Réplica. Receptores de glutamato de tipo kainato y epilepsia / Reply. Kainate-type glutamate receptors and epilepsy

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[The neurochemistry of epilepsy, inhibitory neurotransmission and experimental models: new perspectives]. / Neuroquímica de la epilepsia, neurotransmisión inhibitoria y modelos experimentales: nuevas perspectivas.

AIMS: The biological mechanisms of epilepsy allow pathophysiological patterns to be established which are essential for the selection of new therapeutic targets. The identification of these mechanisms also provides us with knowledge about the dynamics of neuronal arrangement, synaptogenesis, synaptic transmission and the receptors involved, and even the development of the brain. DEVELOPMENT: Recent advances in neurobiology regarding the GABAergic system point to it as playing a leading role in the pathophysiology of epilepsy. We evaluate the different functional formats of the ionotropic (GABAA) and metabotropic (GABAB) gamma-aminobutyric (GABA) receptors. Although the main function posited is inhibitory, owing to the variability of their location, subunits and neuronal physiology/maturation they can even end up expressing excitatory functions. We discuss the anomalies in the GABAergic system identified in animal models with epilepsy and in brain tissue samples from patients submitted to surgery due to epilepsy. The mechanism inhibiting the activation of GABA receptors is performed by hyperpolarisation achieved by entry of Cl- into the neuron--a process mediated by the cotransporter KCC2, typically expressed in the neuron. Mutations in the KCC2 gene produce mice that are susceptible to seizures. In some animal models it has been found that loop diuretics (furosemide) suppress seizures. Mutations in genes that code for ion channels have been identified in numerous epileptic syndromes and this pushes epilepsy ever further inside the broad group of disorders known as channelopathies. The origin could be polygenetic in many cases. CONCLUSIONS: The GABAergic system seems to situate itself as the main system implicated in the pathophysiology of epilepsy, although conditions that have been considered to be idiopathic up till now could have a polygenic nature.

Neuroquímica de la epilepsia, neurotransmisión inhibitoria y modelos experimentales: nuevas perspectivas / The neurochemistry of epilepsy, inhibitory neurotransmission and experimental models: new perspectives

Objetivo. Los mecanismos biológicos de la epilepsia permiten establecer patrones fisiopatológicos clave para la selección de nuevas dianas terapéuticas. La identificación de estos mecanismos aporta además conocimiento sobre la dinámica de ordenación neuronal, la sinaptogénesis, la transmisión sináptica y los receptores implicados e incluso el desarrollo cerebral. Desarrollo. Los recientes avances neurobiológicos sobre el sistema gabérgico identifican a éste como un agente principal implicado en la fisiopatología de la epilepsia. Evaluamos los distintos formatos funcionales de los receptores g-aminobutíricos ionotrópicos (GABAA) y metabotrópicos (GABAB): aunque se postula una función inhibitoria principalmente, con la variabilidad en su localización, las subunidades y la maduración/fisiología neuronal pueden acabar expresando funciones incluso excitadoras. Se discuten las anomalías en el sistema gabérgico identificadas en modelos animales con epilepsia y muestras cerebrales de pacientes sometidos a cirugía a causa de la epilepsia. El mecanismo inhibitorio de la activación de receptores GABA se lleva a cabo por la hiperpolarización obtenida mediante la entrada de Cl– a la neurona, mediada por el cotransportador KCC2, de expresión típicamente neuronal. Mutaciones en el gen de KCC2 producen ratones susceptibles a crisis. En algunos modelos animales se ha comprobado una supresión de las convulsiones con diuréticos de asa (furosemida). La identificación en múltiples síndromes epilépticos de mutaciones en genes que codifican canales iónicos sitúan a la epilepsia dentro del cada vez más amplio grupo de trastornos conocidos como canalopatías. El origen podría ser poligenético en numerosos casos. Conclusión. El sistema gabérgico parece postularse como el principal sistema implicado en la fisiopatología de la epilepsia, aunque los cuadros hasta ahora considerados idiopáticos podrían tener un carácter poligénico (AU)

Aims. The biological mechanisms of epilepsy allow pathophysiological patterns to be established which are essential for the selection of new therapeutic targets. The identification of these mechanisms also provides us with knowledge about the dynamics of neuronal arrangement, synaptogenesis, synaptic transmission and the receptors involved, and even the development of the brain. Development. Recent advances in neurobiology regarding the GABAergic system point to it as playing a leading role in the pathophysiology of epilepsy. We evaluate the different functional formats of the ionotropic (GABAA) and metabotropic (GABAB) gamma-aminobutyric (GABA) receptors. Although the main function posited is inhibitory, owing to the variability of their location, subunits and neuronal physiology/maturation they can even end up expressing excitatory functions. We discuss the anomalies in the GABAergic system identified in animal models with epilepsy and in brain tissue samples from patients submitted to surgery due to epilepsy. The mechanism inhibiting the activation of GABA receptors is performed by hyperpolarisation achieved by entry of Cl¨C into the neuron ¨Ca process mediated by the cotransporter KCC2, typically expressed in the neuron. Mutations in the KCC2 gene produce mice that are susceptible to seizures. In some animal models it has been found that loop diuretics (furosemide) suppress seizures. Mutations in genes that code for ion channels have been identified in numerous epileptic syndromes and this pushes epilepsy ever further inside the broad group of disorders known as channelopathies. The origin could be polygenetic in many cases. Conclusions. The GABAergic system seems to situate it self as the main system implicated in the pathophysiology of epilepsy, although conditions that have been considered to beidiopathic up till now could have a polygenic nature (AU)

The calcium-binding protein calretinin is a marker of the companion cell layer of the human hair follicle.

BACKGROUND: Ultrastructural studies of the hair follicle show that the outer root sheath (ORS) does not consist of a homogeneous cell population. The innermost cell layer of the ORS, also called the companion layer, is a single cell layer closely associated with the Henle layer of the inner root sheath. OBJECTIVES: To describe the immunohistochemical expression of calretinin, a calcium-binding protein, in the human hair follicle. METHODS: Immunohistochemical studies using two different antisera to calretinin were performed in paraffin-embedded and in frozen scalp specimens using standard techniques. RESULTS: Calretinin immunostaining was consistently and specifically found in the companion cell layer of hair follicles. CONCLUSIONS: These findings provide further evidence to support the notion that the companion layer is not only morphologically, but also immunohistochemically, different from the other cells of the ORS.

Balance entre citocinas pro y antiinflamatorias en estados sépticos / The balance between pro-inflammatory and anti-inflammatory citokines in septic states

Para que la defensa contra la infección se inicie de manera eficaz es necesaria la participación de citocinas con función fundamentalmente proinflamatoria (TNF-α, IL-1 ß, IL-12, IFN-γ, IL-6). La respuesta proinflamatoria inicial está controlada por moléculas antiinflamatorias (el antagonista del receptor de la IL-1 [IL-1 ra], el factor transformador del crecimiento beta [TGF-ß], las interleucinas 4, 6, 10, 11 y 13), y los receptores específicos para la IL-1, el TNF y la interleucina 18. En condiciones fisiológicas, todas estas moléculas sirven como inmunomoduladoras y, por lo tanto, limitan el efecto potencialmente dañino de la reacción inflamatoria. Sin embargo, en condiciones patológicas, la respuesta antiinflamatoria puede ser insuficiente para contrarrestar la actividad inflamatoria o, por el contrario, ser sobrecompensadora e inhibir el sistema inmune y dejar al huésped a merced de la infección. Desde el principio del cuadro de sepsis hasta el vigesimo octavo día y cuando ya han desaparecido la clínica de síndrome de respuesta inflamatoria sistémica (SIRS), el balance global entre las moléculas pro y antiinflamatorias estudiadas apunta hacia un incremento muy importante de estas últimas. El papel del TNF-α y de la IL-1 ß en la sepsis parece ser el de desencadenante, pero ambas carecen de valor patogénico posteriormente. El sTNFR-I, sTNFR-II e IL-1 ra, tienen un gran valor pronóstico y sus niveles se relacionan con el desarrollo de síndrome de disfunción multiorgánica (SDMO) y con cada fallo de órganos. Niveles elevados de IL-10 y de TGF-ß también se relacionan con la mortalidad, aunque de modo más tardío. Futuras intervenciones terapéuticas deberán tener en cuenta que la sepsis es un proceso dinámico

The participation of citokines with a predominant pro-inflammatory function (TNF-α, IL-1 ß, IL-12, INF-γ, IL-6) is necessary for the effective beginning of defense mechanisms against infection. Initial pro-inflammatory response is controlled by anti-inflammatoriy molecules (IL-1 receptor antagonist [IL-1 ra], transforming growth factor-beta [TGF-ß], interleukins 4, 6, 10, 11 and 13), and the specific receptors for IL-1, TNF, and interleukin 18. In physiological conditions, all these molecules serve as immunemodulators and as a result they limit the potentially harmful effect of the inflammatory reaction. However, in pathological conditions anti-inflammatory response can be insufficient in order to counteract the inflammatory activity or, on the contrary, can be excesive with immune system inhibition so that fails to help the host faced with the infection. From the start of sepsis symptomatology until the day 28, and when clinical disturbances of SIRS are already gone, the global balance among the pro- inflammatory and anti-inflammatory molecules studied aims at a very important increase of anti-inflammatory molecules. The role of TNF-α and IL-1 ß in sepsis seems to be that of triggering factors, but subsequently both lack of pathogenic role. sTNFR-I, sTNFR-II and IL-1 ar have great prognostic value and their levels are related to the development of MODS and to the failure of every organ system. Higher levels of IL-10 and TFR-ß are also related to mortality, although in late phases. Future therapeutic interventions should take into account the fact that sepsis is a dynamic process

A study on the human mitochondrial RNA polymerase activity points to existence of a transcription factor B-like protein.

In the present work, the RNA polymerase activity of the human mitochondrial RNA polymerase mature protein (h-mtRPOLm) is shown, and its molecular activity calculated (2.1+/-0.9 min(-1)). An activity analysis of h-mtRPOLm and deleted versions of it has demonstrated that the entire recombinant protein is required for this activity. In addition, h-mtRPOLm alone or in presence of the known mitochondrial transcription factors (human mitochondrial transcription factor A and/or human mitochondrial transcription termination factor) is not able to initiate transcription from the specific human mitochondrial promoters pointing to the existence of a human mitochondrial transcription factor B-like protein.