Actualización del manejo diagnóstico y terapéutico del paraganglioma / Update on diagnostic and therapeutic management of paraganglioma

El paraganglioma es un tumor neuroendocrino poco frecuente que puede desarrollarse en diversos sitios del organismo. Alrededor del 97 por ciento son benignos y se curan mediante la extirpación quirúrgica, y el restante 3 por ciento son malignos, y provocar metástasis a distancia. Alrededor del 75 por ciento son esporádicos y el restante 25 por ciento son hereditarios (y tienen una mayor probabilidad de ser múltiples y de desarrollo a una edad temprana). Pueden tener predisposición genética asociada a síndromes tumorales familiares, como la neoplasia endocrina múltiple tipo 2, el síndrome de Von Hippel-Lindau y la neurofibromatosis tipo 1, o mutaciones específicas relacionadas solamente con el desarrollo de paragangliomas. Comparado con la forma de aparición esporádica, la presentación familiar tiene tendencia a aparecer en edades más jóvenes, y a tener múltiple localización. Por la poca disponibilidad de recursos y lo costoso de las investigaciones utilizadas, son de difícil diagnóstico en nuestro medio, por lo cual no se excluye que exista un subregistro en el número de casos que se puedan presentar, razón por la que es importante siempre -ante la sospecha clínica- pensar en su probable confirmación diagnóstica y situación. Los estudios de imágenes y la medición de la producción no fisiológica de catecolaminas, pueden ayudar en el diagnóstico de esta entidad. Las principales modalidades de tratamiento son: la cirugía, la embolización y la radioterapia. Con el objetivo de actualizar y sugerir una guía de tratamiento se realizó la presente revisión(AU)

Paraganglioma is a rare neuroendocrine tumor that may occur in several parts of the body. Roughly 97 percent of these tumors are benign and can be excised through surgery whereas 3 percent of them are malignant and cause distant metastasis. Almost 75 percent are sporadic and the remaining 25 percent are hereditary (more likely to be multiple and developed at early ages). They may be genetically predisposed and associated to family tumor syndromes such as type 2 multiple endocrine neoplasia, Von Hippel-Lindau syndrome and type 1 neurofibromatosis or specific mutations related to development of paragangliomas. When compared to the sporadic occurrence, the family presentation tends to appear at younger ages, with multiple locations. Owing to the low resource availability and the high cost of research, these tumors are difficult to be diagnosed in our conditions, so there may be failures in registering the real number of cases; this is the reason why it is always important to think on possible diagnostic confirmation when clinical suspicion of paraganglioma arises. Imaging studies and measurement of the non-physiological production of catecholamines may help in the diagnosis of this disease. The main therapeutical modalities are surgery, embolization and radiotherapy. The present review was intended to update this topic and to submit a treatment guideline(AU)

Cardiovascular catecholamine receptors in children: their significance in cardiac disease.

Adrenoceptors and dopamine receptors are grouped together under the name 'catecholamine receptors.' Catecholamines and catecholaminergic drugs act on catecholamine receptors located on or near the cardiovascular system. The physiological effects of catecholamine receptor stimulation are only partly understood. The catecholaminergic drugs used in critical care medicine today are not selective, or are, at best, in part selective for the various catecholamine receptor subtypes. Many patients, however, depend on them. A variety of animal models has been developed to unravel catecholamine distribution and function. However, the identification of species heterogeneity makes it imperative to determine catecholamine receptor distribution and function in humans. In addition, age-related alterations in catecholamine receptor distribution and function have been identified in human adults. This might have implications for our understanding of the effect of catecholamines in pediatric patients. This article will focus on the pediatric population and will review currently available in vitro data on the distribution and the function of catecholamine receptors in the cardiovascular system of fetuses and children. Also discussed are relevant young animal models and in vivo hemodynamic effects of cardiotonic drugs acting on the catecholamine receptor in children requiring major cardiac surgery. A better understanding of these topics might provide clues for new, receptor subtype-selective, therapeutic approaches in newborns and children with cardiac disease.

Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders.

The primary symptoms of attention deficit/hyperactivity disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the "top-down" regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α(2A)-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α(2A)-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.

Aging of the autonomic nervous system and possible improvements in autonomic activity using somatic afferent stimulation.

There are significant age-related changes in autonomic nervous system function that are responsible for an impaired ability to adapt to environmental or intrinsic visceral stimuli in the elderly. We review data on changes in autonomic nervous system regulation of cardiovascular and urinary function, as well as data on strategies to improve function. There are data showing alterations in peripheral and central autonomic nerve activity, and decreases in neurotransmitter receptor action that lead to diminished autonomic reactivity (e.g. blood pressure and cerebral blood flow regulation) and poorly coordinated autonomic discharge (e.g. bladder function). Simple strategies for autonomic function improvement and increasing cortical blood flow include walking and somatic afferent stimulation (e.g. stroking skin or acupuncture) to increase sympathetic, parasympathetic and central cholinergic activity.

The neurobiology of the switch process in bipolar disorder: a review.

OBJECTIVE: The singular phenomenon of switching from depression to its opposite state of mania or hypomania, and vice versa, distinguishes bipolar disorder from all other psychiatric disorders. Despite the fact that it is a core aspect of the clinical presentation of bipolar disorder, the neurobiology of the switch process is still poorly understood. In this review, we summarize the clinical evidence regarding somatic interventions associated with switching, with a particular focus on the biologic underpinnings presumably involved in the switch process. DATA SOURCES: Literature for this review was obtained through a search of the MEDLINE database (1966-2008) using the following keywords and phrases: switch, bipolar disorder, bipolar depression, antidepressant, SSRIs, tricyclic antidepressants, norepinephrine, serotonin, treatment emergent affective switch, mania, hypomania, HPA-axis, glucocorticoids, amphetamine, dopamine, and sleep deprivation. STUDY SELECTION: All English-language, peer-reviewed, published literature, including randomized controlled studies, naturalistic and open-label studies, and case reports, were eligible for inclusion. DATA SYNTHESIS: Converging evidence suggests that certain pharmacologic and nonpharmacologic interventions with very different mechanisms of action, such as sleep deprivation, exogenous corticosteroids, and dopaminergic agonists, can trigger mood episode switches in patients with bipolar disorder. The switch-inducing potential of antidepressants is unclear, although tricyclic antidepressants, which confer higher risk of switching than other classes of antidepressants, are a possible exception. Several neurobiological factors appear to be associated with both spontaneous and treatment-emergent mood episode switches; these include abnormalities in catecholamine levels, up-regulation of neurotrophic and neuroplastic factors, hypothalamic-pituitary-adrenal axis hyperactivity, and circadian rhythms. CONCLUSIONS: There is a clear need to improve our understanding of the neurobiology of the switch process; research in this field would benefit from the systematic and integrated assessment of variables associated with switching.

The receptor fingerprint of the human brain and its changes during life.

With the help of PET one can explore the various neurotransmitter-neuroreceptor systems, their interactive balance and their changes during life, i.e., the human brain receptor fingerprint: the highly individual composition of, and balance among, the various receptor systems can be measured both qualitatively (the presence of various receptors in different brain regions) and quantitatively (the density of the receptors, their binding potential, occupancy, etc.). The understanding of the normal constitution of the primate brain neurotransmitter-receptor systems and their pathological changes requires multiligand receptor mapping, using various PET radioligands. Some major components of our brain receptor fingerprint strictly correlate with personality traits, character and temperament, and most probably, with "cognitive styles", as well. The brain receptor fingerprint is continuously changing during our normal life (maturation, ageing) and short term physiological or pharmacological challenges (sensory or cognitive processes, drug administration etc.) can also modify it. Social interactions, learning, habituation and other lasting interactions with our social and physical environment can significantly modify the receptor fingerprint. Pathological conditions, including neurological and psychiatric diseases strongly affect the normal neuroreceptor-neurotransmitter balance of the brain, as do pharmacological treatments or drug abuse.

Arritmias y muerte súbita en la taquicardia ventricular catecolaminérgica de origen hereditario / Ventricular arrhythmias of catecholaminergic origin and sudden death

The hereditary disease known as polymorphic catecholaminergic ventricular tachycardia (PCVT) is highly lethal. Almost 30% of the affected patients die before 40 years old, mainly due to sudden cardiac death. We have used isolated hearts from mutant mice (type 2 ryanodine receptors, RyR2/RyR2(R4496C)) to investigate arrhythmia mechanisms that are adrenergic- and intracellular calcium ([Ca2+]o) levels-dependent. Our results corroborate that polymorphic and bidirectional ventricular arrhythmias, as well as ventricular fibrillation, occurs in 50% of RyR2/ RyR2(R4496C) mice, and in less than 12% of the non-affected mice. Our hypothesis suggests that the origin of catecholaminergic arrhythmias in animals, and possibly in humans, is conditioned by the focal activity that begins by late post-potentials in the Purkinje fibers.

Mechanisms of abnormal calcium homeostasis in mutations responsible for catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia is a heritable arrhythmia unmasked by exertion or stress and is characterized by triggered activity and sudden cardiac death. In this study, we simulated mutations in 2 genes linked to catecholaminergic polymorphic ventricular tachycardia, the first located in calsequestrin (CSQN2) and the second in the ryanodine receptor (RyR2). The aim of the study was to investigate the mechanistic basis for spontaneous Ca2+ release events that lead to delayed afterdepolarizations in affected patients. Sarcoplasmic reticulum (SR) luminal Ca2+ sensing was incorporated into a model of the human ventricular myocyte, and CSQN2 mutations were modeled by simulating disrupted RyR2 luminal Ca2+ sensing. In voltage-clamp mode, the mutant CSQN2 model recapitulated the smaller calcium transients, smaller time to peak calcium transient, and accelerated recovery from inactivation seen in experiments. In current clamp mode, in the presence of beta stimulation, we observed delayed afterdepolarizations, suggesting that accelerated recovery of RyR2 induced by impaired luminal Ca2+ sensing underlies the triggered activity observed in mutant CSQN2-expressing myocytes. In current-clamp mode, in a model of mutant RyR2 that is characterized by reduced FKBP12.6 binding to the RyR2 on beta stimulation, the impaired coupled gating characteristic of these mutations was modeled by reducing cooperativity of RyR2 activation. In current-clamp mode, the mutant RyR2 model exhibited increased diastolic RyR2 open probability that resulted in formation of delayed afterdepolarizations. In conclusion, these minimal order models of mutant CSQN2 and RyR2 provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers for arrhythmia, with implications for the development of targeted therapy.

[Ventricular arrhythmias of catecholaminergic origin and sudden death]. / Arritmias y muerte súbita en la taquicardia ventricular catecolaminérgica de origen hereditario.

The hereditary disease known as polymorphic catecholaminergic ventricular tachycardia (PCVT) is highly lethal. Almost 30% of the affected patients die before 40 years old, mainly due to sudden cardiac death. We have used isolated hearts from mutant mice (type 2 ryanodine receptors, RyR2/RyR2(R4496C)) to investigate arrhythmia mechanisms that are adrenergic- and intracellular calcium ([Ca2+]o) levels-dependent. Our results corroborate that polymorphic and bidirectional ventricular arrhythmias, as well as ventricular fibrillation, occurs in 50% of RyR2/ RyR2(R4496C) mice, and in less than 12% of the non-affected mice. Our hypothesis suggests that the origin of catecholaminergic arrhythmias in animals, and possibly in humans, is conditioned by the focal activity that begins by late post-potentials in the Purkinje fibers.

Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics.

Cognitive complaints are a frequent source of distress and disability after mild and moderate traumatic brain injury (TBI). While there are deficits in several cognitive domains, many aspects of these complaints and deficits suggest that problems in working memory (WM) play an important role. Functional imaging studies in healthy individuals have outlined the neural substrate of WM and have shown that regions important in WM circuitry overlap with regions commonly vulnerable to damage in TBI. Use of functional MRI (fMRI) in individuals with mild and moderate TBI suggests that they can have problems in the activation and allocation of WM, and several lines of evidence suggest that subtle alterations in central catecholaminergic sensitivity may underlie these problems. We review the evidence from fMRI and neurogenetic studies that support the role of catecholaminergic dysregulation in the etiology of WM complaints and deficits after mild and moderate TBI.

Activation by p-chloroamphetamine of the spinal ejaculatory pattern generator in anaesthetized male rats.

In urethane-anesthetized male rats, a branch of the hypogastric nerve was shown, anatomically and electrophysiologically, to supply the vas deferens. Recordings from this nerve revealed a low level of tonic activity, which was predominantly efferent motor activity. Administration of p-chloroamphetamine i.v., elicited a rhythmic burst of neuronal activity, coherent with rhythmic pressure increases in the vas deferens and contractions of the bulbospongiosus muscles, which together comprise ejaculation. This response to p-chloroamphetamine was still present after complete transection of the spinal cord at T8-T9. These data indicate that p-chloroamphetamine is capable of activating the spinal neuronal circuits that generate the pattern of autonomic and somatic responses similar to those of sexual climax. Furthermore based on the best documented action of p-chloroamphetamine, the results suggest that the excitability of the pattern generator is regulated by serotonergic, dopaminergic or noradrenergic receptors in the lumbosacral spinal cord. We conclude this animal model will enable robust studies of the pharmacology and physiology of central neural mechanisms involved in ejaculation and sexual climax.

[Catecholamines: biochemistry, pharmacology, physiology, clinical aspects]. / Katekholaminy: biokhimiia, farmakologiia, fiziologiia, klinika.

Catecholamines (CAs) realise activity of certain cerebral neurons, sympathoadrenal system and peripheral cells producing dopamine. CAs control metabolism, template biosynthesis, cytological, physiological and psychological processes. During recent 10-15 years complex employment of various interdisciplinary approaches (including molecular biology techniques) resulted in some important achievements. Cellular transporters and 10 individual receptors were discovered and studied. Basic mechanisms of CA signal transduction into nucleus and mitochondria, regulation of gene expression, hyperplasia, hypertrophy and biological oxidation have been recognised. It was found that besides central neurotransmitter action DA also acts as peripheral auto- and paracrinic hormone. CA participate in pathogenesis of many illnesses and in the defence mechanisms of a body. CA and related substances are effective and widely used drugs.

Dopamina: síntesis, liberación y receptores en el Sistema Nervioso Central / Dopamine: synthesis, release and receptors in the central nervous system

La dopamina es el neurotransmisor catecolaminérgico más importante del Sistema Nervioso Central (SNC) de los mamíferos y participa en la regulación de diversas funciones como la conducta motora, la emotividad y la afectividad así como en la comunicación neuroendócrina. La dopamina se sintetiza a partir del aminoácido L-tirosina y existen mecanismos que regulan de manera muy precisa su síntesis y liberación. Las técnicas de clonación molecular han permitido la identificación de 5 tipos de receptores dopaminérgicos, todos ellos acoplados a proteínas G y divididos en dos familias farmacológicas denominadas D1 y D2. Los receptores de la familia D1 (subtipos D1 y D5) están acoplados a proteínas Gs y estimulan la formación de AMPc como principal mecanismo de transducción de señales. Los subtipos pertenecientes a la familia D2 (D2, D3 y D4) inhiben la formación de AMPc, activan canales de K+ y reducen la entrada de iones de Ca2+ a través de canales dependientes del voltaje, efectos mediados también por proteínas G (Gai y Gao). Los receptores dopaminérgicos se encuentran ampliamente distribuidos en diversas áreas del SNC (aunque de manera diferencial de acuerdo al subtipo) donde son responsables de las diversas acciones fisiológicas de la dopamina. El estudio de los sistemas y receptores dopaminérgicos del SNC ha generado gran interés, debido a que diversas alteraciones en la transmisión dopaminérgica han sido relacionadas, directa o indirectamente, con transtornos severos como la enfermedad de Parkinson y la esquizofrenia, así como con la adicción a drogas (anfetaminas y cocaína por ejemplo).