Differential effect of serum from bipolar versus schizophrenic patients on spontaneous acetylcholine release at mammalian neuromuscular junction.

OBJECTIVE: The diagnosis of bipolar disease frequently requires a long time since the age of onset, especially because the disease is misdiagnosed with schizophrenia. The aim of the present work was to investigate whether sera from bipolar patients have an active substance that allows making a fast identification of the disease. METHODS: Sera from healthy volunteers, euthymic and non-stabilized bipolar patients, and schizophrenic patients were passively transferred into CF1 mice and after 2 day injections, MEPP frequency from diaphragm muscles was recorded. The same procedure was performed with sera fraction of high and low MW (cut-off 3000). RESULTS: Sera from non-stabilized bipolar patients induced a decreased MEPP frequency and occluded the presynaptic inhibitory effect of the specific adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyl-adenosine (CCPA) in the recipient mice, while in the euthymic bipolar group spontaneous secretion reached control values although the action of CCPA was still prevented. Similar results were obtained with low MW sera fraction from euthymic and non-stabilized bipolar patients. The addition of adenosine deaminase to the sera fraction prevented the modification of spontaneous ACh release. In mice injected with sera from schizophrenic patients, MEPP frequency was within control values and CCPA induced its typical inhibitory action. CONCLUSIONS: These results indicate that bipolar patients contain in their blood an active substance compatible with adenosine, which was able to modify spontaneous ACh release in the recipient mice. This effect was not observed with sera from healthy volunteers and schizophrenic patients. The increase of adenosine concentration may result from synaptic hyperactivity that presumably plays a role in the symptoms of bipolar disorder and/or may derive from peripheral cells through a more general mechanism. SIGNIFICANCE: The different results obtained with bipolar and schizophrenic sera raise the possibility that the passive transfer model could be used as a diagnostic test in the future.

Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction.

1. At the mouse neuromuscular junction, adenosine (AD) and the A(1) agonist 2-chloro-N(6)-cyclopentyl-adenosine (CCPA) induce presynaptic inhibition of spontaneous acetylcholine (ACh) release by activation of A(1) AD receptors through a mechanism that is still unknown. To evaluate whether the inhibition is mediated by modulation of the voltage-dependent calcium channels (VDCCs) associated with tonic secretion (L- and N-type VDCCs), we measured the miniature end-plate potential (mepp) frequency in mouse diaphragm muscles. 2. Blockade of VDCCs by Cd(2+) prevented the effect of the CCPA. Nitrendipine (an L-type VDCC antagonist) but not omega-conotoxin GVIA (an N-type VDCC antagonist) blocked the action of CCPA, suggesting that the decrease in spontaneous mepp frequency by CCPA is associated with an action on L-type VDCCs only. 3. As A(1) receptors are coupled to a G(i/o) protein, we investigated whether the inhibition of PKA or the activation of PKC is involved in the presynaptic inhibition mechanism. Neither N-(2[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89, a PKA inhibitor), nor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H-7, a PKC antagonist), nor phorbol 12-myristate 13-acetate (PHA, a PKC activator) modified CCPA-induced presynaptic inhibition, suggesting that these second messenger pathways are not involved. 4. The effect of CCPA was eliminated by the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) and by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester epsilon6TDelta-BM, which suggests that the action of CCPA to modulate L-type VDCCs may involve Ca(2+)-calmodulin. 5. To investigate the action of CCPA on diverse degrees of nerve terminal depolarization, we studied its effect at different external K(+) concentrations. The effect of CCPA on ACh secretion evoked by 10 mm K(+) was prevented by the P/Q-type VDCC antagonist omega-agatoxin IVA. 6. CCPA failed to inhibit the increases in mepp frequency evoked by 15 and 20 mm K(+). We demonstrated that, at high K(+) concentrations, endogenous AD occupies A1 receptors, impairing the action of CCPA, since incubation with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A(1) receptor antagonist) and adenosine deaminase (ADA), which degrades AD into the inactive metabolite inosine, increased mepp frequency compared with that obtained in 15 and 20 mm K(+) in the absence of the drugs. Moreover, CCPA was able to induce presynaptic inhibition in the presence of ADA. It is concluded that, at high K(+) concentrations, the activation of A(1) receptors by endogenous AD prevents excessive neurotransmitter release.

Effect of amyotrophic lateral sclerosis serum on calcium channels related to spontaneous acetylcholine release.

OBJECTIVES: The aim of this work was to further investigate the effect of sera from sporadic amyotrophic lateral sclerosis (ALS) patients on miniature end-plate potentials (MEPP) frequency, by the mouse passive transfer model, and to study whether the transferred serum induces any change in the sensitivity of the L-type voltage-dependent calcium channels (VDCC) to its specific blocker Nitrendipine. METHODS: A total of 35 CF1 mice were divided into 3 groups: (a) ALS group receiving sera from 15 patients that had been clinically and electromyographycally diagnosed as having sporadic ALS; (b) normal group receiving sera from 13 healthy volunteers and from 3 disease control patients, and (c) control group, which was kept untreated. Animals in groups (a) and (b) received daily intraperitoneal injection of 0.5-1ml of serum for 3 days, and 24h later the left hemidiaphragm was excised for electrophysiological recordings. RESULTS: Analysis of MEPPs frequency recorded from ALS group showed that 3 of them induced an increase in spontaneous neurotransmitter release while in 4 a decrease was observed, suggesting that sera alter spontaneous secretion as result of an increased or decreased Ca(2+) influx through the normally involved N-type or L-type VDCC, respectively. When the effect of Nitrendipine, an L-type VDCC blocker, was studied on ALS sera-injected mice, we found variable responses to the drug: only two mice showed control sensitivity to Nitrendipine, while in 7 its action was lower and surprisingly in 4 was greater than that without the drug. CONCLUSIONS: These results suggest that ALS sera contain factor(s) that are able to modify spontaneous neurotransmitter release by altering calcium current through L-type and N-type VDCC, and even inducing changes in the sensitivity to the L-type VDCC blocker.

[Yawning and temporal lobe epilepsy]. / Bostezo y epilepsia del lóbulo temporal.

Temporal lobe epilepsy is a partial epileptic disorder in which mesial structures are responsible for the principal ictal symptoms. Its characteristic feature is the recurrence of simple and complex partial seizures, associated with postictal confusion and amnesia of the event. The facilitating effect of NREM sleep on the propagation of the seizure, as well as the sleep abnormalities provoked by epilepsy were evident in our two patients. Yawning is a physiological reflex induced by arousal and drowsiness and may appear in different neurological conditions. Its relation with epilepsy of limbic origin has been rarely reported. We describe in a 95 year old male patient, the occurrence of yawning followed by complex partial seizure during a state of drowsiness. His EEG showed independent bilateral interictal foci of temporal sharp waves and after being medicated with carbamazepine 400 mg/day, the episode did not recur. Another patient, a 17 year old female, displayed complex partial seizures and secondarily generalized seizures with yawning during the posictal period, after naps. The EEG was normal and her polysomnography showed bilateral synchronous temporal spikes and slow waves with secondarily generalization during stage 2 of NREM sleep that produce paroxysmal microarousals and increased stages 1 and 2 of NREM sleep and REM sleep diminished. After being medicated with divalproex sodium 750 mg/day, she suffered no further seizures. Temporal lobe epilepsy, sleep-wake cycles and yawning seem not only to share the same anatomic structures but also the same neurochemical mechanisms. The fact that endogenous opiods are considered as part of a protective system that stop and prevent seizures may allow us to postulate that yawning would be the expression of the endogenous opiods induced mechanisms that stop and prevent the recurrence of the temporal lobe epilepsy. Another hypothesis may be that this is only a particular form of temporal lobe epilepsy.

[Yawning]. / Bostezo.

Yawning is a normal reflex triggered by arousal, drowsiness, boredom, hunger and emotional conditions and it is associated to several neurological diseases and drug abuse. Its wide presence in the phylogenetic vertebrate scale and even in human fetuses as young as 12 weeks directed the search for the common anatomic and biochemical mechanisms involved. The demonstration that yawning is not connected with high CO2 or low O2 blood levels left aside a prevalent metabolic hypothesis. Its close relationship with the sleep-wake cycle, specially in moments previous to falling asleep and after awaking has been related to changes in personal situation and activity. A single component of this reflex which is to be found exclusively in humans, is the fact that yawning is contagious. Thus, it is considered a component of the adaptative mechanism that is part of the surveillance reflex, becoming a significant paralinguistic evolutive expression aimed at protection and social cohesion. The common anatomical structures and neurochemical systems taking part in yawning, the sleep-wake cycle and the temporal lobe epilepsy may imply that yawning results from a set of protective systems induced by endogenous opiods which intervene in the inhibition and prevention of the temporal lobe epileptic seizures.

Fibrinolytic and factor XIII activity in subarachnoid hemorrhagge

The balance between fibrinolytic activity and coagulation mechanisms seems to play an important role in the rebleeding of a subarachnoid hemorrhage (SAH) due to aneurysmatic rupture. In the present paper we describe our findings in a group of patients (n10)with SAH. The plasmatic levels of fibrinogen and their degradation products (FDP), APTT, prothrombin activity and factor XIII were determined within 72 hours of initial bleeding, or of eventual rebleeding. Factor XIII activity in the first bleeding was 82.1+4 percent, while the levels of FDP were 3.8+1mug/ml. In patients presenting rebleeding (n4), Factor XIII activity was 67.3+4.5 percent the day it manifested, which is significantly less than the values previously observed (p<0.01), while the FDP level was 4.1+2mug/ml. The decrease of factor XIII activity suggests an important role as regards clot stability in rupture location. It is also possible to attribute a rebleeding predictive value to its activity reduction.

Bostezo / Yawning

El bostezo es un reflejo normal desencadenado por el despertar, el adormecimiento, el aburrimiento, el hambre y los conflictos emocionales, estando también asociado a diversas enfermedades neurológicas y abuso de drogas. Su amplia representación en la escala filogenética de los vertebrados, así también como la presencia en el hombre en edades tan tempranas como las 12 semanas de vida intrauterina, condujo a investigar los mecanismos comunes anátomo-bioquímicos involucrados en este proceso. La demostración que el bostezo no se genera en respuesta a niveles altos de CO 2 o bajos de O 2 en sangre, desechó la hipótesis metabólica ampliamente difundida. Su estrecha relación con el ciclo sueño-vigilia, especialmente en los momentos previos al dormir y siguiendo al despertar, está vinculado a cambios de estado y de actividad. El único componente de este reflejo que se encuentra sólo en el hombre, es que puede contagiarse. Por lo tanto, se lo considera como constituyente del mecanismo adaptativo de respuesta al stress, formando parte del reflejo de vigilancia, el cual ha adquirido un valor paralingüístico con la evolución, destinado a la protección y cohesión social. Las estructuras anatómicas y los sistemas neuroquímicos comunes intervinientes en el bostezo, el ciclo sueño-vigilia y la epilepsia del lóbulo temporal, nos permitirían postular que el bostezo sería la expresión de un sistema de protección inducido por los opiáceos endógenos, que actuarían en la inhibición y prevención de las crisis epilépticas del lóbulo temporal.

Bostezo y epilepsia del lobulo temporal / Yawning and temporal lobe epilepsy

Temporal lobe epilepsy is a partial epileptic disorder in which mesial structures are responsible for the principal ictal symptoms. Its characteristic feature is the recurrence of simple and complex partial seizures, associated with postictal confusion and amnesia of the event. The facilitating effect of NREM sleep on the propagation of the seizure, as well as the sleep abnormalities provoked by epilepsy were evident in our two patients. Yawning is a physiological reflex induced by arousal and drowsiness and may appear in different neurological conditions. Its relation with epilepsy of limbic origin has been rarely reported. We describe in a 95 year old male patient, the occurrence of yawning followed by complex partial seizure during a state of drowsiness. His EEG showed independent bilateral interictal foci of temporal sharp waves and after being medicated with carbamazepine 400 mg/day, the episode did not recur. Another patient, a 17 year old female, displayed complex partial seizures and secondarily generalized seizures with yawning during the posictal period, after naps. The EEG was normal and her polysomnography showed bilateral synchronous temporal spikes and slow waves with secondarily generalization during stage 2 of NREM sleep that produce paroxysmal microarousals and increased stages 1 and 2 of NREM sleep and REM sleep diminished. After being medicated with divalproex sodium 750 mg/day, she suffered no further seizures. Temporal lobe epilepsy, sleep-wake cycles and yawning seem not only to share the same anatomic structures but also the same neurochemical mechanisms. The fact that endogenous opiods are considered as part of a protective system that stop and prevent seizures may allow us to postulate that yawning would be the expression of the endogenous opiods induced mechanisms that stop and prevent the recurrence of the temporal lobe epilepsy. Another hypothesis may be that this is only a particular form of temporal lobe epilepsy

The effect of verapamil and Ca free solution on mechanical and electrical properties in fast twitch mammalian skeletal muscle

Fueron estudiados los efectos del verapamil (0.01-0.1 mM) y de la solución libre de Ca (0 Ca, 3 mM MgCl2, 5 mM EGTA) sobre las propiedades eléctricas y mecánicas del músculo extensor digitorum longus de rata. La solución libre de Ca redujo las tensiones de la contracción simple y tetánica. El verapamil no afectó la respuesta a pulsos simples, pero a medida que la frecuencia de estimulación se incrementó, la tensión pico se redujo gradualmente: efecto frecuencia-dependiente. Ambas soluciones disminuyeron significativamente la tensión de la contractura por cafeína (30 mM). Se observó que las fibras en solución libre de Ca se despolarizó (6 mV) y las +dv/dt. -dv/dt y el "overshoot" del potencial de acción tambén fueron reducidos. En cambio, el verapamil no afectó el potencial de reposo. Las fibras expuestas a 0.1 mM de verapamil perdieron la capacidad de responder a altas frecuencias de estimulación. Concentraciones inferiores de verapamil (0.01 mM) no afectaron la respuesta repetitiva, pero la tensión tetánica disminuyó. Estos hallazgos sostienen parcialmente la hipótesis acerca de la dependencia del músculo esquelético de mamífero del Ca extracelular. El verapamil tendría varios mecanismos de acción: a) bloquente de los canales de Ca; b) efecto anestésico local; c) inhibidor de la liberación de Ca desde el retículo sarcoplásmico

Neuropatia paraneoplasica con anti-Hu positivo / Paraneoplasic neuropathy with positive anti-Hu

Comunicamos una paciente de 72 años de edad, que presentó inicialmente una neuropatía sensitiva pura y detección de anticuerpos anti-Hu. Comenzó un año previo a su internación con parestesias y disestesias en los 4 miembros. Meses después se agregó inestabilidad para la marcha, y un mes antes de la consulta disminución de fureza en miembros inferiores. El examen neurológico mostró anisocoria con diámetro pupilar derecho de 3 mm y 5 mm para el izquierdo , con fotomotor y consensual abolido bilateralmente; la acomodación se hallaba presente en el ojo derecho. Anestesia en bota y guante, e hipoestesia a todas las formas de sensibilidad en toda la extensión de los 4 miembros. Los reflejos osteotendinosos se hallaban abolidos, y la fuerza estaba levemente disminuida en los músculos flexores y extensores de ambos pies. Se observó movimentos involuntarios (pseudoatetosis) en manos y pies. El estudio neurofisiológico mostró una neuropatía desmielinizante. La determinación de anticuerpos anti-Hu fue positiva (técnica de Western blot - Athena Diagnostics). La tomografía computada (TC) abdominal evidenció metástasis abdominales. La TC de tórax mostró una masa heterogénea en lóbulo inferior derecho y adenomegalia retrocavapretraqueal. La anatomía patológica mostró un carcinoma de células pequeñas. La paciente falleció a los 8 días de externada. El caso corresponde a una polineuropatía sensitiva, eventualmente mixta, que precedió en un año a la detección del tumor pulmonar. En este caso, la clínica fue de curso indolente, con presencia de anticuerpos anti-Hu.

Dolicoectasia de las arterias intracraneales: adelantos en imagenes y terapeutica / Dolichoectatic intracranial arteries: advances in images and therapeutics

Las dolicoectasias de las arterias intracraneanas es una entidad caracterizada por la dilatación y elongación de las arterias intracraneales, siendo la base del encéfalo el sitio más afectado. Su incidencia es menor del 0,05 por ciento y representan el 7 por ciento de los aneurismas intracraneanos. Predomina en el sexo masculino, habitualmente adultos de más de 40 años y con historia de hipertensión arterial. La presentación clínica es variada dependiendo del área vascular afectada. Si se afecta el territorio carotídeo predominan los cuadros isquémicos, mientras que cuando el afectado es el vertebrobasilar, los fenómenos compresivos sobre el tronco cerebral y/o pares craneales son más frecuentes. Es rara la ruptura de esta malformación ocasionando hemorragia intracraneana, así como también la producción de trastornos neurovegetativos. La anatomía patológica muestra engrosamiento de la pared arterial, degeneración hialina de la capa muscular, esclerosis de la íntima en parches y pérdida de la membrana elástica interna, esto último en forma casi constante. La metodología diagnóstica ha mejorado notablemente con la introducción de la tomografía computada, la resonancia magnética (RM) y la angiografía por RM. La angiografía convencional y por substracción digital dejó de ser necesaria, excepto en los casos en que se sospecha aneurisma sacular coexistente, evidencia de hemorragia subaracnoidea, o se decida tratamiento quirúrgico de la malformación vascular. El tratamiento quirúrgico endovascular consiste en la colocación de balón y espirales de platino. El tratamiento quirúrgico extravascular pasa por la oclusión arterial, y la envoltura de la malformación y clipado de refuerzo. El pronóstico es variable dependiendo de la edad del paciente, la precocidad en el diagnóstico y el manejo de los factores de riesgo, aunque en general presentan una evolución poco favorable

Linfoma primario del sistema nervioso central: localizacion infratentorial y prolongada sobrevida / Primary CNS lymphoma: infratentorial localization and prolonged survival

Se describe el caso de una paciente de 35 años de edad, con linfoma primario del sistema nervioso central de localización infratentorial. Una inicial resonancia magnética (RM) reveló la lesión en bulbo, protuberancia, pedúnculos cerebelosos y vermis cerebeloso. Aunque durante el 1er año no se efectuó tratamiento, una posterior RM mostró menor extensión del tumor. Posteriormente la paciente recibió corticoides y 12 meses después, ya aceptada la biopsia estereot xica, pudo comprobarse un linfoma B difuso no Hodgkin. Se instituyó tratamiento radiante, llegando a una dosis total de 50 Gy. Durante 5 años la paciente tuvo una buena calidad de vida, con una sobrevida actual de 79 meses.

Diagnostico y tratamiento de la myasthenia gravis: experiencia 1974-1992 / Diagnosis and treatment of myasthenia gravis: experience 1974-1992

En el Hospital Ramos Mejía entre los años 1974 y 1992, se asistieron 118 pacientes con myasthenia gravis (MG). En la población adulta se observó un predominio en el sexo femenino de 1,87:1 y una mayor prevalencia en la tercera década de la vida. Las pruebas diagnósticas resultaron positivas en el siguiente orden: medición de la amplitud de los potenciales miniatura de placa (mepp's) en el ratón inyectado con suero de paciente miasténico (100 por ciento), prueba del cloruro de Edrofonio (97 por ciento), estímulo repetitivo (83 por ciento) y anticuerpos antirreceptor colinérgico (78 por ciento). Estas dos últimas pruebas resultaron positivas más frecuentemente en las formas generalizadas que en las formas oculares de la enfermedad. La neumomediastinografía con tomografía lineal mostró mayor coincidencia con el estudio anatomopatológico del timo que la TAC. La medida terapéutica más efectiva resultó ser la inmunosupresión esteroidea. El 28 por ciento de los pacientes tratados con esteroides desarrolló un deterioro transitorio al inicio de la medicación y una evolución desfavorable a largo plazo que otorgaría a este fenómeno cierto valor pronóstico. La vía de abordaje quirúrgico del timo más efectiva resultó ser la cervicotomía con manubriotomía. Con cervicotomía simple se observaron 4 casos de recidiva que debieron ser reintervenidos