The RING ubiquitin E3 RNF114 interacts with A20 and modulates NF-κB activity and T-cell activation.

Accurate regulation of nuclear factor-κB (NF-κB) activity is crucial to prevent a variety of disorders including immune and inflammatory diseases. Active NF-κB promotes IκBα and A20 expression, important negative regulatory molecules that control the NF-κB response. In this study, using two-hybrid screening we identify the RING-type zinc-finger protein 114 (RNF114) as an A20-interacting factor. RNF114 interacts with A20 in T cells and modulates A20 ubiquitylation. RNF114 acts as negative regulator of NF-κB-dependent transcription, not only by stabilizing the A20 protein but also IκBα. Importantly, we demonstrate that in T cells, the effect of RNF114 is linked to the modulation of T-cell activation and apoptosis but is independent of cell cycle regulation. Altogether, our data indicate that RNF114 is a new partner of A2O involved in the regulation of NF-κB activity that contributes to the control of signaling pathways modulating T cell-mediated immune response.

Intervención grupal del síndrome subacromial en atención primaria / A group intervention for shoulder impingement syndrome in primary care

Introducción. El aumento de consultas por dolor de hombro en los servicios de rehabilitación impone buscar alternativas eficientes para mejorar su manejo. Objetivos. Evaluar la efectividad de un programa de rehabilitación grupal para mejorar la funcionalidad y el dolor en pacientes afectos de síndrome subacromial y ver qué variables se asocian a un mejor resultado funcional final. Métodos. Estudio longitudinal prospectivo de intervención antes/después. Muestra: 211 pacientes. La intervención consistió en 10 sesiones de electroterapia analgésica individual, 5 sesiones de cinesiterapia grupal y una sesión informativa: «escuela de hombro». El seguimiento fue de un año. Medimos la funcionalidad con el test de Constant y el dolor con la escala visual analógica. Pruebas estadísticas: chi cuadrado, T-test, ANOVA y regresión lineal múltiple (p < 0,05). Resultados. La funcionalidad mejoró significativamente en los 4 períodos estudiados respecto al valor inicial y se estabilizó a los 6 meses. El perfil de paciente que obtuvo mayor funcionalidad fue: mujer, mayor de 60 años, sin dolor en reposo inicial y laboralmente no activa. La mejora del dolor observada a largo plazo no fue significativa. El consumo de analgésicos se redujo significativamente a los 3 meses. La adherencia al tratamiento domiciliario de ejercicios fue del 81% a los 3 y 6 meses y del 70,6% al año. Conclusiones. La aplicación de un programa de rehabilitación grupal en pacientes afectos de síndrome subacromial se ha mostrado efectivo para mejorar la funcionalidad a largo plazo. Sin embargo, el dolor no ha mostrado mejoría significativa a lo largo del estudio (AU)

Introduction. Due to the increase in consultations for shoulder pain in rehabilitation services, there is a need for efficient alternatives to improve the management of this disorder. Objectives. To evaluate the effectiveness of a supervised group exercise program to improve functionality and pain in patients with shoulder impingement syndrome and to identify the variables that are associated with a better functional outcome. Methods. A prospective longitudinal, pre and post intervention study was carried out in a sample of 211 patients. The treatment consisted of 10 individual sessions of analgesic electrotherapy, 5 sessions of group exercise therapy and an educational session: «shoulder school». One year follow-up was performed. Shoulder function and pain were assessed using Constant's test and the visual analogue scale. The statistical analysis was carried out with the chi-square test, T-test, ANOVA and multiple linear regression (P < .05). Results. Functionality improved significantly in all periods studied compared with baseline and stabilized at 6 months. The profile of patients who achieved greater functionality was female, older than 60 years, with no initial rest pain and occupationally inactive. Long-term pain improvement was not significant. Analgesic use was significantly reduced at 3 months. Adherence to home exercise treatment was 81% at 3 and 6 months and 70.6% at one year. Conclusions. The application of a group rehabilitation program in patients with shoulder impingement syndrome was effective in improving long-term functionality. However, there was no significant pain improvement during the study (AU)

Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia.

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment.

Increased levels of circulating endothelial progenitor cells in patients with ischaemic stroke treated with statins during acute phase.

BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPCs) have been suggested to be a therapeutic option in ischaemic stroke. Our aim was to study whether statin treatment during acute phase could increase circulating EPCs after acute ischaemic stroke. METHODS: We studied 48 patients with a first-ever non-lacunar ischaemic stroke (<12 h from stroke onset). Sixteen patients received statin treatment (20 mg atorvastatin/day) during the first 4 days. We defined the EPC increment during the first week as the difference in the number of early outgrowth colony-forming unit-endothelial cell (CFU-EC) between day 7 and at admission (previous to atorvastatin treatment). Serum levels of vascular endothelial growth factor and active matrix metalloproteinase 9 (determined by ELISA), and nitric oxide metabolites (NOx) (determined by high-performance liquid chromatography) were measured at admission, 24 and 72 h, and day 7. RESULTS: Colony-forming unit-endothelial cells were similar at baseline between patients treated (n = 16) and non-treated (n = 32) with statins (10.1 ± 3.9 vs. 7.9 ± 6.9 CFU-EC, P = 0.223). However, patients treated with statins showed a higher EPC increment (24.0 ± 17.3 vs. 6.0 ± 17.8 CFU-EC, P = 0.002) during the first week. An EPC increment ≥ 4 CFU-EC predicted with the highest sensitivity (88%) and specificity (92%) the probability of good outcome (area under the curve 0.903, P < 0.0001). Statin treatment (OR, 13.1; CI 95%, 2.2-76.9, P = 0.004) was independently associated with an EPC increment ≥ 4 CFU-EC after adjustment for confounder factors, but this association was lost when adjusting for NOx levels. CONCLUSIONS: Statin treatment for 4 days may increase circulating EPC levels, probably by NO-related mechanisms.

Comparación de la lesión producida en tres modelos animales de isquemia cerebral focal permanente mediante resonancia magnética / Comparison of the lesion produced by permanent focal cerebral ischaemia in three animal models using magnetic resonance imaging

Introducción. Los modelos animales de isquemia cerebral son indispensables en la investigación de la patología cerebrovascular. Actualmente, no existe un modelo experimental que refleje perfectamente la fisiopatología del ictus, por lo que la selección de éste es fundamental para una interpretación correcta de los resultados obtenidos. Objetivo. Caracterizar la evolución temporal de tres modelos comunes de isquemia cerebral focal permanente mediante resonancia magnética. Materiales y métodos. Treinta ratas macho Sprague-Dawley se dividieron en tres grupos, cada uno sometido a los siguientes modelos quirúrgicos: sutura intracraneal de la arteria cerebral media (ACM), electrocoagulación de la ACM y oclusión intraluminal de la ACM. Cada animal se sometió a una exploración por resonancia magnética los días 1, 2, 3, 4, 7 y 14 tras la cirugía. A partir de imágenes adquiridas con secuencias potenciadas en T2 se calcularon tanto el volumen de lesión como el grado de edema. Resultados. El modelo intraluminal presentó mayor volumen de infarto (media: 297 ± 163 mm3 de volumen máximo) y mayor edema (media: 17 ± 9% de edema máximo) frente al modelo de sutura intracraneal (178 ± 62 mm3 y 9 ± 6%, respectivamente) y electrocoagulación (181 ± 45 mm3 y 9 ± 6%, respectivamente). Discusión. Pese a presentar una mayor mortalidad (28%), el modelo de oclusión intraluminal de la ACM es el más adecuado para estudios a largo plazo al no precisar craneotomía, al contrario que los modelos transcraneales. El modelo de oclusión por electrocoagulación muestra una región cerebral de lesión no isquémica y una evolución de la lesión diferente a los otros dos modelos (AU)

Introduction. Animal models of brain ischemia are essential to reveal the full aspects of cerebrovascular pathologies. The perfect animal model that reflects every aspect of stroke pathophysiology does not exist, hence there is a need for a proper selection of the animal model in order to interpret properly the results from experimental research. Aim. To characterize and compare the temporal evolution of three common models of focal brain ischemia using magnetic resonance imaging (MRI) techniques. Materials and methods. Thirty Sprague-Dawley rats were distributed into three groups, each of them submitted to one of the following surgery procedures: middle cerebral artery (MCA) intracranial suture, MCA electrocoagulation, and MCA intraluminal suture. Each rat was subjected to an MRI study at days 1, 2, 3, 4, 7 and 14 post-surgery. T2 weighted images were obtained in order to calculate both lesion volumes and edema. Results. Infarct volume and edema were maximal for the intraluminal model (peaks of mean 297 ± 163 mm3 and mean 17 ± 9%, respectively) compared to intracranial suture (178 ± 62 mm3 and 9 ± 6%, respectively) and electrocoagulation (181 ± 45 mm3 and 9 ± 6%, respectively) models. Discussion. The intraluminal occlusion of the MCA model, although yields in the highest mortality rate (28%), it is the more suitable for long term studies, mainly because of the absence of craniotomy. In the electrocoagulation model a non ischemic lesion region is observed which leads to an abnormal lesion evolution as compared with the other two models (AU)

[Comparison of the lesion produced by permanent focal cerebral ischaemia in three animal models using magnetic resonance imaging]. / Comparacion de la lesion producida en tres modelos animales de isquemia cerebral focal permanente mediante resonancia magnetica.

INTRODUCTION: Animal models of brain ischemia are essential to reveal the full aspects of cerebrovascular pathologies. The perfect animal model that reflects every aspect of stroke pathophysiology does not exist, hence there is a need for a proper selection of the animal model in order to interpret properly the results from experimental research. AIM: To characterize and compare the temporal evolution of three common models of focal brain ischemia using magnetic resonance imaging (MRI) techniques. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were distributed into three groups, each of them submitted to one of the following surgery procedures: middle cerebral artery (MCA) intracranial suture, MCA electrocoagulation, and MCA intraluminal suture. Each rat was subjected to an MRI study at days 1, 2, 3, 4, 7 and 14 post-surgery. T2 weighted images were obtained in order to calculate both lesion volumes and edema. RESULTS: Infarct volume and edema were maximal for the intraluminal model (peaks of mean 297 ± 163 mm3 and mean 17 ± 9%, respectively) compared to intracranial suture (178 ± 62 mm3 and 9 ± 6%, respectively) and electrocoagulation (181 ± 45 mm3 and 9 ± 6%, respectively) models. DISCUSSION: The intraluminal occlusion of the MCA model, although yields in the highest mortality rate (28%), it is the more suitable for long term studies, mainly because of the absence of craniotomy. In the electrocoagulation model a non ischemic lesion region is observed which leads to an abnormal lesion evolution as compared with the other two models.

Fármacos hemostáticos en paciente con síndrome antifosfolípido y hemorragia perioperatoria importante / Hemostatic drugs in a patients with antiphospholipid syndrome and clinically significant perioperative bleeding

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Comparación del bloqueo del tobillo y metamizol para la analgesia postoperatoria de la cirugía del hallux valgus / Comparison of ankle blockade and metamizol for postoperative analgesia in hallux valgus surgery

El dolor postquirúrgico que sigue a una intervención de corrección de hallux valgus es muy severo y presenta una alta prevalencia, por lo que es necesario el empleo sistemático de pautas de analgesia postoperatoria. En este estudio hemos pretendido valorar de manera cuantitativa y cualitativa la calidad de la analgesia durante el postoperatorio de la corrección del hallux valgus, comparando para ello la realización, posteriormente a la intervención, de un bloqueo de tobillo con una pauta de analgesia intravenosa convencional realizada con metamizol. Material y método: En el estudio se incluyeron, tras la obtención del consentimiento informado, a 40 pacientes que se intervenían de cirugía de corrección de hallux valgus. Todos los enfermos eran ASA I-II, con edades comp rendidas entre 39 y 65 años. Éstos fueron divididos aleatoriamente en dos grupos (grupo A y grupo B). En todos los casos se sometieron a anestesia raquídea a nivel de L3L4. Una vez terminada la cirugía y antes de abandonar el quirófano se practicó un bloqueo de tobillo a 20 de estos pacientes (grupo A) según la técnica de localización anatómica clásica a nivel de los cinco nervios del tobillo. Al resto de los pacientes (grupo B), terminada la intervención, se les administró una pauta analgésica intravenosa con metamizol a dosis de 2 g cada 6 horas. Como analgesia de rescate empleamos, en ambos grupos, tramadol por vía i.v. según dosis recomendadas, administrándose la misma cuando la puntuación de la escala visual-analógica superaba los 4 puntos. Valoramos el dolor a partir de la desaparición del bloqueo espinal, a intervalos establecidos de 30 minutos, 1, 2, 4, 6, 12 y 24 horas según escala visual-analógica, el momento de la administración de la primera dosis de analgésico de rescate y el consumo total del mismo en cada grupo. También se valoraron las constantes hemodinámicas, frecuencia respiratoria y efectos adversos. Resultados : El tiempo medio para la primera dosis de analgésico de rescate fue de 135 ñ 21 minutos en el grupo B y de 550 ñ 17 minutos en el grupo con bloqueo de tobillo (p<0,01). El consumo medio total de tramadol fue en el grupo B de 325 ñ 55 mg mientras que en el grupo A alcanzó los 110 ñ 30 mg (p<0,05). Las puntuaciones obtenidas en la escala visual analógica fueron inferiores en todo momento en el grupo al que se le aplicó bloqueo de tobillo. No se obtuvieron diferencias significativas referidas a los parámetros hemodinámicos, frecuencia respiratoria o efectos adversos entre ambos grupos. El bloqueo de tobillo realizado inmediatamente después de finalizar la cirugía de hallux valgus bajo raquianestesia mejora ostensiblemente el confort del paciente durante las primeras 24 horas postquirúrgicas y reduce de forma significativa el dolor postoperatorio y el consumo de analgésicos parenterales, retrasando el momento de administración de los mismos. El bloqueo de tobillo se mostró como una técnica segura y efectiva para la analgesia postoperatoria de este tipo de cirugía y bastante superior a una técnica analgésica basada en metamizol i.v (AU)

[Dexmedetomidine, a promising drug]. / Dexmedetomidina, un fármaco prometedor.

Surgical patients and others admitted to recovery and intensive care units require sedation and pain therapy, for which a range of pharmaceuticals is available. Their use is more or less widespread, but other drugs, such as dexmedetomidine, have been and continue to be studied for application in such patients. Dexmedetomidine, a compound derived from imidazole, has a high affinity for the alpha-2 adrenoreceptor, on which it acts as a potent agonist. A large number of laboratory and animal studies have been performed, as have clinical trials enrolling healthy volunteers or patients with the aim of shedding shed light on the main pharmacological features of dexmedetomidine. As a result, dexmedetomidine is known to have sedative, hypnotic and analgesic properties. It diminishes the need for other anesthetics and sympathicolytics, and it reduces catecholamine release. Controlled clinical trials have looked at the use of dexmedetomidine in patients who require sedation and analgesia in postoperative intensive care units. Research shows that dexmedetomidine lowers the need both for other sedatives, such as propofol or midazolam, and for analgesic morphine. Moreover, its effect on ventilation is scarce. Dexmedetomidine is presently distributed in the United States but not in the European Union. The aim of this review was to outline the main pharmacological properties of dexmedetomidine, including its pharmacokinetics and pharmacodynamics, to give an overall view of this promising drug.

Dexmedetomidina, un fármaco prometedor / Dexmedetomidine, a promising drug

Los pacientes que son atendidos en quirófano y los ingresados en las Unidades de Reanimación y Cuidados Críticos, requieren de la aplicación de técnicas de sedación y tratamiento del dolor. Para ello existen una serie de fármacos de uso más o menos extendido que tratan de cubrir ese papel, y otros como la dexmedetomidina que ha sido y es estudiada para su empleo en estos pacientes con el fin de proporcionarles sedación y analgesia. Dexmedetomidina es un compuesto derivado imidazólico, con una alta afinidad por el receptor 2 adrenérgico, siendo un potente agonista sobre él. Se han desarrollado un buen número de estudios de laboratorio, experimentos con animales y ensayos clínicos controlados sobre voluntarios y sobre pacientes con el objeto de dilucidar las principales características farmacológicas de la dexmedetomidina. Como fruto de todos estos trabajos de investigación se pudo constatar que dexmedetomidina posee propiedades sedantes, hipnóticas, analgésicas, de disminución de los requerimientos de otros anestésicos, simpaticolíticas y de disminución de la liberación de catecolaminas, habiéndose desarrollado ensayos clínicos controlados en los que se ha estudiado la aplicación de estas propiedades farmacológicas antes referidas, para su posible administración en pacientes ingresados en Unidades de Reanimación que necesiten de la aplicación de técnicas de sedación y analgesia. Estos estudios muestran que dexmedetomidina disminuye los requerimientos de otros fármacos sedantes como propofol o midazolam para proporcionar sedación o de morfina para la analgesia, con unos efectos muy discretos sobre la ventilación de los pacientes. Dexmedetomidina se encuentra actualmente comercializada en Estados Unidos, pero no en la Unión Europea. El objetivo de la presente revisión ha sido repasar los principales aspectos farmacológicos de la dexmedetomidina incluyendo sus características farmacocinéticas y farmacodinámicas más sobresalientes para intentar dar una visión global sobre este interesante fármaco (AU)

Incidencia de escalofríos postquirúrgicos en relación al tiempo de suspensión del sevoflurano / Early versus late termination of sevoflurane anesthesia: effect on the incidence of postoperative shivering

OBJETIVOS: Comprobar si la suspensión de sevoflurano con la suficiente antelación disminuye la incidencia de temblor postanestésico. MATERIAL Y MÉTODOS: Incluimos 80 pacientes ASA IIII, que distribuimos al azar en dos grupos de 40 (Grupo A y Grupo B). Todos fueron premedicados con bromazepam oral. Empleamos para la inducción fentanilo (2 µg/kg), propofol (2,5 mg/kg) y atracurio (0,5 mg/kg).El mantenimiento fue con sevoflurano a 1 CAM en N2O al 60 por ciento en O2, durante el mismo administramos bolos de fentanilo y atracurio a demanda. Interrumpimos la administración de sevoflurano 30 minutos antes del despertar en el grupo A y 10 minutos antes en el grupo B.En esos intervalos de tiempo y en ambos grupos se usó protóxido al 60 por ciento en oxígeno. Valoramos cada 5 minutos presión arterial media, frecuencia cardíaca y temperatura periférica y central en el intraoperatorio. Se documentó la aparición de escalofrío postquirúrgico hasta una hora después en el despertar RESULTADOS: Los datos demográficos y el tiempo de duración de la anestesia fueron similares en ambos grupos. La incidencia de temblor se redujo significativamente en el grupo A (4 por ciento) frente al grupo B (57 por ciento). No se observaron diferencias significativas en el resto de las variables medidas. CONCLUSIONES: La importancia de este estudio viene determinada por la reducción en la incidencia de escalofríos postoperatorios en el grupo A con respecto al grupo B frente a los resultados obtenidos con otros estudios publicados similares (AU)

[Incidence of postoperative shivering in relation to the time of sevoflurane discontinuation]. / Incidencia de escalofríos postquirúrgicos en relación al tiempo de suspensión del sevoflurano.

OBJECTIVES: We aimed to determine whether early termination of sevoflurane administration lowers the incidence of postanesthetic shivering. MATERIAL AND METHODS: Eighty ASA I-III patients were randomized to two groups of 40 (Group A and Group B). All were premedicated with oral bromazepam. Fentanyl (2 micrograms/Kg), propofol (2.5 mg/Kg) and atracurium (0.5 mg/Kg) were used for induction. Anesthesia was maintained with sevoflurane in 60% N2O in oxygen at 1 maximum alveolar concentration, with boluses of fentanyl and atracurium on demand. Sevoflurane administration was terminated 30 minutes before awakening in group A and 10 minutes before awakening in group B. After termination, 60% N2O in oxygen was used in both groups. Mean blood pressure, heart rate and peripheral and core temperatures were measured at 5 minutes intervals during surgery. Postoperative shivering was recorded until one hour after awakening. RESULTS: Patient characteristics and duration of anesthesia were similar in both groups. The incidence of shivering was significantly lower in group A (4%) than in group B (57%). No significant differences were observed in other variables. CONCLUSIONS: The important observation in this study was that the incidence of postoperative shivering in group A was lower than in group B and lower than the incidences reported in other similar studies.

[Paraplegia after left thoracotomy in a patient carrying an epidural catheter]. / Paraplejía tras toracotomía izquierda en un paciente portador de un catéter epidural.

A 61-year-old man undergoing left thoracotomy, in whom a lumbar epidural catheter had been inserted, experienced paraplegia in the immediate recovery period. Diagnostic tests and clinical examinations ruled out neurological causes attributable to the catheter, indicating that the cause was surgical. Paraplegia after thoracotomy is rare but has been described in the literature. We discuss ways that injuries may produce medullary lesions related to thoracic surgery.

Paraplejía tras toracotomía izquierda en un paciente portador de un catéter epidural / Paraplegia after left thoracotomy in a patient carrying an epidural catheter

Un paciente de 61 años fue sometido a toracotomía izquierda, previamente a la cirugía se le había implantado un catéter epidural lumbar, y presentó una paraplejía en el postoperatorio inmediato. Las pruebas diagnósticas y los exámenes clínicos realizados descartaron que el origen de la lesión neurológica fuera achacable al catéter epidural, teniendo ésta un origen quirúrgico.La paraplejía postoracotomía es una entidad infrecuente, pero descrita en la bibliografía científica. Se discuten los posibles mecanismos lesivos implicados en la producción de este tipo de lesiones medulares relacionadas con la cirugía torácica (AU)

Decreased insulin requirements after LAR-octreotide but not after lanreotide in an acromegalic patient.

A diabetic acromegalic man, not cured after surgery and radiosurgery, received lanreotide i.m. with great clinical and biochemical improvement. He required NPH insulin (76 to 84 units/day) to control his diabetes mellitus. Thirty-six hours after changing to LAR-octreotide (20 mg i.m/month) he presented symptomatic hypoglycemia, repeated at 48 and 72 h (50 mg/dL), despite reducing insulin to 26 Units/day. Thereafter, he reduced insulin by 30 to 50% for the first week after each LAR-octreotide injection, and gradually increased it again over the next 3 weeks. This situation persists after every injection 3 years later; this consistent behavior supports a specific effect of LAR-octreotide, and not a by chance phenomenon. No marked changes in circulating GH, IGF-1, immunoreative insulin, C-peptide, testosterone and glucose were observed prior to, and 3, 7, 14, 21, and 28 days after LAR-octreotide; however, there was 28% fall in plasma glucagon after 7 days, which rose thereafter. C-peptide (< 1.8 ng/mL) was indicative of decreased beta-cell function. To our knowledge, this is the first report of such a distinct differential behaviour of blood glucose and insulin requirements with different somatostatin analogs, and is worth recalling when starting an insulin-treated diabetic patient on this treatment. It may be related to a preferential binding of LAR-octreotide to subtype 2 somatostatin receptors in the pancreas, while lanreotide preferentially binds to subtype 5, not expressed in this tissue; this would explain the fall in glucagon, in parallel to the decrease in insulin requirements after LAR-octreotide; however, a contribution of differences in the effect of both somatostatin analogues on postreceptor signalling systems and/or intestinal carbohydrate absorption cannot be entirely ruled out.

Antiproliferative effect and cell cycle modulation by melatonin on GH(3) cells.

We have investigated the effect of melatonin on cell proliferation and modulation, in the GH(3) experimental rat pituitary cell line; the expression of oncogenes c-myc, c-jun and the tumor suppressor gene p53 were also analyzed basally and after exposure to melatonin (10(-6), 10(-8) and 10(-10) M). Melatonin exhibited an antiproliferative effect at all the doses tested, decreasing the proliferating index by 50%. After exposure to melatonin, a decrease in Ki67 and Proliferation cell nuclear antigen occurred acute- and transiently (at 2 h) after a single dose which recovered at 4 h, as well as chronically after repeated 12-hour doses which persisted at 48 h; a similar behavior was observed both acute- and chronically for c-myc and c-jun, while it was opposite for p53, rising acute- and transiently as well as after repeated exposure. These results demonstrate that melatonin modulates the proliferation mechanisms of the GH(3) cells.

[Ultrastructural study on intracerebral small blood vessels and fluorescent granular perithelial (FGP) cells in experimental cerebral ischemia].

In order to clarify the sequential changes of the morphology of vascular cells and FGP cells under cerebral ischemia, 32 male Wistar rats were employed. The FGP cells in the present paper are distributed along cerebral microvessels, and markedly potent in the uptake capacity for endo- and exogenous substances under the physiological and pathological conditions. Under the anesthesia of pentobarbital, experimental animals suffered from cerebral ischemia were produced by (1) occlusion of bilateral vertebral arteries, (2) unilateral ligation of common carotid artery accompanied with occlusion of vertebral arteries and (3) temporary clipping of bilateral common carotid arteries accompanied with occlusion of vertebral arteries. On 1 to 14 days after the treatments mentioned above, the cerebral cortices of animals were examined with the electron microscope with paying special attention to morphological changes of FGP cells. From the observation, it is confirmed that: (1) after occlusion of vertebral arteries (first group of experimental animals), the FGP cells become edematous without any severe damage of cerebral neurons through 2 weeks.: (2) In case of the unilateral ligation of common carotid artery (second group of experimental animals), the FGP cells and neurons tend to degenerate at the ligated side on 14 days, but at the opposite side, the considerable vacuolation and swelling of the FGP cells are evident, without accompanying with any degeneration of neurons and FGP cells, and: (3) In the reflow experiment (third group of experimental animals), the neurons are not affective and the FGP cells show some degenerative changes on 7 days, but most of them recovered on 14 days. From these observations, it may be concluded that the morphological changes of FGP cells run parallel with the change of microenvironment surrounding neurons, and the FGP cells, in addition to astrocytes, are reliable morphological markers of cerebral edema.

Regional difference of lipid distribution in brain of apolipoprotein E deficient mice.

According to recent knowledge, apolipoprotein E (apo E) plays a significant role in the homeostasis of intracellular cholesterol level in various tissues. Apo E deficient mice develop hyperlipidemia, and suffer from atherosclerosis in extracerebral blood vessels and neurodegeneration in the central nervous system. Furthermore, Walker et al. (Am. J. Path., 1997;151:1371-1377) demonstrated cerebral xanthomas of various sizes in the brain of apo E deficient mice. In the present study, it is illustrated that in the homozygous apo E deficient mice of advancing age, a great number of foamy macrophages extravasate from microvessels in thalamus and fimbria hippocampi, and scatter in the perivascular regions and migrate toward the ependyma, fimbria hippocampi, hippocampus, and thalamus. Here, it must be pointed out that under hyperlipidemia, although foamy macrophages made clusters in the perivascular region, the cerebral microvessels did not develop atherosclerosis. On the other hand, in the other cerebral regions such as cerebral cortex, caudoputamen, globus pallidus, and substantia nigra, macrophages did not appear and microvessels retained normal shapes, but the fluorescent granular perithelial (in short, FGP) cells accompanied by these vessels contained a certain amount of lipids. That is, in the cerebral cortex and caudoputamen, lipid components are detected in FGP cells and microglia, while in the globus pallidus and substantia nigra, they are mainly localized in astrocytes. The reason why the astrocytes in such defined regions contain, specifically, a high quantity of lipid components remains unsettled. Axonal degenerations are often represented in thalamus, globus pallidus, and substantia nigra. On the other hand, in the specimens of Wild-type mice, lipid components were observed only in FGP cells, and the vascular architecture took a normal profile. Any lipid laden macrophages and the axonal degenerations could not be detected through the cerebral parenchyma. Furthermore, it is also a noticeable finding that immunohistochemically, the FGP cells express a positive reaction against the antibody of apo E in the Wild-type mice, but those of homozygous apo E deficient mice are immunonegative. FGP cells are not only provided with the scavenger receptor, but also contribute to the lipid metabolism in the brain.