bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Cyclooxygenase‐2 and Brain Reactive Astrogliosis by Purinergic P2 Receptors
Authors: BRAMBILLA ROBERTA , ABBRACCHIO MARIA P.
Published: July 2010

Abstract:Astroglial cells respond to trauma and ischemia with reactive gliosis, a reaction characterized by increased astrocytic proliferation and hypertrophy. Although beneficial to a certain extent, excessive gliosis may be detrimental, contributing to neuronal death in neurodegenerative diseases. We have tested the hypothesis that ATP may act as a trigger of reactive gliosis in anin vitromodel (rat brain primary astrocytes) where reactive astrogliosis can be quantified as elongation of astrocytic processes. Challenge of cells with the ATP analog α,βmethyleneATP (α,βmeATP) resulted in concentration dependent elongation of astrocytic processes, an effect that was fully counteracted by the non‐selective ATP/P2 receptor antagonists suramin and pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS). Signalling studies revealed that α,βmeATP‐induced gliosis is mediated by a novel G‐protein‐coupled receptor (a P2Y receptor) coupled to an early release of arachidonic acid. Challenge of cells with α,βmeATP also resulted in an increase of inducible cyclooxygenase‐2 (COX‐2), the activity of which has been reported to be pathologically increased in a variety of neurodegenerative diseases characterized by inflammation and astrocytic activation. Induction of COX‐2 by α,βmeATP was causally related to reactive astrogliosis, since the selective COX‐2 inhibitor NS‐398 prevented both the purine‐induced elongation of astrocytic processes and the associated COX‐2 increase. Preliminary data on the putative receptor‐to‐nucleus pathways responsible for purine‐induced gliosis suggest that induction of the COX‐2 gene may occur through the protein kinase C/mitogen activated protein kinase system, and may involve the formation of activated AP‐1 transcription complexes. We speculate that antagonists selective at this novel P2Y receptor subtype may represent a novel class of neuroprotective agents able to slow down neurodegeneration by counteracting the inflammatory events contributing to neuronal cell death.
The A3Adenosine Receptor Induces Cytoskeleton Rearrangement in Human Astrocytoma Cells via a Specific Action on Rho Proteins
Authors: ABBRACCHIO MARIA P. , CAMURRI ALESSANDRA , CERUTI STEFANIA , CATTABENI FLAMINIO , FALZANO LOREDANA , GIAMMARIOLI ANNA MARIA , JACOBSON KENNETH A. , TRINCAVELLI LETIZIA , MARTINI CLAUDIA , MALORNI WALTER , FIORENTINI CARLA
Published: July 2010

Abstract:In previous studies, we have demonstrated that exposure of astroglial cells to A3adenosine receptor agonists results in dual actions on cell survival, with “trophic” and antiapoptotic effects at nanomolar concentrations and induction of cell death at micromolar agonist concentrations. The protective actions of A3agonists have been associated with a reinforcement of the actin cytoskeleton, which likely results in increased resistance of cells to cytotoxic stimuli. The molecular mechanisms at the basis of this effect and the signalling pathway(s) linking the A3receptor to the actin cytoskeleton have never been elucidated. Based on previous literature data suggesting that the actin cytoskeleton is controlled by small GTP‐binding proteins of the Rho family, in the study reported here we investigated the involvement of these proteins in the effects induced by A3agonists on human astrocytoma ADF cells. The presence of the A3adenosine receptor in these cells has been confirmed by immunoblotting analysis. As expected, exposure of human astrocytoma ADF cells to nanomolar concentrations of the selective A3agonist 2‐chloro‐N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluronamide (Cl‐IB‐MECA) resulted in formation of thick actin positive stress fibers. Preexposure of cells to the C3B toxin that inactivates Rho‐proteins completely prevented the actin changes induced by Cl‐IB‐MECA. Exposure to the A3agonist also resulted in significant reduction of Rho‐GDI, an inhibitory protein known to maintain Rho proteins in their inactive state, suggesting a potentiation of Rho‐mediated effects. This effect was fully counteracted by the concomitant exposure to the selective A3receptor antagonist MRS1191. These results suggest that the reinforcement of the actin cytoskeleton induced by A3receptor agonists is mediated by an interference with the activation/inactivation cycle of Rho proteins, which may, therefore, represent a biological target for the identification of novel neuroprotective strategies.
Monitoring for Neuroprotection
Authors: ANDREWS RUSSELL J.
Published: July 2010

Abstract: Monitoring for neuroprotection, like surgery, has placed an emphasis on minimal or non‐invasiveness. Monitoring of parameters that truly reflect the degree of injury to the nervous system is another goal. Thus, two themes for the coming decade in neuromonitoring will be: (1) less‐invasive monitoring; and (2) parameters that more closely reflect the etiological factors in ischemic or other neuroinjury. In this paper, we review neuromonitoring techniques and devices that can be used readily in the operating room or intensive care unit setting. Those that require transport of the patient to a special facility (e.g., for computed tomography or magnetic resonance imaging/spectroscopy) and those that have been in standard practice for neuromonitoring (e.g., electrophysiological monitoring—EEG, evoked potentials) are not considered. The two techniques considered in detail are (1) continuous multiparameter local brain tissue monitoring with microprobes, and (2) non‐invasive continuous local brain tissue oxygenation monitoring by near infrared spectroscopy. Both techniques have been cleared by the Food and Drug Administration (FDA) for clinical use. The rationale for their use, the nature of the devices, and clinical results to date are reviewed. It is expected that both techniques will gain wide acceptance during the coming decade; further advances in neuromonitoring that can be expected further into the twenty‐first century are also discussed.
Neuroprotection for the New Millennium
Authors: ANDREWS RUSSELL J.
Published: July 2010

Abstract: A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention—hence the abandonment of the “magic bullet” single pharmacologic agent for neuroprotection in favor of pharmacologic “cocktails”. A second theme of the 1990s has been the progress in technology for neuroprotection, minimally‐ or non‐invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely “jamming” the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or “hardware” interventions to influence the programming or “software” of the nervous system's physiologic response in certain disease states.
Neuroprotective Effects of Novel Cholinesterase Inhibitors Derived from Rasagiline as Potential Anti‐Alzheimer Drugs
Authors: WEINSTOCK MARTA , KIRSCHBAUM‐SLAGER NATANJA , LAZAROVICI PHILIP , BEJAR CORINA , YOUDIM MOUSSA B.H. , SHOHAM SHAI
Published: July 2010

Abstract: TV3326, (N‐propargyl‐(3R)‐aminoindan‐5‐yl‐ethyl, methyl carbamate) was prepared in order to combine the neuroprotective effects of rasagiline, a selective inhibitor of monoamine oxidase (MAO)‐B with the cholinesterase (ChE) inhibitory activity of rivastigmine as a potential treatment for Alzheimer's disease. The study reported here examined the neuropotective effects of TV3326 against various insults in vitro and in vivo. TV3326 caused a dose related (10–500 μM) reduction in death induced in NGF differentiated rat pheochromocytoma (PC12) cells by 3–4 hour exposure to oxygen‐glucose deprivation. A single sc injection of TV3326 given five minutes after closed head injury in mice significantly reduced the cerebral edema, and accelerated the recovery of motor function and spatial memory several days later. Unilateral icv injection of streptozotocin (STZ) 1.5 mg in rats, caused specific damage to myelinated neurones in the fornix and corpus callosum accompanied by microgliosis. Three bilateral injections of STZ, 0.25 mg each, caused more widespread damage, and a marked impairment in spatial memory. Chronic oral treatment with TV3326 (75 μmols/kg) reduced the neuronal damage and microgliosis and almost completely prevented the memory impairment. The neuroprotective effect in PC12 cells may be due to a combination of ChE inhibition and antiapoptotic activity. The latter does not result from ChE inhibition. It is associated with the presence of the propargyl group, since it occurs with other propargylamines that do not inhibit MAO, but not with drugs that inhibit only ChE.
Rescue of Dying Neurons by (R)‐Deprenyl in the MPTP‐Mouse Model of Parkinson's Disease Does Not Include Restoration of Neostriatal Dopamine
Authors: STEYN STEFANUS J. , CASTAGNOLI KAY , CASTAGNOLI NEAL
Published: July 2010

Abstract: Chronic (8‐ to 10‐week) administration of the selective, potent, and irreversible monoamine oxidase B inhibitor (R)‐deprenyl has been shown to increase the tyrosine hydroxylase immunoreactivity in the substantia nigra of mice that had been treated three days earlier with a neurotoxic dose of the parkinsonian‐inducing agent 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). This reported rescuing of lesioned nigrostriatal cell bodies by (R)‐deprenyl prompted us to investigate if this (R)‐deprenyl treatment also could restore neostriatal dopamine levels that are depleted by MPTP. The results of these experiments show that long term (8 or 10 weeks) treatment with (R)‐deprenyl beginning three days post MPTP administration did not result in restoration of depleted neostriatal dopamine levels in C57BL/6 mice. We conclude that, although (R)‐deprenyl may rescue MPTP‐injured nigrostriatal neurons, it does not lead to functional recovery of these neurons as measured by the restoration of neostriatal dopamine levels.
Biomarkers of 3‐Nitropropionic Acid (3‐NPA)‐Induced Mitochondrial Dysfunction as Indicators of Neuroprotection
Authors: SCALLET A.C. , NONY P.L. , ROUNTREE R.L. , BINIENDA Z.K.
Published: July 2010

Abstract:In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3‐Nitropropionic acid (3‐NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans.In vitro, 3‐NPA irreversibly inactivates SDH, a Complex II respiratory enzyme important for mitochondrial energy production. We have been studying biomarkers of 3‐NPA exposure in the expectation that such markers may be useful in the screening process to identify neuroprotective agents against neurotoxicity produced by mitochondrial energy dysfunction. Animals were sacrificed at various times after 3‐NPA exposure for histochemical visualization of SDH activity and measurement of immediate postmortem rectal temperature. 3‐NPA‐treated rats experienced progressive hypothermia that reached a loss of 3°C or more in core body temperature by three hours after dosing. The optical density of the SDH stain in brain was reduced, following a similar time course, most prominently in the cerebellum and least sharply in the thalamus. Some rats were given injections of l‐carnitine (an enhancer of fatty acid transport) either alone, or as a pretreatment prior to a dose of 3‐NPA. Although l‐carnitine deficiency by itself can produce mitochondrial dysfunction, pretreatment with l‐carnitine was of limited efficacy at overcoming the effects of 3‐NPA on either body temperature or quantitative SDH histochemistry. Body temperature and SDH histochemistry may be useful biomarkers for evaluating the efficacy of neuroprotective agents against lower doses of 3‐NPA, against other pharmacological models of mitochondrial dysfunction, or even against genetic mitochondrial diseases.
Mechanisms Determining Sensitivity of Baroreceptor Afferents in Health and Disease
Authors: CHAPLEAU MARK W. , LI ZHI , MEYRELLES SILVANA S. , MA XIUYING , ABBOUD FRANÇOIS M.
Published: July 2010

Abstract: Baroreceptors sense and signal the central nervous system of changes in arterial pressure through a series of sensory processes. An increase in arterial pressure causes vascular distension and baroreceptor deformation, the magnitude of which depends on the mechanical viscoelastic properties of the vessel wall. Classic methods (e.g., isolated carotid sinus preparation) and new approaches, including studies of isolated baroreceptor neurons in culture, gene transfer using viral vectors, and genetically modified mice have been used to define the cellular and molecular mechanisms that determine baroreceptor sensitivity. Deformation depolarizes the nerve endings by opening a new class of mechanosensitive ion channel. This depolarization triggers action potential discharge through opening of voltage‐dependent sodium (Na+) and potassium (K+) channels at the “spike initiating zone” (SIZ) near the sensory terminals. The resulting baroreceptor activity and its sensitivity to changes in pressure are modulated through a variety of mechanisms that influence these sensory processes. Modulation of voltage‐dependent Na+ and K+ channels and the Na+ pump at the SIZ by membrance potential, action potential discharge, and chemical autocrine and paracrine factors are important mechanisms contributing to changes in baroreceptor sensitivity during sustained increases in arterial pressure and in pathological states associated with endothelial dysfunction, oxidative stress, and platelet activation.
Properties of NTS Neurons Receiving Input from Barosensitive Receptors
Authors: SEAGARD J. L. , DEAN C. , HOPP F. A.
Published: July 2010

Abstract: Afferent input from barosensitive receptors, including carotid baroreceptors and cardiac mechanoreceptors, has been found to produce different types of discharge patterns in neurons in the nucleus tractus solitarius (NTS). The discharge patterns of the neurons may be dependent on many factors, including input from the different barosensitive receptor subtypes, the contribution of different ionotropic glutamate receptors [NMDA (N‐methyl‐D‐aspartate) versus nonNMDA receptors] in transmission of the input, effects of different neuropeptide neurotransmitters/neuromodulators on afferent transmission, or the order of the neuron within the barosensitive reflex arc. It is not clear if the roles of the glutamate receptor subtypes are the same for neurons activated by the different barosensitive inputs. In addition, the amount of afferent input from the barosensitive receptors, due to increases or decreases in stimulating pressures, may result in altering the roles of the ionotropic glutamate receptor subtypes. While most evidence suggests that nonNMDA receptors play the greatest role in the transmission of afferent activity to second‐order NTS neurons, it is possible that increases in afferent input may lead to an enhanced role for NMDA receptors in the transmission of the barosensitive input, since increased depolarization of the NTS neurons may lead to removal of a Mg2+ block of the NMDA channel. Transmission of baroreceptor input at third‐ and higher‐order neurons has been found to involve both nonNMDA and NMDA receptors, suggesting a possible functional role for the distribution of these receptor types. The roles of these different factors in the initiation of NTS neuronal discharge will be discussed.
Oxytocin in the NTS
Authors: MICHELINI LISETE COMPAGNO
Published: July 2010

Abstract: The role of brain stem oxytocinergic projections in the modulation of heart rate control during exercise is discussed on the basis of both changes in endogenous peptide content and heart rate changes observed during exercise. Running on a treadmill caused an increase in oxytocin content in dorsal/ ventral brain stem areas and spinal cord, specifically in trained rats. Trained rats pretreated with a specific oxytocin receptor antagonist into the dorsal brain stem area (corresponding to the nucleus tractus solitarii and dorsal motor nucleus of the vagus, or NTS/DMV) showed a significant potentiation of exercise tachycardia with no change in the blood pressure response. The same treatment in sedentary rats was without effect. On the other hand, administration of exogenous oxytocin into this area caused significant blunting of exercise tachycardia in both groups, with no change in the pressure response. It is proposed that long‐descending oxytocinergic pathways from the hypothalamus to the NTS/DMV area serve as a link between the two main neural controllers of the circulation—that is, the central command and feedback control mechanisms driven by the peripheral receptor signals. Our results strongly suggest that oxytocinergic input to NTS/DMV, by restraining the tachycardic response of trained individuals, contributes to the smaller response observed after training, without compromising cardiac output adjustment and the circulatory demand during exercise.
The Role of the Medullary Lateral Tegmental Field in the Generation and Baroreceptor Reflex Control of Sympathetic Nerve Discharge in the Cat
Authors: BARMAN SUSAN M. , ORER HAKAN S. , GEBBER GERARD L.
Published: July 2010

Abstract:Data from experiments with single neuron recordings as well as central microinjections ofN‐methyl‐d‐aspartate (NMDA) and non‐NMDA excitatory amino receptor antagonists that have led to a model of central sympathetic pathways that includes synaptic relays in the medullary lateral tegmental field (LTF) of the cat are summarized. Evidence is presented that (1) the LTF contains a population of tonically active sympathoexcitatory neurons that drive rostral ventrolateral medullary neurons, (2) blockade of non‐NMDA receptors in the LTF significantly reduces basal levels of sympathetic nerve discharge (SND) and mean arterial pressure in baroreceptor‐denervated cats, and (3) blockade of NMDA‐mediated neurotransmission in the LTF prevents baroreceptor reflex control of SND. Thus, LTF neurons play an important role in the generation and baroreceptor reflex control of SND in the cat.
Heterogeneous Receptor Distribution in Autonomic Neurons
Authors: AICHER SUE A.
Published: July 2010

Abstract:The central nervous system components for baroreflex regulation of sympathetic outflow include specific sets of neurons in the brain and spinal cord. Critical nuclei containing sympathetic baroreceptive neurons are the nuclei of the solitary tract, regions of the caudal and rostral ventrolateral medulla, and the intermediolateral cell column in the spinal cord. While many other brain regions project to these nuclei, cells in these areas appear to form the minimal required pathway for baroreflex control of sympathetic outflow. Synaptic connections have been identified between cells in these nuclei that are consistent with a serial relay from baroreceptor afferents through the brain stem and to sympathetic preganglionic neurons in the spinal cord. In recent years, we have examined the distribution of receptor proteins in these neurons, with a focus on receptors that are most likely to modulate the activity of these cells. In three studies examining the distribution of different receptors on distinct neurons, each study found some type of heterogeneity in the distribution of each receptor within a particular type of neuron. This heterogeneity was seen with regard to the distribution of receptor protein within the dendritic tree of individual neurons, as well as between pre‐ and postsynaptic sites on the same cell. This heterogeneous distribution of receptors suggests that receptors undergo dendritic targeting within autonomic neurons. This receptor trafficking may be regulated by heterogeneous afferent input to autonomic neurons and could be changed under conditions where afferent activity is significantly altered.
CNS Effects of Ovarian Hormones and Metabolites on Neural Control of Circulation
Authors: HEESCH CHERYL M. , FOLEY C. MICHAEL
Published: July 2010

Abstract:Pregnant women often experience orthostatic hypotension, and pregnancy is associated with increased susceptibility to hemorrhagic hypotension. Experiments evaluating arterial baroreflex control of efferent sympathetic nerve activity in virgin and term‐pregnant rats revealed that arterial baroreflex sympathoexcitation is attenuated, while sympathoinhibitory responses are well‐maintained or potentiated. Following a hypotensive challenge, pregnant animals exhibit attenuated Fos expression in the rostral ventrolateral medulla (RVLM), suggesting that unloading of arterial baroreceptors results in less excitation of presympathetic neurons in the brain stem. Other experiments, in which afferent baroreceptor discharge was recorded, suggest that this was not due to differences in afferent baoreceptor function. GABAergic mechanisms are responsible for tonic inhibition of sympathoexcitatory neurons in the RVLM and the major metabolite of progesterone, 3α‐OH‐dihydroprogesterone (3α‐OH‐DHP), which is elevated in pregnancy, is the most potent endogenous positive modulator of CNS GABAAreceptor function. Additional experiments revealed that acutely administered 3α‐OH‐DHP, either intravenously or directly into the RVLM, mimicked the effects of pregnancy on baroreflex control of efferent sympathetic nerve activity and potentiated pressure sensitivity of spinally projecting RVLM neurons. Preliminary experiments using semiquantitative RT‐PCR, evaluated the relative expression of three subunits (α1–3) of the GABAAreceptor, and suggest that chronic exposure to elevated levels of ovarian hormones can result to changes in GABAAreceptor subunit composition. It is likely that changes in control of sympathetic outflow in pregnancy are related to complex interactions between genomic and nongenomic actions of ovarian hormones and metabolites.
Central Angiotensin and Baroreceptor Control of Circulation
Authors: HEAD GEOFFREY A. , MAYOROV DMITRY N.
Published: July 2010

Abstract:Angiotensin (Ang) receptors are located in many important central nuclei involved in the regulation of the cardiovascular system. While most interest has focused on forebrain circumventricular actions, areas of the brainstem such as the nucleus of the solitary tract and the ventrolateral medulla contain high concentrations of AT1receptors. The present review encompasses the physiological role of Ang II in the hindbrain, particularly in relation to its influence on baroreflex control mechanisms. In rabbits there are sympatho‐excitatory AT1receptors in the rostral ventrolateral medulla (RVLM), accessible to Ang II from the cerebrospinal fluid. Activation of these receptors acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. However, blockade of endogenous Ang receptors in the brainstem also shows sympathoexcitation, suggesting there is greater endogenous activity of a sympathoinhibitory Ang II action. Microinjections of angiotensin antagonists into the RVLM showed relatively little tonic activity of endogenous Ang II influencing sympathetic activity in conscious rabbits. However, Ang II receptors in the RVLM mediate sympathetic responses to airjet stress in conscious rabbits. Similarly with respect to heart rate baroreflexes, there appears to be little tonic effect of angiotensin in the brainstem in normal conscious animals. Chronic infusion of Ang II for two weeks into the fourth ventricle of conscious rabbits inhibits the cardiac baroreflex while infusion of losartan increases the gain of the reflex. These actions suggest that Ang II in the brainstem modulates sympathetic responses depending on specific afferent and synaptic inputs in both the short term but importantly also in the long term, thus forming an important mechanism for increasing the range of adaptive response patterns.
Peripheral and Central Interactions between the Renin‐Angiotensin System and the Renal Sympathetic Nerves in Control of Renal Function
Authors: DiBONA GERALD F.
Published: July 2010

Abstract:Increases in renal sympathetic nerve activity (RSNA) regulate the functions of the nephron, the vasculature, and the renin‐containing juxtaglomerular granular cells. As increased activity of the renin‐angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between RSNA and the renin‐angiotensin system in the control of renal function. These interactions can be intrarenal, that is, the direct (via specific innervation) and indirect (via angiotensin II) contributions of increased RSNA to the regulation of renal function. The effects of increased RSNA on renal function are attenuated when the activity of the renin‐angiotensin system is suppressed or antagonized with angiotensin‐converting enzyme inhibitors or angiotensin II‐type AT1receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated following renal denervation. These interactions can also be extrarenal, that is, in the central nervous system, wherein RSNA and its arterial baroreflex control are modulated by changes in activity of the renin‐angiotensin system. In addition to the circumventricular organs, the permeable blood‐brain barrier of which permits interactions with circulating angiotensin II, there are interactions at sites behind the blood‐brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II type AT1receptor antagonists, into the ventricular system or microinjected into the rostral ventrolateral medulla, are modulated by changes in activity of the renin‐angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin‐angiotensin and sympathetic nervous systems is increased (e.g., congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin‐angiotensin system and RSNA are involved in influencing the neural control of renal function.
The Regulation of Sympathetic Outflow in Heart Failure
Authors: ZUCKER IRVING H. , WANG WEI , PLIQUETT RAINER U. , LIU JUN‐LI , PATEL KAUSHIK P.
Published: July 2010

Abstract:Sympatho‐excitation is a hallmark of the chronic heart failure (CHF) state. It has long been assumed that this sympatho‐excitation is mediated by a reduction in sensory input from cardiopulmonary and arterial baroreceptors. However, recent data suggest that these reflexes may only be important in the initiation of the sympatho‐excitatory state and may not be necessary for the sustained increase in sympathetic nerve activity (SNA) in CHF. Two humoral factors that can influence SNA are nitric oxide (NO) and angiotensin II (AngII). Animals with CHF exhibit a downregulation in central gene expression for the neuronal isoform of nitric oxide synthase (nNOS). In addition, blockade of AngII receptors in combination with NO donation reduces SNA in animals with CHF, while NO donation alone has no effect on SNA. Chronic exercise training (EX) reduces both plasma AngII and SNA in rabbits with CHF while improving baroreflex function. Blockade of AT1receptors enhances baroreflex function in non‐EX CHF rabbits, but has little effect in EX CHF rabbits. These data suggest that the sympatho‐excitatory state that is typical of CHF is, in part, due to changes in AngII and NO. Depressed baroreflex function and the elevated SNA can be improved by EX in animals with CHF.
Regulation of Sympathetic Nervous System Function after Cardiovascular Deconditioning
Authors: HASSER EILEEN M. , MOFFITT JULIA A.
Published: July 2010

Abstract:Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb‐unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex‐mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex‐mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA‐mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.
Dynamic Modulation of Baroreflex Sensitivity in Health and Disease
Authors: PARATI GIANFRANCO , Di RIENZO MARCO , MANCIA GIUSEPPE
Published: July 2010

Abstract:Assessment of arterial baroreflex function in humans through laboratory tests has provided a great deal of information of pathophysiological and clinical relevance. Indeed, the sensitivity of the baroreceptor‐heart rate reflex quantified through these laboratory methods was shown to predict the risk of cardiovascular events and death from myocardial infarction, heart failure, and in diabetic patients. This traditional approach, however, does not provide information on daily life baroreflex cardiovascular control. Modern techniques, based on computer analysis of spontaneous blood pressure and heart rate fluctuations, are now available and allow baroreflex sensitivity to be assessed under real‐life conditions with no need for external stimulation. In particular, these methods offer the possibility of investigating the dynamic modulation of baroreflex sensitivity occurring either on a minute‐to‐minute basis or over 24 hours.
Molecular Genetics of Cutaneous Lymphomas
Authors: WHITTAKER SEAN
Published: July 2010

Abstract: The underlying molecular basis of primary cutaneous lymphomas has not yet been clarified. However, abnormalities of cell cycle control genes and well‐defined tumor suppressor genes such as p53 are common and may contribute to disease progression and treatment resistance. Biallelic inactivation of tumor suppressor genes usually occurs by a combination of deletion, point mutation, and/or promotor hypermethylation. The detection of UVB‐specific mutations of p53 requires confirmation but may have important implications for the management of patients with mycosis fungoides. Molecular cytogenetic studies have identified common regions of chromosomal deletion and amplification, which suggests the presence and location of genes that are of critical importance in the pathogenesis of cutaneous lymphoma.
Association between Sézary T Cell‐activating Factor, Chlamydia pneumoniae, and Cutaneous T Cell Lymphoma
Authors: ABRAMS J. TODD , BALIN BRIAN J. , VONDERHEID ERIC C.
Published: July 2010

Abstract: Séezary T cell‐activating factor (SAF) was originally defined as an inducer of functional interleukin‐2 (IL‐2) receptors on normal and malignant T cells in patients suffering from Sézary syndrome. In fact, a combination of SAF and IL‐2 stimulated the propagation of T cell lines from the peripheral blood mononuclear cells (PBMC) of those patients, with approximately one third of those cell lines containing the predominant malignant clone as determined via cytogenetic and/or T cell receptor gene rearrangement analysis. Although the primary source of SAF was mitogen‐stimulated PBMC of a patient with Sézary syndrome, we were unable to isolate the gene encoding SAF from eukaryotic libraries. However, we observed SAF activity in the cytoplasm of one of the malignant cell lines in a complex containing RNA and DNA. This observation led us to consider the possibility that SAF is not of eukaryotic origin. Intracellular pathogens replicate in the cytoplasm of host cells and contain proteins, DNA, and RNA. Using a panel of antichlamydial antibodies with confirmation from polymerase chain reaction primers, we found that most patients with mycosis fungoides were positive for these determinants. Immunoelectron microscopy and protein blotting further confirmed antibody reactivity. We showed that Chlamydia pneumoniae were capable of infecting normal human keratinocytes in culture. We also demonstrated that C. pneumoniae antigen expression was associated with active disease because these determinants were not expressed after psoralen and ultraviolet A therapy. We hypothesize that chronic infection by C. pneumoniae leads to expansion of C. pneumoniae‐specific T cells, thereby potentiating the development of cutaneous T cell lymphoma.
T Cell Antigen Receptor Vaccines for Active Therapy of T Cell Malignancies
Authors: REDDY SUNIL A. , OKADA CRAIG , WONG CARMEN , BAHLER DAVID , LEVYA RONALD
Published: July 2010

Abstract: T cell lymphoproliferative disorders continue to be serious management problems, and so alternative therapeutic modalities are continuously being explored. One such strategy involves immunotherapy using the T cell receptor (TCR) as a target. Specifically we are attempting to develop a T cell receptor idiotype (TCR‐Id) vaccine because the TCR‐Id can serve as a tumor‐specific antigen. In this article we will briefly review the rationale for TCR‐Id vaccines, the preclinical models as developed in our laboratory, and a discussion of our current plans for a vaccine trial in mycosis fungoides.
Autologous Peripheral Blood Stem Cell Transplantation in Tumor‐stage Mycosis Fungoides: Predictors of Disease‐free Survival
Authors: RUSSELL‐JONES R. , CHILD F. , OLAVARRIA E. , WHITTAKER S. , SPITTLE M. , APPERLEY J.
Published: July 2010

Abstract: Nine patients with mycosis fungoides (age range 27–67) underwent autologous peripheral blood stem cell transplantation (PBSCT). All patients had tumor‐stage disease, and four had lymph node involvement. Eight patients exhibited a peripheral blood T cell clone using PCR/SSCP analysis of the TCR gamma gene, six prior to harvest and two at the time of harvest. Mobilization of CD34+ stem cells was achieved with etoposide and G‐CSF. Harvested cells were positively selected for CD34. After negative selection for CD4 and CD8, only two samples became PCR negative. Conditioning prior to reinfusion of stem cells was achieved with various combinations of total skin electron beam (TSEB), total body irradiation (TBI), and chemotherapy, depending upon the patient's prior exposure to radiotherapy. One patient failed to engraft and died of candidal septicemia 15 days posttransplant. The other eight patients achieved complete remission, but this was short‐lived in four (median disease‐free survival [DFS] = 2 months) and prolonged in three (median DFS 11 months). Those with a short DFS were distinguished by rapid tumor onset prior to transplant but not by stage at transplant. Loss of a detectable T cell clone after manipulation of the harvest did not discriminate between the two groups, but rapid relapsers had been subjected to a greater degree of T cell depletion, possibly indicating a compromised cytotoxic response post‐PBSCT. The median survival of the cohort is four years from tumor onset, 15 months from PBSCT, and 27 months from the date a peripheral blood clone was first detected in the presence of tumor‐stage disease. Rapid relapse was associated with poor overall survival. Our data demonstrate the value of PBSCT for inducing remission in tumor‐stage mycosis fungoides. Reinfusion of neoplastic cells could be avoided by harvesting stem cells at an earlier stage in the disease process, preferably before a T cell clone is detectable in the peripheral blood. Alternatively T cell depletion should be restricted to the CD4 subset.
Interleukin‐2 Fusion Toxin: Targeted Therapy for Cutaneous T Cell Lymphoma
Authors: FOSS FRANCINE M.
Published: July 2010

Abstract: The interleukin (IL)‐2 receptor has proved an attractive target for T cell‐directed therapies. Agents including monoclonal antibodies, single‐chain antibody immunoconjugates, radioimmunoconjugates, and, most recently, ligand fusion toxins have demonstrated activity in vitro and in clinical trials in both hematologic malignancies and diseases characterized by proliferation of activated T cells, such as graft‐versus‐host disease. DAB389IL‐2 (ONTAK) is a ligand fusion toxin consisting of the full‐length sequence of the IL‐2 gene genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB389IL‐2 and its predecessor, DAB486IL‐2, have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV infection. Further clinical development of IL‐2 fusion toxins in CTCL and other hematopoietic malignancies is predicated on identification of the high‐affinity IL‐2 receptor complex on the malignant cells and on a better understanding of the biological determinants of cytotoxicity of these molecules in vivo.
The Role for Interleukin‐12 Therapy of Cutaneous T Cell Lymphoma
Authors: ROOK ALAIN H. , ZAKI MOHAMED H. , WYSOCKA MARIA , WOOD GARY S. , DUVIC MADELEINE , SHOWE LOUISE C. , FOSS FRANCINE , SHAPIRO MICHAEL , KUZEL TIMOTHY M. , OLSEN ELISE A. , VONDERHEID ERIC C. , LALIBERTE ROBERT , SHERMAN MATTHEW L.
Published: July 2010

Abstract: Recent phase I and phase II trials using recombinant human interleukin‐12 (rhIL‐12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA‐1+ T cells. These results suggest that rhIL‐12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL‐12.
Apoptosis and Cutaneous T Cell Lymphoma
Authors: KACINSKI BARRY M. , FLICK MARYANN
Published: July 2010

Abstract: The most successful therapies in the treatment of cutaneous T cell lymphoma (CTCL), which include localized X‐ray therapy, total skin electron beam therapy, total skin therapy with psoralen and UVA or other forms of UV light therapy, topical chemotherapy, and even topical steroids, all work by inducing T cell apoptosis. Yet, these same malignant T cells, which readily undergo apoptosis after these therapies, are far less likely to do so after therapy with systemic chemotherapeutic agents that are often curative in B cell lymphomas. Apoptosis in T cells is a normal phenotype in that only a small fraction of nonneoplastic T cells fail to undergo apoptosis. Although we still understand relatively little regarding the molecular biology of CTCL, it is clear that the neoplastic cell clone or clones that predominate in this disease have defects in normal apoptotic control mechanisms. These can be overridden in most cases by the strong proapoptotic signals triggered by ionizing radiation and other agents. Better understanding of the mechanisms by which the latter occurs should help us both improve our current therapies and devise new ones.
Vestibular Discrimination of Gravity and Translational Acceleration
Authors: ANGELAKI DORA E. , WEI MIN , MERFELD DANIEL M.
Published: July 2010

Abstract: According to Einstein's equivalence principle, linear accelerations experienced during translational motion are physically indistinguishable from changes in orientation relative to gravity experienced during tilting movements. Nevertheless, despite these ambiguous sensory cues provided by the primary otolith afferents, perceptual and motor responses discriminate between gravity and translational acceleration. There is growing evidence to suggest that the brain resolves this ambiguity primarily by combining signals from multiple sensors, the semicircular canals being a main extra otolith contributor. Here, we summarize the experimental evidence in support of the canal influences on the neural processing of otolith cues, provide specific experimental results in rhesus monkeys, and discuss and compare previously proposed models that combine otolith and semicircular‐canal signals in order to provide neural estimates of gravity and linear acceleration.
Vestibular Compensation and Orientation during Locomotion
Authors: RAPHAN THEODORE , IMAI TAKAO , MOORE STEVEN T. , COHEN BERNARD
Published: July 2010

Abstract: Body, head, and eye movements were studied in three dimensions while walking and turning to determine the role of the vestibular system in directing gaze and maintaining spatial orientation. The body, head, and eyes were represented as three‐dimensional coordinate frames, and the movement of these frames was related to a trajectory frame that described the motion of the body on a terrestrial plane. The axis‐angle of the body, head, and eye rotation were then compared to the axis‐angle of the rotation of the gravitoinertial acceleration (GIA). We inferred the role of the vestibular system during locomotion and the contributions of the VCR and VOR by examining the interrelationship between these coordinate frames. Straight walking induced head and eye rotations in a compensatory manner to the linear accelerations, maintaining head pointing and gaze along the direction of forward motion. Turning generated a combination of compensation and orientation responses. The head leads and steers the turn while the eyes compensate to maintain stable horizontal gaze in space. Saccades shift horizontal gaze as the turn is executed. The head pitches, as during straight walking. It also rolls so that the head tends to align with the orientation of the GIA. Head orientation changes anticipate orientation changes of the GIA. Eye orientation follows the changes in GIA orientation so that the net orientation gaze is closer to the orientation of the GIA. The study indicates that the vestibular system utilizes compensatory and orienting mechanisms to stabilize spatial orientation and gaze during walking and turning.
The Human Vestibulo‐Ocular Reflex during Linear Locomotion
Authors: MOORE STEVEN T. , HIRASAKI EISHI , RAPHAN THEODORE , COHEN BERNARD
Published: July 2010

Abstract: During locomotion, there is a translation and compensatory rotation of the head in both the vertical and horizontal planes. During moderate to fast walking (100 m/min), vertical head translation occurs at the frequency of stepping (2 Hz) and generates peak linear acceleration of 0.37 g. Lateral head translation occurs at the stride frequency (1 Hz) and generates peak linear acceleration of 0.1 g. Peak head pitch and yaw angular velocities are approximately 178°/s. The frequency and magnitude of these head movements are within the operational range of both the linear and angular vestibulo‐ocular reflex (lVOR and aVOR). Vertical eye movements undergo a phase reversal from near to far targets. When viewing a far (>1 m) target, vertical eye velocity is typical of an aVOR response; that is, it is compensatory for head pitch. At close viewing distances (<1 m), vertical eye velocity is in phase with head pitch and is compensatory for vertical head translation, suggesting that the lVOR predominantly generates the eye movement response. Horizontal head movements during locomotion occur at the stride frequency of 1 Hz, where the lVOR gain is low. Horizontal eye movements are compensatory for head yaw at all viewing distances and are likely generated by the aVOR.
Age‐Related Changes in Vestibular Function
Authors: BALOH ROBERT W. , ENRIETTO JANE , JACOBSON KATHLEEN M. , LIN ADAM
Published: July 2010

Abstract: The objective of this study was to identify age‐related changes in the vestibulo‐ocular reflex (VOR) in normal older subjects and patients complaining of disequilibrium followed serially over time. Cross‐sectional studies have found decreases in vestibular function in older subjects compared to younger subjects, but no prior longitudinal studies have been made following the same older subjects over time. We measured VOR responses using step and sinusoidal stimuli in 110 normal subjects and 51 patients with disequilibrium of unknown cause. This report focuses on 57 normal subjects who were able to return for five yearly examinations and 7 patients who were found to have severe bilateral vestibulopathy on the initial examination. In the normal subjects, there was a significant shortening of the VOR time constant to step changes in angular velocity and an amplitude‐dependent decrease in gain and increase in phase lead of low‐frequency sinusoidal responses over the five examinations. There was also a decrease in the gain of visual‐vestibular responses at low frequencies of sinusoidal stimulation over the five examinations. The patients with bilateral vestibulopathy showed relatively little change in vestibular function over the five years of follow‐up.

This is the first longitudinal study to show age‐related decreases in vestibular responses in normal older subjects. The VOR changes identified were not associated with symptoms or signs of disequilibrium. A small subgroup of patients with disequilibrium of unknown cause had profound bilateral vestibulopathy that remained stable during follow‐up. These patients likely had an underlying disease even though in most cases the disease process could not be identified.