed normal short- and long-term retention of a step-down inhibitory avoidance task and normal behavior in an elevated plus maze test of anxiety. During a 5-min exploration of an open field, Prnp(0/0) mice showed normal number of rearings, defecation, and latency to initiate locomotion, but a significant increase in the number of crossings. The results suggest that Prnp(0/0) mice show normal fear-motivated memory, anxiety and exploratory behavior, and a slight increase in locomotor activity during exploration of a novel environment.

Cellular prion protein binds laminin and mediates neuritogenesis.

Laminin (LN) plays a major role in neuronal differentiation, migration and survival. Here, we show that the cellular prion protein (PrPc) is a saturable, specific, high-affinity receptor for LN. The PrPc-LN interaction is involved in the neuritogenesis induced by NGF plus LN in the PC-12 cell line and the binding site resides in a carboxy-terminal decapeptide from the gamma-1 LN chain. Neuritogenesis induced by LN or its gamma-1-derived peptide in primary cultures from rat or either wild type or PrP null mice hippocampal neurons, indicated that PrPc is the main cellular receptor for that particular LN domain. These results point out to the importance of the PrPc-LN interaction for the neuronal plasticity mechanism.

Memory processing by the limbic system: role of specific neurotransmitter systems.

Experiments using localized infusions into selected brain structures of agonists and antagonists of various synaptic receptors, given before or after behavioral training, have led to the following conclusions: (1) Memory is processed shortly after training in the amygdala, medial septum and hippocampus by glutamatergic NMDA and AMPA receptors activated in that sequence. Cholinergic muscarinic receptors are activated concurrently with the former. GABAA receptors modulated by brain benzodiazepines and by beta-noradrenergic receptors inhibit the process. (2) The sequential involvement of NMDA and AMPA receptors suggests that long-term potentiation (LTP) of the synapses activated by the learning experiences in the hippocampus and/or amygdala and medial septum is the crucial event. Expression of this LTP at the time of testing is necessary for retrieval: AMPA receptor blockade in the hippocampus and amygdala at the time of testing hinders retrieval. This suggests that the LTP underlies the memory process itself. (3) The amygdala, medial septum and hippocampus mediate different types of memory and/or different components of memories. The entorhinal cortex, through mechanisms that require intact NMDA receptors and are inhibited by GABAA receptors, intervenes in post-training memory processing 90-180 min after the other limbic regions. The entorhinal cortex integrates consecutively acquired memories; this role could be maintained by the LTP that is generated after training in the amygdala, hippocampus and medial septum. Post-training intervention of the entorhinal cortex does not occur if this region is inhibited at the time of training.

Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures.

Mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated in and required for both the induction of long-term potentiation (LTP) in hippocampal slices and the acquisition of fear conditioning training in rats. The present work was performed in order to test the effect of the specific inhibitor of MAPK kinase (MAPKK), PD 098059, on retention of a step-down inhibitory avoidance (IA). Adult male Wistar rats were bilaterally injected (0.5 microl/side) with PD 098059 (at 0.5, 5, or 50 microM) or vehicle into the entorhinal cortex or into the parietal cortex immediately after IA training using a 0.4 mA footshock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the entorhinal cortex at the dose of 50 microM, but not at the doses of 5 or 0.5 microM. When infused into the parietal cortex, PD 098059 was amnestic at the doses of 5 and 50 microM. The drug had no effect when infused at the highest dose in either structure 6 h after training. Our results suggest that the MAPKK inhibitor impairs IA retention memory in a dose-dependent manner when injected immediately after training into entorhinal cortex or parietal cortex. The effective dose is variable according to the neocortical structure studied.

Memory facilitation by post-training intraperitoneal, intracerebroventricular and intra-amygdala injection of Ro 5-4864.

Post-training i.p. (2.0 or 5.0 mg/kg), i.c.v. (2.5 micrograms/rat), or intra-amygdala (1.6-40 ng/amygdala) administration of Ro 5-4864 causes memory facilitation of step-down inhibitory avoidance in rats. The effect is expressed as an increased latency to step down in a retention test carried out 24 h after training. Ro 5-4864 is a blocker of the Cl(-)-channel associated with GABAA receptors, at a site sensitive to the antagonist, PK11195, and different from that sensitive to picrotoxin. PK11195, given i.c.v. (2.5 micrograms/rat) or into the amygdala (8 ng/amygdala), antagonized the effect of Ro 5-4864. Intra-amygdala picrotoxin administration (80 ng/amygdala) also caused retrograde memory facilitation, but its effect was not antagonized by PK11195. At a higher dose (40 ng/amygdala), PK11195 had an amnestic effect of its own, which suggests that it might be acting against an endogenous ligand of receptor to Ro 5-4864 in the Cl(-)-channel. These findings support the hypothesis that there is a GABAA mechanism in the amygdala normally involved in the modulation of the post-training memory processing of aversive learnings.

A peptide muscarinic toxin from the Green Mamba venom shows agonist-like action in an inhibitory avoidance learning task.

A peptide, muscarinic toxin 2 (MTX2), isolated from Dendroaspis angusticeps venom was previously shown to displace the specific binding of [3H]pirenzepine, a muscarinic M1 receptor ligand, from rat brain synaptosomal membranes. We have tested MTX2 for muscarinic agonist or antagonist actions in an inhibitory avoidance task in rats. Infusion of the muscarinic receptor antagonist scopolamine into the hippocampus of rats immediately after the training period produced amnesia, whereas the muscarinic agonist oxotremorine increased retention. When MTX2 was injected into the hippocampus of rats after the inhibitory avoidance task, it caused memory facilitation, which could be suppressed by the concomitant infusion of scopolamine. Hence, in this test, MTX2 showed muscarinic receptor agonist-like actions, which are probably mediated by the M1 subtype of muscarinic acetylcholine receptors.

Changes in cortical and hippocampal ectonucleotidase activities in mice lacking cellular prion protein.

Animals lacking cellular prion protein (PrP(c)) expression are more susceptible to seizures. Adenosine is an endogenous anticonvulsant agent and it levels in the synaptic cleft are regulated by ectonucleotidases. We evaluated ectonucleotidase activities in synaptosomes from hippocampus and cerebral cortex of adult PrP(c) null mice and wild-type mice (genetic background 129/Sv X C57BL/6J). There was an increase (47%) in adenosine triphosphate (ATP) hydrolysis in hippocampal synaptosomes of PrP(c) knockout mice as compared with the wild-type animals. In cortical synaptosomes, ATP hydrolysis was similar in both PrP(c) mice and controls. However, there was a significant decrease in adenosine diphosphate (ADP) hydrolysis in both hippocampal (-39%) and cortical (-25%) synaptosomes in PrP(c) null animals compared to wild-type mice. Changes in brain ectonucleotidases activities related to modifications in the PrP(c) expression may contribute, at least in part, to the higher sensitivity to seizures of PrP(c) null mice.

Lipid peroxidation in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acid in Wistar rats.

Oxidative stress has been implicated in a variety of acute and chronic neurologic conditions, including epilepsy. Both the kainic acid and pilocarpine are useful models of temporal lobe epilepsy in rodents. As an index of lipid peroxidation the level thiobarbituric acid reactive substances (TBARS) was measured after the status epileticus induced by pilocarpine or kainic acid. In hippocampus there was a slight enhancement in the TBARS levels measured 12-14 h after the end of status epileticus induced by pilocarpine and kainic acid. The TBARS levels in pilocarpine treated animals was significantly decreased late after status epileticus and in kainic acid model the TBARS returned to basal levels. These results indicating a putative role of reactive oxygen species in kainic acid and pilocarpine induced epilepsy.

Muscimol infused into the entorhinal cortex prior to training blocks the involvement of this area in post-training memory processing.

Muscimol infusions into the entorhinal cortex (ERC) have previously been reported to impair the retention of passive avoidance learning, but only when infusions were delayed until 90min after training. In the present study, three experiments were carried out to examine further the effects of muscimol infusions into the ERC prior to training. In Experiment 1, muscimol infusions prior to training had no effect on retention, confirming earlier findings, but blocked the amnestic effect of a second muscimol infusion 90min post-training. In Experiment 2, muscimol infusions prior to training blocked the improvement of retention normally seen following a second training trial 2h after the first. In Experiment 3, the technique of summation of performance across training trials was used to confirm that the direct effects of muscimol infusions lasted less than 2h. The results indicate that the GABA-ergic mechanism in the ERC is normally involved in the formation of memory for passive avoidance, but if the ERC is inactivated at the time of training, memory formation is diverted to other structures, which appear less capable of integrating consecutive memories across time.

NMDA-receptor-dependent, muscimol-sensitive role of the entorhinal cortex in post-training memory processing.

The bilateral infusion into the entorhinal cortex of the NMDA receptor antagonist, AP5 (5.0µg) or of the GABA(A) agonist, muscimol (0.03µg) 90min after training but not 30min before training, 0min after training or 10min before testing, hindered retention test performance 24h after inhibitory avoidance in rats. Glutamate (5.0µg) or picrotoxin (0.08µg) infused 90min after training had no effect. In animals trained with a low level footshock a second training session, 120min after the first, was needed in order to obtain a good retention test performance. This was taken to reflect summation of the consecutive memory traces left by the two training sessions. In these animals, the infusion of AP5 or muscimol into the entorhinal cortex between the two training sessions impeded their summation. The present results suggest that the entorhinal cortex plays a late role in memory processing, that this role does not need a hyperactivation of the entorhinal cortex, and that it is important for the interaction between consecutive memory traces.

Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy.

Adenosine has been proposed as an endogenous anticonvulsant which can play an important role in seizure initiation, propagation and arrest. Besides the release of adenosine per se, the ectonucleotidase pathway is an important metabolic source of extracellular adenosine. Here we evaluated ATP diphosphohydrolase and 5'-nucleotidase activities in synaptosomes from hippocampus and cerebral cortex at different periods after induction of status epilepticus (SE) by intraperitoneal administration of pilocarpine or kainate. Ectonucleotidase activities from synaptosomes of hippocampus and cerebral cortex of rats were significantly increased at 48-52 h, 7-9 days and 45-50 days after induction of SE by pilocarpine. In relation to kainate model, both hippocampal enzymes were enhanced at 7-9 days and 45-50 days, but only 5'-nucleotidase remained elevated at 100-110 days after the treatment. In cerebral cortex, an increase in ATP diphosphohydrolase was observed at 48-52 h, 7-9 days and 45-50 days after induction of SE by kainate. However, 5'-nucleotidase activity only presented significant changes at 45-50 and 100-110 days. Our results suggest that SE can induce late and prolonged changes in ectonucleotidases activities. The regulation of the ectonucleotidase pathway may play a modulatory role during the evolution of behavioral and pathophysiological changes related to temporal lobe epilepsy.

Posttraining presentation of a flashing light alters retrieval of a two-way active avoidance task in rats.

Rats were trained and tested in a two-way active avoidance task (30 trials, 0.4-mA footshock, 24-h training-test interval). Exposure to an open field with flashing light (60-W lamp, 30 Hz, for 7 min, OFL) 2 h after training caused a retrieval impairment for the avoidance task, a phenomenon called retroactive interference. Animals familiarized with the OFL 24 h before training showed no retrieval impairment when exposed to the OFL 2 h after training. Both adrenal medullectomy (performed 7 to 14 days before training) and dexamethasone treatment (2 mg/kg, injected IP 24 h and 12 h before training) prevented the OFL interfering effect. Time-course experiments revealed that OFL presented either 1 or 4 h after training caused no retrieval deficit, and that animals exposed to the OFL 2 h after training and receiving another OFL presentation 1 or 2 h, but not 4 h, prior to testing had normal retrieval performance. These results suggest: 1) that the retroactive interference caused by presentation of OFL 2 h after training is due to failure of retrieval of the avoidance task since it is counteracted by the pretest presentation to the OFL, 2) that the OFL-induced retrieval interfering effect partly depends on the novelty of the OFL situation, and on the functional integrity of pituitary ACTH and adrenomedullar-dependent mechanisms and 3) that there are different mechanisms involved in posttraining and pretest OFL effects since they present distinct time-courses.