Cardiac Corpuscles: A "New" Morphofunctional Entity? / Corpúsculos Cardíacos: ¿Una "Nueva" Entidad Morfofuncional?

SUMMARY: The existence of "transitional muscular structures" between subendocardial branches (Purkinje fibers) and ventricular working muscle fibers (WF) was first described by the German anatomist, Kurt Goerttler, in 1964. He designated them as "subendocardial nucleus organs." He supposed such fibers functioned as mechanoreceptors, controlling of the intensity of contraction of the ventricular musculature. Brazilian anatomist Ferraz de Carvalho described similar structures in 1993. A thorough literature search failed to identify any other research articles confirming or denying their existence. The objective of this work was to find such structures in subendocardial ventricular walls in human hearts. We collected fifteen formalin-preserved hearts from the Anatomy Department of São Paulo University and sectioned the apical portions on the right and left ventricles according to method used by Goerttler. We utilized conventional histology (light microscopy- LM), scanning electron microscopy (SEM), and a new preservation method called micro- plastination (MP). At the anterior wall of the right ventricle in the subendocardial region between the interventricular septum and moderator band, we found several bundles of fusiform and helicoidal fibers of similar histology to the WF. The bundles measured between 400 and 1150 µm in length and were separated from adjacent muscular fibers by thin collagen fiber, thus acting as a "pseudo capsule." Some structures seemed to be linked to PF and were appeared to be lymphatic and blood vessels and nerves. We called those structures "cardiac corpuscles" (CC). The observation of the previously "unknown" CC in this initial study confirmed the previous descriptions and its discovery may contribute to new perspectives in the study of cardiac muscle structure and function.

La existencia de "estructuras musculares de transición" entre los ramos subendocárdicos (fibras de Purkinje) y las fibras musculares ventriculares activas(FMV) fue descrita por primera vez por el anatomista alemán Kurt Goerttler en 1964, quien las denominó "órganos del núcleo subendocárdico". Supuso que tales fibras funcionaban como mecanoreceptores, controlando la intensidad de la contracción de la musculatura ventricular. El anatomista brasileño Ferraz de Carvalho describió estructuras similares en 1993. Una búsqueda bibliográfica exhaustiva no logró identificar ningún otro artículo de investigación que confirmara o negara su existencia. El objetivo de este trabajo fue encontrar dichas estructuras en las paredes ventriculares subendocárdicas de corazones humanos. Recolectamos 15 corazones conservados en formalina del Departamento de Anatomía de la Universidad de São Paulo y seccionamos las porciones apicales de los ventrículos derecho e izquierdo según el método utilizado por Goerttler. Utilizamos histología convencional (microscopía de luz-LM), microscopía electrónica de barrido (SEM) y un nuevo método de conservación llamado microplastinación (MP). En la pared anterior del ventrículo derecho en la región subendocárdica entre el tabique interventricular y la banda moderadora, encontramos varios haces de fibras fusiformes y helicoidales de histología similar a la FMV. Los haces medían entre 400 y 1150 µm de longitud y estaban separados de las fibras musculares adyacentes por una fina fibra de colágeno, actuando así como una "pseudocápsula". Algunas estructuras parecían estar vinculadas a la fibras de purkinje y parecían ser vasos linfáticos, sanguíneos y nerviosos. Llamamos a esas estructuras "corpúsculos cardíacos" (CC). La observación del CC previamente "desconocido" en este estudio inicial confirmó las descripciones anteriores y su descubrimiento puede contribuir a nuevas perspectivas en el estudio de la estructura y función del músculo cardíaco.

Study of Cerebellar Tissue Following Induction of Aging in Mice By Di-Galactose / Estudio del Tejido Cerebeloso tras la Inducción del Envejecimiento en Ratones por D-Galactosa

SUMMARY: The cerebellum is a crucial area of the hindbrain that plays an essential role in balancing, excitement control, and subtle and accurate functions. Studies have shown that long-term use of D-galactose in mice, as with the symptoms of aging, causes morphological and functional disorders in the brain. This study was performed to evaluate the changes in the cerebellum cortex tissue and the measurement of reactive oxygen species (ROS) in the cerebellum following the induction of aging in mice by D-galactose. Accordingly, subjects were randomly assigned into two groups: Normal saline group and Aging group (D-galactose). To create an aging model, D- galactose, and saline solution (sodium chloride 0.9 %) were used. After completing the preparation and passage of the tissue, the cerebellum specimens were cut in 5 microns thickness and then stained with hematoxylin-eosin stain and finally examined under a Nikon microscope. Quantitative variables were analyzed by SPSS software using T-test. In the observations of cerebellum tissue samples, in the aged induced group by D-galactose, the most changes were observed in the Neuron purkinjense (Purkinje cells) layer. In the observations of the cerebellum tissue samples of aging group induced by D-galactose, the most changes were observed in the Neuron purkinjense, and the arrangement and placement of these cells were disorientated. The nucleus positioning was not central, and the Neuron purkinjense induced by aging were seen in different morphological forms. Necrosis, Chromatolysis, and Pyknosis were found. Based on the results, D-galactose (induction of aging) causes pathological changes in the cerebellar cortex, especially in the Neuron purkinjense layer.

El cerebelo es un área crucial del rombencéfalo que desempeña un papel esencial en el equilibrio, el control de la excitación y las funciones sutiles y precisas. Los estudios han demostrado que el uso a largo plazo de D-galactosa en ratones, al igual que con los síntomas del envejecimiento, provoca trastornos morfológicos y funcionales en el cerebro. Este estudio se realizó para evaluar los cambios en el tejido de la corteza del cerebelo y la medición de especies reactivas de oxígeno (ROS) en el cerebelo luego de la inducción del envejecimiento en ratones por D-galactosa. En consecuencia, los sujetos fueron asignados aleatoriamente a dos grupos: grupo de solución salina normal y grupo de envejecimiento (D-galactosa). Para crear un modelo de envejecimiento, se utilizaron D-galactosa y solución salina (cloruro de sodio al 0,9 %). Después de completar la preparación y el paso del tejido, las muestras de cerebelo se cortaron en un grosor de 5 µm y luego se tiñeron con tinción de hematoxilina-eosina y finalmente se examinaron bajo un microscopio Nikon. Las variables cuantitativas se analizaron mediante el software SPSS utilizando la prueba T. En las observaciones de muestras de tejido de cerebelo, en el grupo envejecido inducido por D-galactosa, la mayoría de los cambios se observaron en la capa de neuronas purkinjenses (células de Purkinje). En las observaciones de las muestras de tejido del cerebelo del grupo de envejecimiento inducidas por D-galactosa, la mayoría de los cambios se observaron en las neuronas purkinjenses, y la disposición y ubicación de estas células estaban desorientadas. El posicionamiento del núcleo no era central y las neuronas purkinjenses inducidas por el envejecimiento se observaban en diferentes formas morfológicas. Se encontró necrosis, cromatólisis y picnosis. Según los resultados, la D-galactosa (inducción del envejecimiento) provoca cambios patológicos en la corteza cerebelosa, especialmente en la capa de neuronas purkinjenses.

Expression changes of NaV channel subunits correlate with developmental maturation of electrophysiological characteristics of rat cerebellar Purkinje neurons / 南方医科大学学报

OBJECTIVE@#To investigate the variations in the expression of voltage-gated sodium (Nav) channel subunits during development of rat cerebellar Purkinje neurons and their correlation with maturation of electrophysiological characteristics of the neurons.@*METHODS@#We observed the changes in the expression levels of NaV1.1, 1.2, 1.3 and 1.6 during the development of Purkinje neurons using immunohistochemistry in neonatal (5-7 days after birth), juvenile (12-14 days), adolescent (21-24 days), and adult (42-60 days) SD rats. Using whole-cell patch-clamp technique, we recorded the spontaneous electrical activity of the neurons in ex vivo brain slices of rats of different ages to analyze the changes of electrophysiological characteristics of these neurons during development.@*RESULTS@#The expression of NaV subunits in rat cerebellar Purkinje neurons showed significant variations during development. NaV1.1 subunit was highly expressed throughout the developmental stages and increased progressively with age (P < 0.05). NaV1.2 expression was not detected in the neurons in any of the developmental stages (P > 0.05). The expression level of NaV1.3 decreased with development and became undetectable after adolescence (P < 0.05). NaV1.6 expression was not detected during infancy, but increased with further development (P < 0.05). NaV1.1 and NaV1.3 were mainly expressed in the early stages of development. With the maturation of the rats, NaV1.3 expression disappeared and NaV1.6 expression increased in the neurons. NaV1.1 and NaV1.6 were mainly expressed after adolescence. The total NaV protein level increased gradually with development (P < 0.05) and tended to stabilize after adolescence. The spontaneous frequency and excitability of the Purkinje neurons increased gradually with development and reached the mature levels in adolescence. The developmental expression of NaV subunits was positively correlated with discharge frequency (r=0.9942, P < 0.05) and negatively correlated with the excitatory threshold of the neurons (r=0.9891, P < 0.05).@*CONCLUSION@#The changes in the expression levels of NaV subunits are correlated with the maturation of high frequency electrophysiological properties of the neurons, suggesting thatmature NaV subunit expressions is the basis of maturation of electrophysiological characteristics of the neurons.

Impressions of the chronic 900-MHz electromagnetic field in the prenatal period on Purkinje cells in male rat pup cerebella: is it worth mentioning?

SUMMARY OBJECTIVE: The aim of this study was to examine the changes on the Purkinje cells in the cerebella of male rat pups born to pregnant dams that were exposed to an electromagnetic field in the prenatal period. METHODS: The first stage of the study involved 12 Sprague-Dawley rats, 6 male and 6 female, weighing between 180 and 250 g. The female rats in the experimental group were exposed to a 900-MHz electromagnetic field for 1 h at the same time every day, and no procedure was performed on the control group. Following pregnancy, six male pups from each group were divided into experimental and control groups without any procedure on the pups. After 2 months, they were sacrificed and their cerebella were removed. Histopathologically, following routine processing and fixation procedures, the cerebella were embedded in the tissue blocks. The sections taken from these blocks were stained with cresyl violet. The Purkinje cells in the cerebella were then counted on sections using the optical dissector method on an image analysis system. RESULTS: The estimation of number of the Purkinje cells in the groups revealed more cells in rats in the control group than in the experimental group. Histopathologically, Purkinje cells exhibited a normal morphological structure in the control group, while the cells in the experimental group showed damage. CONCLUSIONS: It might be asserted that the exposure of mothers to an electromagnetic field in the prenatal period may affect the development of Purkinje cells in the pup cerebella.

Idiopathic left fascicular ventricular tachycardia in children and adolescents / Taquicardia ventricular fascicular izquierda idiopática en niños y adolescentes

Abstract Background: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. Methods: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. Results: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. Conclusions: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

Resumen Introducción: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. Métodos: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. Resultados: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. Conclusiones: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

Effects of prenatal tobacco smoke on cerebellum histomorphological changes at critical developmental stages in CD-1 mice / Efectos del humo de tabaco en los cambios histomorfológicos del cerebelo en las etapas críticas del desarrollo prenatal en ratones CD-1

SUMMARY: In this study the consequences of prenatal exposure to tobacco smokes on the histo-morphological changes of cerebellum was assessed by comparing the smoker mice to the nonsmoker mice. A total of 30 pregnant cd-1 mice were divided into three groups of 10 mice each and with two replicates per group (5 mice each). Following acclimation for five days, the mice were placed in a special modified smoking machine for 2 hours per day over a two- and three-week period for group two and group three, respectively. Group one was considered as a control group. Mice in the control group were exposed simultaneously to fresh air from the room, while those in the treatment groups were exposed to tobacco smoke from six commercial filter cigarettes, containing 0.8 mg of nicotine, 10 mg of tar, and 10 mg of carbon monoxide, for three 1-hour exposure periods every day for three weeks. The mice in the control group were exposed to room air for three 1-hour periods every day for the same period of three weeks. The results from this study showed a correlation between maternal smoking and histological changes in Neuron purkinjense (Purkinje cells) of the cerebellum. They also showed that prenatal smoking period may have caused more damage in the histology and structure of Neuron purkinjense in some juvenile mice. An increased incidence of morphology damage of the cerebellum's Neuron purkinjense' structures was also observed in fetuses with prolonged exposure to tobacco smoking. Exposure of in utero maternal smoking may interfere with brain biological development parameters, giving rise to structural abnormalities of the cerebellum. This study concluded that tobacco smoke exposure to pregnant mice may affect neurodevelopment which may induce behavioural changes as a result of reduced cerebellar size and function.

RESUMEN: Se evaluaron los efectos producidos por la exposición prenatal al humo de tabaco en ratones expuestos y no expuestos y los cambios histomorfológicos observados en el cerebelo en ambos grupos. Un total de 30 ratones cd-1 preñados se dividieron en tres grupos de 10 ratones cada uno y con dos réplicas por grupo (5 ratones cada uno). Después de la aclimatación durante cinco días, los ratones se colocaron en una máquina de fumar modificada, especial durante 2 horas al día, durante un período de dos y tres semanas para el grupo dos y el grupo tres, respectivamente. El grupo uno se consideró como grupo control. Los ratones del grupo de control fueron expuestos simultáneamente al aire limpio de la habitación, mientras que los grupos de tratamiento fueron expuestos al humo de tabaco de seis cigarrillos comerciales, que contenían 0,8 mg de nicotina, 10 mg de alquitrán y 10 mg de monóxido de carbono. durante tres períodos de 1 hora diariamente, durante tres semanas. Los ratones del grupo de control se expusieron al aire ambiente durante tres períodos de 1 hora todos los días durante el mismo período de tres semanas. Los resultados de este estudio mostraron una correlación entre el tabaquismo materno y los cambios histológicos en las neuronas purkinjenses (células de Purkinje). Se observó además que el período de tabaquismo prenatal puede haber causado mayor daño en la histología y estructura de las neuronas purkinjenses en algunos ratones jóvenes. También se observó una mayor incidencia de daño morfológico de las estructuras de las neuronas purkinjenses del cerebelo en fetos con exposición prolongada al tabaquismo. La exposición al tabaquismo materno en el útero puede interferir con los parámetros de desarrollo biológico del cerebro, dando lugar a anomalías estructurales del cerebelo. Este estudio concluyó que la exposición al humo del tabaco en ratones preñados puede afectar el desarrollo neurológico, lo que puede inducir cambios de comportamiento como resultado de la reducción del tamaño y la función del cerebelo.

Intrauterine hypoxia slowing the development of Purkinje cells and reducing the expression of cerebellin in mice / 解剖学报

Objective To investigate the effects of the development of Purkinje cells and expression of cerebellin in postnatal mice with intrauterine hypoxia. Methods Twenty healthy adult Kunming mice were randomly divided into two groups : control group and hypoxia group, with 10 mice in each group. Mice in the hypoxia group were placed in the hypoxia chamber of the animal since the 14th day of gestation to make an animal model of intrauterine hypoxia. After the mother gave birth, the experimental animals were divided into hypoxia group and control group. There were 6 age groups including postnatal day (P)0, P5, P9, P14, P21 and P30 in each group, and 5 mice in each age group. The cerebellum tissue was taken for vibrating sectioning. The developmental changes of calbindin-positive Purkinje cells were detected by immunofluorescence technique. The expression of cerebellin in Purkinje cell protuberances was detected by cerebellin (CBLN)l, CBLN4 and calbindin double labeling. Finally, Western blotting was used to semi-quantitatively analyze the protein expression of cerebellar peptide in cerebellum at each time point. Results Compared with the control group of the same age, the number of cerebellar Purkinje cells in the hypoxic group decreased, the dendritic branches decreased, and the arrangement was disordered, and the expression of CBLN1 and CBLN4 in the cortex were significantly reduced. Conclusion Intrauterine hypoxia leads to abnormal development of the cerebellar Purkinje cells and synaptic changes.

Effects of CTNND2 knockout on cerebellar development and motor function in mice / 解剖学报

Objective To investigate the effects of CTNND2 knockout on cerebellar neuronal development and motor function in mice, as well as its possible mechanisms. Methods The mice were divided into two groups (n = 10 in each group), all of them were 7 weeks old : wild-type (WT) C57BL/6J mice were treated as control group, and homozygous of CTNND2 knockout (CTNND2 7) mice were treated as experimental group, the genotype of CTNND2 7 mice were detected with PCR. The motor function of two groups were detected by beam walking test, hanging wire test and gait analysis test. The changes of cerebellar Purkinje cells were detected by immunofluorescence staining and Golgi staining. Western blotting was performed to detect the expression levels of synapse-associated proteins phosphorylated synapsin 1 (p-Synl), synapsin 1 (Synl), ELKS and postsynaptic density protein 95(PSD95), as well as phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), protein kinase B (Akt), phosphorylated mammalian target of rapamycin (p-mTOR) and mammalian target of rapamycin (mTOR). Results Compared with the WT mice, except the increase in time to traverse the beam, there was a decrease in the proportion of pass on the beam, or latency to fall from the hanging wire, or score of hanging wire, or fore-stride length and hind-stride length of CTNND2 7 mice. There was also a decrease in numbers of Purkinje cells and its dendritic arborization in cerebellum of CTNND2 7 mice. The ratio of p-Synl/ Synl, p-Akt/Akt and p-mTOR/mTOR, as well as the expression levels of ELKS, PSD95 and PI3K were lower than those of WT mice. Conclusion CTNND2 knockout can affect the number and dendritic architecture of Purkinje cells, as well as synthesis of synapse-associated proteins in cerebellum by down-regulating PI3K/Akt/mT0R signaling pathway, resulting in cerebellar developmental disorder, thereby affecting motor function of mice.

Challenges and opportunities in improving left ventricular remodelling and clinical outcome following surgical and trans-catheter aortic valve replacement / 医学前沿

Over the last half century, surgical aortic valve replacement (SAVR) has evolved to offer a durable and efficient valve haemodynamically, with low procedural complications that allows favourable remodelling of left ventricular (LV) structure and function. The latter has become more challenging among elderly patients, particularly following trans-catheter aortic valve implantation (TAVI). Precise understanding of myocardial adaptation to pressure and volume overloading and its responses to valve surgery requires comprehensive assessments from aortic valve energy loss, valvular-vascular impedance to myocardial activation, force-velocity relationship, and myocardial strain. LV hypertrophy and myocardial fibrosis remains as the structural and morphological focus in this endeavour. Early intervention in asymptomatic aortic stenosis or regurgitation along with individualised management of hypertension and atrial fibrillation is likely to improve patient outcome. Physiological pacing via the His-Purkinje system for conduction abnormalities, further reduction in para-valvular aortic regurgitation along with therapy of angiotensin receptor blockade will improve patient outcome by facilitating hypertrophy regression, LV coordinate contraction, and global vascular function. TAVI leaflet thromboses require anticoagulation while impaired access to coronary ostia risks future TAVI-in-TAVI or coronary interventions. Until comparable long-term durability and the resolution of TAVI related complications become available, SAVR remains the first choice for lower risk younger patients.

Papel del sistema Purkinje y del tracto de salida del ventrículo derecho en las arritmias ventriculares malignas y la muerte súbita / Role of the Purkinje system and right ventricular outflow tract in malignant ventricular arrhythmias and sudden death

RESUMEN El sistema Purkinje y el tracto de salida del ventrículo derecho tienen un papel trascendente en relación con las arritmias ventriculares malignas (taquicardia y fibrilación ventriculares, torsión de puntas) y con la muerte súbita cardíaca. Se discuten su fisiopatología, participación en el origen (extrasístoles desencadenantes) y mantenimiento de estas arritmias, y las posibilidades ablativas para disminuir las recurrencias y los episodios de tormenta eléctrica. Se expone el diagnóstico diferencial entre variantes benignas y malignas de la taquicardia ventricular relacionada con el tracto de salida del ventrículo derecho y la relación entre factores genéticos, estructurales, electroanatómicos y funcionales (inflamación, fibrosis), con los eventos clínicos y la vulnerabilidad a las arritmias. Se necesita reclasificar algunas de estas enfermedades, vistas ahora en su carácter orgánico-funcional (síndrome de Brugada, por ejemplo), lo cual implica cambios revolucionarios en algunos conceptos clásicos y una nueva visión en cuanto a la estratificación de riesgo y la conducta terapéutica.

ABSTRACT The Purkinje system and the right ventricular outflow tract play a pivotal role in relation to malignant ventricular arrhythmias (ventricular tachycardia and fibrillation, torsades de pointes) and sudden cardiac death. Details such as their pathophysiology, origin involvement (triggering extrasystoles) maintenance of such arrhythmias, and ablative possibilities to reduce recurrences and electrical storm events are discussed herein. The differential diagnosis between benign and malignant ventricular tachycardia related to the right ventricular outflow tract, and the relationship between genetic, structural, electroanatomical and functional factors (inflammation, fibrosis) with clinical events and vulnerability to arrhythmias are presented. Some of these diseases need to be reclassified as they are now seen in their organic-functional character (Brugada syndrome, for example), and this implies radical changes in some classical concepts as well as a new perspective on risk stratification and therapeutic management.

Ryanodine receptor 2 mutation: Not only catecholaminergic polymorphic ventricular tachycardia but also epileptiform discharges in electroencephalogram

@#Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias, and RyR2 mutations have been shown in the aetiology of catecholaminergic polymorphic ventricular tachycardia. We report the case of a patient with catecholaminergic polymorphic ventricular tachycardia resulting from a RYR2 mutation who had not only typical electroencephalogram changes, but also epileptiform discharges in electroencephalogram. We believe the changes were closely related to the RYR2 mutation.

The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish / 神经科学通报·英文版

Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.

Neuronal Activity in the Cerebellum During the Sleep-Wakefulness Transition in Mice / 神经科学通报·英文版

Cerebellar malfunction can lead to sleep disturbance such as excessive daytime sleepiness, suggesting that the cerebellum may be involved in regulating sleep and/or wakefulness. However, understanding the features of cerebellar regulation in sleep and wakefulness states requires a detailed characterization of neuronal activity within this area. By performing multiple-unit recordings in mice, we showed that Purkinje cells (PCs) in the cerebellar cortex exhibited increased firing activity prior to the transition from sleep to wakefulness. Notably, the increased PC activity resulted from the inputs of low-frequency non-PC units in the cerebellar cortex. Moreover, the increased PC activity was accompanied by decreased activity in neurons of the deep cerebellar nuclei at the non-rapid eye-movement sleep-wakefulness transition. Our results provide in vivo electrophysiological evidence that the cerebellum has the potential to actively regulate the sleep-wakefulness transition.

The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish / 神经科学通报·英文版

Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome.

Jan Evangelista Purkinje, a brilliant, multifaceted Czech biologist: nerve tissue / Jan Evangelista Purkinje, um brilhante multifacetado biólogo checo: tecido nervoso

Jan Evangelista Purkinje was a Czech physician with an exceptional capacity for innovative thinking, and he was one of the fathers of experimental physiology, experimental pharmacology, experimental psychology, histology, embryology, and physical anthropology. Several achievements are named after him, from his prodigious productivity. Of special interest of this paper was his pioneering role in the rise of experimental physiology, microscopical anatomy, and histological methods by the 1830´s that allowed him define more accurate data concerning the structure of nerve tissue of animals and humans such as the now known "Purkinje's cells" and others cells of the brain. He investigated the structure of neuronal processes, including the dendrites. Purkinje recognized possible functional differences between a variety of types of neurons and speculated about their interrelations. He was one of the great geniuses of science.

Jan Evangelista Purkinje foi um médico checo com excepcional capacidade de pensamento inovador e um dos pais da fisiologia experimental, farmacologia experimental, psicologia experimental, histologia, embriologia e antropologia física. Várias conquistas receberam o nome dele, de sua produtividade prodigiosa. De interesse especial deste trabalho enaltece-se o seu papel pioneiro no surgimento da fisiologia experimental, anatomia microscópica e métodos histológicos na década de 1830. Isso permitiu que ele definisse dados mais precisos sobre a estrutura do tecido nervoso de animais e humanos, como as agora conhecidas "células de Purkinje" e outras células do cérebro. Ele investigou a estrutura dos processos neuronais, incluindo os dendritos. Purkinje reconheceu possíveis diferenças funcionais entre uma variedade de tipos de neurônios e especulou sobre suas inter-relações. Ele foi um dos grandes gênios da ciência.

Screening and Verification of RNA-seq-based PBCRS for Treating Key Genes of Breast Cancer / 中国实验方剂学杂志

Objective: To study the inhibitory effect of the medicine group of promoting blood circulation and removing stasis (PBCRS) on breast cancer induced by 7, 12-dimethylbenz(a)anthracene (DMBA) in rats, and screen out and verify key genes based on RNA Sequencing (RNA-seq) technology and Ingenuity Pathway Analysis (IPA). Method: Totally 96 Sprague-Dawley (SD) rats were randomly divided into blank group, DMBA model control group, tamoxifen (TAM) group (1.9 mg·kg-1·d-1), high-dose, middle-dose and low-dose PBCRS groups (12.96, 6.48, 3.24 g·kg-1·d-1). One week after drug intervention, except for the blank group, the DMBA was used to induce the rat model of breast cancer (with an interval of a week, irrigation for two times at the dose of 100 mg·kg-1). After 10 weeks, the changes in tumor weight and tumor volume were observed. The total RNA was extracted by total RNA extraction kit, and three RNA samples were collected from the DMBA model control group and the middle-dose PBCRS group for genetic testing. Based on RNA-seq, key differential genes were screened out and verified by Real-time PCR. Result: Comparing with the DMBA model control group, the tumor volume and tumor weight in middle-dose PBCRS group were decreased significantly (PPConclusion: PBCRS may inhibit the occurrence of breast cancer by interfering with the expression of FBP1 in breast cancer tissue.

Neuroprotective effect of melatonin in cerebellums in Alzheimer's disease animal models via MAPK/ERK signaling pathway / 中国药理学通报

Aim: To investigate the effect of melatonin on neuroprotection in cerebellums of rats with Alzheimer' s disease via MAPK/ERK signaling pathway. Methods: Thirty-two male Sprague-Dawley rats were randomly divided into four groups: control group, Aβ1-42 lateral ventricle injection group (AD), and melatonin intraperitoneal injection group (MT), and Aβ1-42 lateral ventricle injection combined with melatonin intraperitoneal injection group (AD + MT). The pathological changes of rat cerebellar cortex were detected by HE staining; the expression of NeuN (neuronal marker), Calbindin(Purkinje cell marker) and p-ERK protein in each group was detected by immunofluorescence; the expression of ERK and p-ERK in each group was determined by Western blot. Results: The HE staining showed that the expression of neurons decreased, followed with the disordered arrangement and morphological alteration of cells in AD. Melatonin could significantly alleviate the pathological damage in cerebellum. Immunofluorescence results showed that compared with AD group, the expression of NeuN (neuronal marker) increased, the number of Purkinje cells marked by Calbindin significantly was up-regulated(P < 0. 01), and the expression of p-ERK was down-regulated in AD + MT group. Western blot showed that the expression of p-ERK was down-regulated by melatonin. Conclusions: Melatonin may exert the neuroprotective effect and relieve the pathological changes by inhibiting the activation of MAPK/ERK signaling pathway.

Unsolved Questions on the Anatomy of the Ventricular Conduction System

We reviewed the anatomical characteristics of the conduction system in the ventricles of human and ungulate hearts and then raised some questions to be answered by clinical and anatomical studies in the future. The ventricular conduction system is a 3-dimensional structure as compared to the 2-dimensional character of the atrial conduction system. The proximal part consisting of the atrioventricular node, the bundle of His and fascicles are groups of conducting cells surrounded by fibrous connective tissue so as to insulate from the underlying myocardium. Their location and morphological characters are well established. The bundle of His is a cord like structure but the left and right fascicles are broad at the proximal and branching at the distal part. The more distal part of fascicles and Purkinje system are linear networks of conducting cells at the immediate subendocardium but the intra-mural network is detected at the inner half of the ventricular wall. The papillary muscle also harbors Purkinje system not in the deeper part. It is hard to recognize histologically in human hearts but conducting cells as well as Purkinje cells are easily recognized in ungulate hearts. Further observation on human and ungulate hearts with myocardial infarct, we could find preserved Purkinje system at the subendocardium in contrast to the damaged system at the deeper myocardium. Further studies are necessary on the anatomical characteristics of this peripheral conduction system so as to correlate the clinical data on hearts with ventricular arrhythmias.

The Emerging Concept of Intrinsic Plasticity: Activity-dependent Modulation of Intrinsic Excitability in Cerebellar Purkinje Cells and Motor Learning

What is memory? How does the brain process the sensory information and modify an organism's behavior? Many neuroscientists have focused on the activity- and experience-dependent modifications of synaptic functions in order to solve these fundamental questions in neuroscience. Recently, the plasticity of intrinsic excitability (called intrinsic plasticity) has emerged as an important element for information processing and storage in the brain. As the cerebellar Purkinje cells are the sole output neurons in the cerebellar cortex and the information is conveyed from a neuron to its relay neurons by forms of action potential firing, the modulation of the intrinsic firing activity may play a critical role in the cerebellar learning. Many voltage-gated and/or Ca²⁺-activated ion channels are involved in shaping the spiking output as well as integrating synaptic inputs to finely tune the cerebellar output. Recent studies suggested that the modulation of the intrinsic excitability and its plasticity in the cerebellar Purkinje cells might function as an integrator for information processing and memory formation. Moreover, the intrinsic plasticity might also determine the strength of connectivity to the sub-cortical areas such as deep cerebellar nuclei and vestibular nuclei to trigger the consolidation of the cerebellar-dependent memory by transferring the information.