Neurobehçet disease: clinical and demographic characteristics.

BACKGROUND: Neurobehçet disease (NBD) is a rare complication of Behçet disease (BD) but with important burdens of morbidity and mortality. Little is known about this complication because there are no validated diagnostic criteria, and all the studies have small number of patients. The prevalence reported normally ranges between 5% and 15% and it is more frequent amongst men between 20 and 40 years old. The typical presentations include focal parenchymal lesions, vascular thrombosis, arterial vasculitis, and aseptic meningo-encephalitis. METHODS: We retrospectively studied medical histories of all patients admitted to the hospital and discharged from it with diagnosis of BD from January 1996 to September 2009. NBD was defined as having neurological and/or psychiatric symptoms with compatible abnormalities in MRI and/or cerebrospinal fluid and without another possible explanation for their symptoms. RESULTS: Behcet disease was diagnosed in 25 patients and seven from these patients fulfilled our criteria of Neurobehcet disease (28%). Patients with NBD were significantly younger at the onset of their symptoms and had a significantly longer evolution until diagnosis and treatment compared to patients with non-Neuobehçet disease. Six presented a relapsing-remitting pattern, with a good outcome with corticosteroids. CONCLUSIONS: As reported in previous studies, progressive course was less frequent, with only one case, and had a more aggressive disease. Brainstem involvement bears a poorer prognosis because it is linked with a progressive evolution. In our series, NBD complication was not that infrequent. It is very important to be highly suspicious of this possibility to start early a correct treatment.

Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.

Many neurons receive a continuous, or 'tonic', synaptic input, which increases their membrane conductance, and so modifies the spatial and temporal integration of excitatory signals. In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA (gamma-aminobutyric acid) gives rise to a persistent conductance mediated by the GABA A receptor that also modifies the excitability of granule cells. Here we show that this tonic conductance is absent in granule cells that lack the alpha6 and delta-subunits of the GABAA receptor. The response of these granule cells to excitatory synaptic input remains unaltered, owing to an increase in a 'leak' conductance, which is present at rest, with properties characteristic of the two-pore-domain K+ channel TASK-1 (refs 9,10,11,12). Our results highlight the importance of tonic inhibition mediated by GABAA receptors, loss of which triggers a form of homeostatic plasticity leading to a change in the magnitude of a voltage-independent K + conductance that maintains normal neuronal behaviour.

Expression of the neuronal calcium sensor protein family in the rat brain.

The neuronal calcium sensor proteins are members of the calcium-binding protein superfamily. They control localized calcium signalling on membranes and may make G-protein cascades sensitive to cytosolic calcium. The family members are recoverin (visinin, S-modulin), neuronal calcium sensor-1 (frequenin), hippocalcin, neuronal visinin-like protein-1 (visinin-like protein, neurocalcin-alpha), neuronal visinin-like protein-2 and neuronal visinin-like protein-3. Recoverin is expressed only in the retina and pineal gland. Using in situ hybridization, we mapped the expression of the other neuronal calcium sensor protein genes in the adult rat brain. Neuronal visinin-like protein-1 messenger RNA has a widespread distribution and is abundant in all brain areas except the caudate-putamen. Neuronal calcium sensor-1 gene expression is pan-neuronal. Neuronal calcium sensor-1 messenger RNA is present in the dendrites of hippocampal pyramidal and granule cells, suggesting a specific role in dendritic function. Hippocalcin and neuronal visinin-like protein-2 are mainly expressed in the forebrain and have similar expression patterns (neocortex, hippocampus and caudate-putamen). Neuronal visinin-like protein-3 has the most restricted expression; its highest expression level is in the cerebellum (Purkinje and granule cells). However, the neuronal visinin-like protein-3 gene is also expressed in many ventral nuclei throughout the fore- and midbrain, in the medial habenulae, and in the superior and inferior colliculi. The neuronal calcium sensor proteins are a relatively unexplored family of Ca(2+)-binding proteins. They are likely to be involved in many diverse areas of neuronal signalling. In this paper, we describe their expression in the rat brain as determined by in situ hybridization. As all five neuronal calcium sensor protein genes have distinctive expression patterns, they probably perform specific functions.

Towers of Hanoi and London: is the nonshared variance due to differences in task administration?

Although it has been assumed that the Tower of Hanoi and Tower of London are more or less interchangeable tasks dependent on executive function, a series of studies in our laboratory have indicated substantial nonshared variance between the performances on the two tasks. The purpose of the present study was to examine how much methods of administration, such as number of trials per problem, contribute to this nonshared variance. A new one-trial version of the Tower of Hanoi was developed to be identical to the Tower of London in four procedural characteristics. The one-trial version of the Tower of Hanoi was administered to 39 normal adults along with the traditional Tower of Hanoi and the Tower of London-Revised in two test sessions 5-7 weeks apart. The correlations between the two tasks were in the same range as found previously with the traditional task, indicating that administration differences do not account for the nonshared variance between the tasks. A reliability analysis of the one-trial tasks showed poor internal consistency. Also, the internal consistency of the 6-trial tower was artificially inflated by aspects of the administration and scoring procedures. Moreover, this task exhibited a ceiling effect on repeated testing. These results suggest that it would be of value to redesign the one-trial Tower of Hanoi systematically to increase its reliability and, potentially, its validity as a measure of executive functions.

Autoradiographic characterisation of beta-adrenoceptors in chick brain using [3H]CGP 12177.

An autoradiographic method for labelling beta(1)- and beta(2)-adrenoceptors using [3H]CGP 12177 as a radioligand is described as well as the procedure for an autoradiographic saturation kinetic study. The method afforded higher quality autoradiographs as well as an improvement in the tissue preservation when assayed in birds and chick embryos. The results confirmed the K(d) values previously reported for membrane homogenate binding. The use of different radioligands to characterise beta-adrenoceptors, the higher B(max) values found with autoradiography than those obtained by the membrane homogenate binding method and the typical errors in quantifying autoradiography are discussed. It is concluded that the method described here considerably improves autoradiographic beta-adrenergic characterisation.

Effect of surgical stress on benzodiazepine receptors as a consequence of placebo pellet implantation in rat: an autoradiographic study.

This paper reports modifications in benzodiazepine (BZ) receptors induced by minimally invasive surgery, such as pellet implantation, a widely used surgical process for chronic drug administration. The intrinsic stress induced by this manipulation on BZ receptors was analysed in an autoradiographic saturation study determining the affinity (K(D)) and total number (Bmax) of binding sites of a number of brain areas from the mesencephalon, cerebral cortex, hippocampus, and cerebellum. The radioligand used for the study was [3H]flunitrazepam, which permitted overall characterization of BZ binding sites. Use of the specific BZ1 agonist zolpidem as an inhibitor of this radioligand permitted the direct characterization of subtype 2 (BZ2) and the indirect characterization of subtype 1 receptor (BZ1). Significant increases in Bmax and K(D) values were observed in pellet-implanted animals with respect to those not implanted. The results support the notion of an up-regulation of these receptors, mainly in BZ1 receptors, following sustained desensitization as a result of the surgical stress induced by pellet implantation.

A comparative study of the beta-adrenoceptors in higher song nuclei of birds.

The present study analyses the presence of beta-adrenoceptors in the main telencephalic song nuclei of the goldfinch and parakeet, species belonging to the two most important groups of birds that reproduce learned songs: oscine songbirds and parrots, respectively. Brains of both species sectioned at appropriate levels were used to perform autoradiographic saturation studies using [3H]CGP 12177 as a radioligand. The results show similar K(D)values for both species (0.1-0.3 nM) and striking differences in Bmax. Thus, beta-adrenoceptors are abundant in the telencephalic vocal control nuclei of the parakeet but not of the goldfinch. The predominance of the beta2 subtype in the song nuclei of both species is also confirmed. We conclude that these receptors could be involved in functions unique to the parakeet and therefore may contribute to the greater flexibility of the vocal system of this species. Our findings also support the possible involvement of beta-adrenoceptors in the evolution of the avian brain.

Seizure-refractory period after a single stimulation and inhibition of seizures after repetitive stimulation in the gerbil: effects on blood cortisol levels.

PURPOSE: To determine the epileptic response of gerbils to external shock stimulus, assessing blood cortisol levels as a parameter to determine stress conditions. METHODS: Five sets of two-month-old Mongolian gerbils were stimulated to elicit seizures by the clapping of a sheaf of papers. Stimulation was done once a week over a 10-week period to obtain a stable situation and a similar response in all the animals. Four of the sets were killed to collect blood samples: those not manipulated; those stimulated twice a day for 5 days; those stimulated once to obtain samples immediately after seizure recovery; and those stimulated once to obtain samples 30 min after seizure recovery. Blood samples from the fifth set of animals were taken in vivo from the retro-orbital plexus. RESULTS: Eliciting seizures with this stimulus, twice a day in a repetitive way, prevented further induced seizures from the second day of stimulation on. Changes in the gerbils' behavior--from exploratory to escape mode--were also observed. The blood cortisol levels found in the sets of animals killed without induced seizures were similar to the others, regardless of whether the animals had been subjected to repetitive stimulation. Additionally, significant decreases in blood cortisol levels were detected in the animals killed immediately and 30 min after recovering from an induced epileptic episode. CONCLUSIONS: The normal refractory period in gerbils can be estimated at 1 h. The lack of correlation between cortisol levels and the inhibition of seizure-elicitation through repetitive stimulation supports the environmental and exploratory hypothesis of seizure generation rather than a stress hypothesis.

Pre- and post-hatching developmental changes in beta-adrenoceptor subtypes in chick brain.

This study used [3H]CGP 12177 as a radioligand to determine the beta1 and beta2-adrenoceptor changes from the pre-hatching E17 stage, where the beta2 subtype is first detected, to the post-hatching P30 stage. While beta1-adrenoceptors were found to be present from E18 and were limited to cerebellum and hyperstriatum in all stages studied, beta2-adrenoceptors showed a wider distribution throughout the brain. In most of the structures analysed both beta1- and beta2-adrenoceptor binding values reached a maximum in the P2 stage, followed by a decrease over the following days. A second increase in both subtypes was detected again in the P15 and P30 stages. These results support the notion of a specific role for beta-adrenoceptors in neural plasticity in the first week after hatching and suggest that the beta2 subtype is the main adrenoceptor in chick brain throughout its development.

A comparative study of the beta-adrenoceptors in higher visual centres of birds.

This report describes the distribution of beta-adrenergic receptors in the telencephalic visual nuclei of chick, duck, pigeon, parakeet and goldfinch using [3H]CGP 12177 (4-3-t-butylamino-2-hydroxypropoxy-[5,7(3)H] benzimidazol-2-one) as a radioligand. The results reveal a predominance of the beta2-adrenoceptor subtype in all the species studied and that this subtype fits the pharmacological profile described for mammals. It is also demonstrated that the autoradiographic interspecific differences described in previous studies are due to changes in Bmax, while KD values remain in a similar range (0.1-0.6 nM). The distribution of beta-adrenoceptors was fairly similar in the areas of the visual Wulst of all five species studied while striking differences were found in the ectostriatum, the higher centre of the tectofugal pathway. Our findings support a role for ectostriatal beta-adrenoceptors in the visual adaptation and evolution of birds.

A comparative study of alpha2- and beta-adrenoceptor distribution in pigeon and chick brain.

The pharmacological properties and anatomical distribution of alpha2-, beta1- and beta2-adrenoceptors in pigeon and chick brains were studied by both homogenate binding and tissue section autoradiography. [3H]Bromoxidine (alpha2-adrenoceptor-), [3H]CGP 12177 (beta-adrenoceptor) and [125I]cyanopindolol (beta-adrenoceptor) were used as radioligands. In both species, [3H]bromoxidine binding to avian brain tissue showed a pharmacological profile similar to that previously reported for alpha2-adrenoceptors in mammals. Regarding the anatomical distribution, the areas with the highest densities of alpha2-adrenoceptors in the pigeon brain included the hyperstriatum, nuclei septalis, tectum opticum and some brainstem nuclei. Most beta-adrenoceptors found in tissue membranes and sections from chick and pigeon brain were of the beta2 subtype, in contrast to what has been reported in the mammalian brain, where the beta1 subtype is predominant. A striking difference was found between the two species regarding the densities of these receptors: while pigeon brain was extremely rich in [125I]cyanopindolol binding throughout the brain (mainly cerebellum) in the pigeon, the levels of labelling in the chick brain were much lower; the exception was the cerebellum, which displayed a higher density than other parts of the brain in both species. Overall, our results support the proposed anatomical equivalences between a number of structures in the avian and mammalian encephalon.

Antecedent tone presentation differentially alters the rate of amygdala kindling: continued exposure is not required for this region-specific effect.

Recently we reported that antecedent tone presentation significantly delays the rate of amygdala kindling when it precedes and overlaps with every kindling trial. The goal of the present study was to determine if there is a minimal number of pairings required for the tone to exert its effects or if continued exposure is required. To investigate this, male Long-Evans hooded rats were implanted with a bipolar electrode in the right amygdala and assigned to a Tone, No Tone, or Tone Discontinued group and kindled once daily. The Tone group was exposed to the auditory stimulus on every kindling trial, while the Tone Discontinued group received it for only the first 5 days and subsequently was kindled in the same manner as the No Tone group (i.e., not exposed to the tone while receiving the kindling stimulation). In agreement with our earlier report, antecedent tone presentation significantly delayed seizure progression for subjects kindled in the central nucleus. However, the antecedent tone also significantly accelerated epileptogenesis for rats kindled in the amygdalostriatal transition area and produced no significant difference for those kindled in the basolateral nucleus. Furthermore, presentation of the tone was not required with every kindling trial in order for these effects to be seen, suggesting that a critical period might exist early in the kindling process during which epileptogenesis is acutely vulnerable to intervention. Additional research is necessary to determine the nature of these interventions and what effects they may have on seizure genesis.

An autoradiographical saturation kinetic study of the different benzodiazepine binding sites in rat brain by using [3H] flunitrazepam as a radioligand.

The present study reports on the equilibrium association constant (KD) and receptor density (Bmax) values of a number of brain areas from the mesencephalon, cerebral cortex, hippocampus, and cerebellum for the overall benzodiazepine (BZ) binding sites as well as for benzodiazepine binding site subtype 1 (BZ1) and subtype 2 (BZ2), determined by autoradiographical procedures using [3H] flunitrazepam. The differences between BZ1 and BZ2 binding sites were analyzed using the specific BZ1 agonist zolpidem as inhibitor of the radioligand. Statistically significant differences in the affinities of BZ2 with respect to BZ and BZ1 binding site were mainly found in cortical layers when pKD (negative logarithms of KD values) values were compared (ANOVA-SNK test). The distribution of Bmax, as well as the percentages of BZ1 and BZ2 and Hill coefficients which, surprisingly, are always close to 1 (> 0.9) for all the saturation kinetics analyzed, are also described. The possibility of heterogeneity related to anatomical distribution in the different subtypes is discussed.

Identification of beta-adrenoceptors in rat lymph nodes and spleen: an autoradiographic study.

The anatomical localization of beta 1 and beta 2-adrenoceptors was studied in rat lymphoid tissues by quantitative autoradiography using [125I]cyanopindolol as a ligand. In lymph nodes, a significant density of these receptors was found in the medullary cords and the interfollicular cortex, while only low densities were observed in the paracortex. No detectable binding appeared in the remaining areas. In the spleen, these receptors were mainly localized in the capsule, marginal zone of white pulp and red pulp, while the labelling over the white pulp was extremely low. The subtype beta 2 was predominant in both lymph nodes and spleen. The results suggest that beta-adrenoceptors are present in mature cells in lymphoid tissues and are probably not involved in homing mechanisms.

Effect of morphine and abstinence syndrome on [3H]bromoxidine binding to alpha 2-adrenoceptors in rat brain.

At 4 days after the implantation of two subcutaneous 75 mg morphine pellets in the back skin, rats were morphine-dependent. In the three layers studied in the occipital cortex we found that the values of the alpha 2-adrenergic agonist [3H]bromoxidine binding increased with respect to animals implanted with placebo pellets. Typical behavioral and physiological symptoms of the abstinence syndrome appeared 30 minutes after administration of naloxone, [3H]bromoxidine binding values being similar to those obtained in animals implanted with placebo pellets. The pattern of response of the [3H]bromoxidine binding was similar in the hippocampus and the superficial gray layer of the superior colliculus of the mesencephalon, but the differences were not statistically significant in these areas. This paper concludes that exist brain regional differences in the alpha 2-adrenoceptors response under morphine-treatment and possibly under naloxone-induced morphine abstinence syndrome.