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  1. Endocannabinoids mediate neuron-astrocyte communication.

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    Navarrete, Marta; Araque, Alfonso

    2008-03-27

    Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.

  2. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

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    María-Paz Viveros

    2007-01-01

    Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  3. Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPAR

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    Saoirse E. O'Sullivan

    2009-01-01

    Full Text Available The aim of the present study was to examine whether endocannabinoids cause PPAR-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA, but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours. Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 M, and vasorelaxation to both anandamide and NADA was inhibited by PPAR antagonism (GW9662, 1 M. Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 M inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPAR-mediated vasorelaxation. Activation of PPAR in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation.

  4. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

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    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-01-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

  5. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

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    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  6. “Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

    Science.gov (United States)

    2012-01-01

    Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203

  7. Endocannabinoids in the Dentate Gyrus

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    Frazier, Charles J.

    2007-01-01

    Recent years have produced rapid and enormous growth in our understanding of endocannabinoid-mediated signalling in the CNS. While much of the recent progress has focused on other areas of the brain, a significant body of evidence has developed that indicates the presence of a robust system for endocannabinoid-mediated signalling in the dentate gyrus. This chapter will provide an overview of our current understanding of that system based on available anatomical and physiological data.

  8. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.

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    Russo, Ethan B

    2016-01-01

    Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

  9. Emerging Role of (EndoCannabinoids in Migraine

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    Pinja Leimuranta

    2018-04-01

    Full Text Available In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i the current knowledge on the endocannabinoid system (ECS with emphasis on expression of its components in migraine related structures; (ii distinguishing peripheral from central site of action of cannabinoids, (iii proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v dual (possibly opposing actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components or novel endocannabinoid therapeutics in migraine treatment.

  10. An endocannabinoid hypothesis of drug reward and drug addiction.

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    Onaivi, Emmanuel S

    2008-10-01

    Pharmacologic treatment of drug and alcohol dependency has largely been disappointing, and new therapeutic targets and hypotheses are needed. There is accumulating evidence indicating a central role for the previously unknown but ubiquitous endocannabinoid physiological control system (EPCS) in the regulation of the rewarding effects of abused substances. Thus an endocannabinoid hypothesis of drug reward is postulated. Endocannabinoids mediate retrograde signaling in neuronal tissues and are involved in the regulation of synaptic transmission to suppress neurotransmitter release by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatory action on synaptic transmission has significant functional implications and interactions with the effects of abused substances. Our data, along with those from other investigators, provide strong new evidence for a role for EPCS modulation in the effects of drugs of abuse, and specifically for involvement of cannabinoid receptors in the neural basis of addiction. Cannabinoids and endocannabinoids appear to be involved in adding to the rewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine, and BDZs. The results suggest that the EPCS may be an important natural regulatory mechanism for drug reward and a target for the treatment of addictive disorders.

  11. The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers

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    Thangesweran Ayakannu

    2013-01-01

    Full Text Available The “endocannabinoid system (ECS” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2, some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis. Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.

  12. The endocannabinoid system in brain reward processes.

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    Solinas, M; Goldberg, S R; Piomelli, D

    2008-05-01

    Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

  13. Dual-acting compounds targeting endocannabinoid and endovanilloid systems — a novel treatment option for chronic pain management.

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    Natalia Malek

    2016-08-01

    Full Text Available Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.

  14. A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition.

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    Margarita Zachariou

    Full Text Available Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI, a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of

  15. Endocannabinoids, Related Compounds and Their Metabolic Routes

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    Filomena Fezza

    2014-10-01

    Full Text Available Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol. These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA and 2-arachidonoylglycerol (2-AG, respectively, their main representatives. During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds have been discovered and their activities biological is the subject of intense investigations. Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

  16. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex.

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    Mathieu Lafourcade

    2007-08-01

    Full Text Available Cannabinoids have deleterious effects on prefrontal cortex (PFC-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha, the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602 but not of anandamide (with URB 597 converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

  17. Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration

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    Daniel J. Liput

    2017-11-01

    Full Text Available Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs. The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs, and then evaluated the efficacy of fatty acid amide hydrolase (FAAH inhibition on attenuating alcohol-induced neurodegeneration. Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in [3H]-CP-55,940 binding in the entorhinal cortex and hippocampus following two days, but not four days, of treatment. Furthermore, binge alcohol treatment did not change the tissue content of the three NAEs quantified, including the endocannabinoid and anandamide. In a separate study, the FAAH inhibitor, URB597 was administered to rats during alcohol treatment and neuroprotection was assessed by FluoroJade B (FJB staining. The administration of URB597 during binge treatment did not significantly reduce FJB+ cells in the entorhinal cortex or hippocampus, however, a follow up “target engagement” study found that NAE augmentation by URB597 was impaired in alcohol intoxicated rats. Thus, potential alcohol induced alterations in URB597 pharmacodynamics may have contributed to the lack of neuroprotection by FAAH inhibition.

  18. Alternative Argets Within the Endocannabinoid System for Future Treatment of Gastrointestinal Diseases

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    Rudolf Schicho

    2011-01-01

    Full Text Available Many beneficial effects of herbal and synthetic cannabinoids on gut motility and inflammation have been demonstrated, suggesting a vast potential for these compounds in the treatment of gastrointestinal disorders. These effects are based on the so-called ‘endocannabinoid system’ (ECS, a cooperating network of molecules that regulate the metabolism of the body’s own and of exogenously administered cannabinoids. The ECS in the gastrointestinal tract quickly responds to homeostatic disturbances by de novo synthesis of its components to maintain homeostasis, thereby offering many potential targets for pharmacological intervention. Of major therapeutic interest are nonpsychoactive cannabinoids or compounds that do not directly target cannabinoid receptors but still possess cannabinoid-like properties. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids are becoming increasingly promising alternative therapeutic tools to manipulate the ECS.

  19. The endocannabinoid system: a new pharmacological target for obesity treatment?

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    Hu, Jia; Zhu, Chao; Huang, Mao

    2009-06-01

    Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.

  20. Peripheral endocannabinoids regulate skeletal muscle development and maintenance

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    Dongjiao Zhao

    2010-12-01

    Full Text Available As a principal tissue responsible for insulin-mediated glucose uptake, skeletal muscle is important for whole-body health. The role of peripheral endocannabinoids as regulators of skeletal muscle metabolism has recently gained a lot of interest, as endocannabinoid system disorders could cause peripheral insulin resistance. We investigated the role of the peripheral endocannabinoid system in skeletal muscle development and maintenance. Cultures of C2C12 cells, primary satellite cells and mouse skeletal muscle single fibers were used as model systems for our studies. We found an increase in cannabinoid receptor type 1 (CB1 mRNA and endocannabinoid synthetic enzyme mRNA skeletal muscle cells during differentiation. We also found that activation of CB1 inhibited myoblast differentiation, expanded the number of satellite cells, and stimulated the fast-muscle oxidative phenotype. Our findings contribute to understanding of the role of the endocannabinoid system in skeletal muscle metabolism and muscle oxygen consumption, and also help to explain the effects of the peripheral endocannabinoid system on whole-body energy balance.

  1. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    International Nuclear Information System (INIS)

    Sanson, Benoît; Wang, Tao; Sun, Jing; Wang, Liqun; Kaczocha, Martin; Ojima, Iwao; Deutsch, Dale; Li, Huilin

    2014-01-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels

  2. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    Energy Technology Data Exchange (ETDEWEB)

    Sanson, Benoît; Wang, Tao [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Sun, Jing; Wang, Liqun; Kaczocha, Martin [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Ojima, Iwao [Stony Brook University, Stony Brook, NY 1794-3400 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Deutsch, Dale, E-mail: dale.deutsch@stonybrook.edu [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Li, Huilin, E-mail: dale.deutsch@stonybrook.edu [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States)

    2014-02-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.

  3. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

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    Jantana Keereetaweep

    2016-01-01

    Full Text Available The endocannabinoids N-arachidonoylethanolamide (or anandamide, AEA and 2-arachidonoylglycerol (2-AG belong to the larger groups of N-acylethanolamines (NAEs and monoacylglycerol (MAG lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example, N-palmitoylethanolamine (PEA, N-stearoylethanolamine (SEA, and N-oleoylethanolamine (OEA are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further, the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. The recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.

  4. The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

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    Seillier, Alexandre; Giuffrida, Andrea

    2018-03-01

    Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Endocannabinoids and the Cardiovascular System in Health and Disease.

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    O'Sullivan, Saoirse Elizabeth

    2015-01-01

    The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

  6. Role of endocannabinoids in regulating drug dependence

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    Daniela Parolaro

    2007-01-01

    Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

  7. The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

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    Corcoran, Louise; Roche, Michelle; Finn, David P

    2015-01-01

    Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.

  8. Motion sickness, stress and the endocannabinoid system.

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    Alexander Choukèr

    Full Text Available BACKGROUND: A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the activity of the ECS in human volunteers (n = 21 during parabolic flight maneuvers (PFs. During PFs, microgravity conditions (<10(-2 g are generated for approximately 22 s which results in a profound kinetic stimulus. Blood endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG were measured from blood samples taken in-flight before start of the parabolic maneuvers, after 10, 20, and 30 parabolas, in-flight after termination of PFs and 24 h later. Volunteers who developed acute motion sickness (n = 7 showed significantly higher stress scores but lower endocannabinoid levels during PFs. After 20 parabolas, blood anandamide levels had dropped significantly in volunteers with motion sickness (from 0.39+/-0.40 to 0.22+/-0.25 ng/ml but increased in participants without the condition (from 0.43+/-0.23 to 0.60+/-0.38 ng/ml resulting in significantly higher anandamide levels in participants without motion sickness (p = 0.02. 2-AG levels in individuals with motion sickness were low and almost unchanged throughout the experiment but showed a robust increase in participants without motion sickness. Cannabinoid-receptor 1 (CB1 but not cannabinoid-receptor 2 (CB2 mRNA expression in leucocytes 4 h after the experiment was significantly lower in volunteers with motion sickness than in participants without N&V. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that stress and motion sickness in humans are associated with impaired endocannabinoid

  9. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

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    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

  10. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

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    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

  11. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

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    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress

  12. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena.

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    Solbrig, Marylou V; Adrian, Russell; Baratta, Janie; Piomelli, Daniele; Giuffrida, Andrea

    2005-08-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

  13. Potential of Endocannabinoids to Control Bladder Pain

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    Dale E. Bjorling

    2018-05-01

    Full Text Available Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA and 2-arachidonoylglycerol (2-AG, are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA and monacylglycerol lipase (MAGL; degrades 2-AG, cyclooxygenase (COX acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1 channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.

  14. Essential fatty acids and lipid mediators. Endocannabinoids

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    G. Caramia

    2012-03-01

    Full Text Available In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in polyunsaturated fatty acids (PUFA as precursors of “lipid mediator” molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines, maresins that regulate immunity, platelet aggregation, inflammation, etc. They showed that the balance between omega-3 and omega-6 acids has a profound influence on all the body’s inflammatory responses and a raised level of PUFA omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer’s. The CYP-catalyzed epoxidation and hydroxylation of arachidonic acid (AA were established recently as the so-called third branch of AGE cascade. Cytochrome P450 (CYP epoxygenases convert AA to four epoxyeicosatrienoic acid (EET regioisomers, that produce vascular relaxation anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. Eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA are accessible to CYP enzymes in the same way as AA. Metabolites derived from EPA include epoxyeicosatetraenoic acids (EETR and hydroxyeicosapentaenoic acids (19- and 20-HEPE, whereas DHA include epoxydocosapentaenoic acids (EDPs hydroxydocosahexaenoic acids (21- and 22-HDoHE. For many of the CYP isoforms, the n-3 PUFAs are the preferred substrates and the available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA. From AA derives also endocannabinoids like anandamide (N-arachidonoylethanolamine and 2-arachidonoylglycerol, capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as

  15. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.

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    Mach, François; Montecucco, Fabrizio; Steffens, Sabine

    2009-01-01

    The endocannabinoid system is a crucial player in the inflammatory processes underlying atherosclerosis. Recently, basic research studies and animal models have strongly supported the role of the endocannabinoid system not only in the regulation of classical cardiovascular risk factors (including lipid profile and glucose homeostasis), but also in the activation of immune cells and inflammatory mediators. Clinical trials investigating treatment with rimonabant (a selective antagonist of the cannabinoid type 1 receptor) have suggested a beneficial effect of this drug in the management of obesity. Further studies are needed to explore a possible use for rimonabant in treating type 2 diabetes and acute and chronic cardiovascular disease. Despite the slight increase in adverse events (mainly psychiatric), which has led to the recent withdrawal of rimonabant from the market, CB(1) receptor antagonism might represent a very promising therapeutic strategy to reduce the cardiovascular risk. In the present review, we focused on the most important experimental investigations into the role of the endocannabinoid system in atherosclerosis and cardiovascular risk.

  16. Peripheral Endocannabinoid System Activity in Patients Treated With Sibutramine

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    Engeli, Stefan; Heusser, Karsten; Janke, Jürgen; Gorzelniak, Kerstin; Bátkai, Sándor; Pacher, Pál; Harvey-White, Judith; Luft, Friedrich C.; Jordan, Jens

    2008-01-01

    Objective The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS. Methods and Procedures Twenty obese otherwise healthy patients received randomized, double-blind, crossover treatment with placebo and 15 mg/day sibutramine for 5 days each, followed by 12 weeks open-label sibutramine treatment. We determined circulating anandamide and 2-arachidonoylglycerol and expression levels of endocannabinoid genes in subcutaneous abdominal adipose tissue biopsies. Results Body weight was stable during the acute treatment period and decreased by 6.0 ± 0.8 kg in those patients completing 3 months of sibutramine treatment (P sibutramine treatment. Discussion The ECS is activated in obesity. We did not find any influence of 5% body weight loss induced by sibutramine on circulating levels of endocannabinoids and adipose-tissue expression of endocannabinoid genes in obese subjects. These data confirm our previous findings on dietary weight loss and suggest that the dysregulation of the ECS may be a cause rather than a consequence of obesity. PMID:18356837

  17. The endocannabinoid system and nondrug rewarding behaviours.

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    Fattore, Liana; Melis, Miriam; Fadda, Paola; Pistis, Marco; Fratta, Walter

    2010-07-01

    Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed. Copyright 2010 Elsevier Inc. All rights reserved.

  18. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

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    Thomas Schwitzer

    2016-01-01

    Full Text Available Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

  19. Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

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    Bilgic, Elif; Guzel, Elif; Kose, Sevil; Aydin, Makbule Cisel; Karaismailoglu, Eda; Akar, Irem; Usubutun, Alp; Korkusuz, Petek

    2017-06-01

    Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. Copyright

  20. Translational Evidence for a Role of Endocannabinoids in the Etiology and Treatment of Posttraumatic Stress Disorder

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    Neumeister, Alexander; Seidel, Jordan; Ragen, Benjamin J.; Pietrzak, Robert H.

    2014-01-01

    Introduction Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Methods Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. Results There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Conclusion Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. PMID:25456347

  1. The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

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    Ahmet Ulugöl

    2014-06-01

    Full Text Available Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MAGL, the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.

  2. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Elphick Maurice R

    2009-07-01

    Full Text Available Abstract Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG, and the related compound N-palmitoylethanolamine (PEA, in neuropathic spinal cord. Selective spinal nerve ligation (SNL in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P P P P P

  3. Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation.

    Directory of Open Access Journals (Sweden)

    András Iring

    Full Text Available Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1 receptor blockade and inhibition of cannabinoid reuptake, respectively on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H.In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v. failed to influence blood pressure (BP, cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v. induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the

  4. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits.

    Science.gov (United States)

    Lau, Benjamin K; Cota, Daniela; Cristino, Luigia; Borgland, Stephanie L

    2017-09-15

    The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. The endocannabinoid system and associative learning and memory in zebrafish.

    Science.gov (United States)

    Ruhl, Tim; Moesbauer, Kirstin; Oellers, Nadine; von der Emde, Gerhard

    2015-09-01

    In zebrafish the medial pallium of the dorsal telencephalon represents an amygdala homolog structure, which is crucially involved in emotional associative learning and memory. Similar to the mammalian amygdala, the medial pallium contains a high density of endocannabinoid receptor CB1. To elucidate the role of the zebrafish endocannabinoid system in associative learning, we tested the influence of acute and chronic administration of receptor agonists (THC, WIN55,212-2) and antagonists (Rimonabant, AM-281) on two different learning paradigms. In an appetitively motivated two-alternative choice paradigm, animals learned to associate a certain color with a food reward. In a second set-up, a fish shuttle-box, animals associated the onset of a light stimulus with the occurrence of a subsequent electric shock (avoidance conditioning). Once fish successfully had learned to solve these behavioral tasks, acute receptor activation or inactivation had no effect on memory retrieval, suggesting that established associative memories were stable and not alterable by the endocannabinoid system. In both learning tasks, chronic treatment with receptor antagonists improved acquisition learning, and additionally facilitated reversal learning during color discrimination. In contrast, chronic CB1 activation prevented aversively motivated acquisition learning, while different effects were found on appetitively motivated acquisition learning. While THC significantly improved behavioral performance, WIN55,212-2 significantly impaired color association. Our findings suggest that the zebrafish endocannabinoid system can modulate associative learning and memory. Stimulation of the CB1 receptor might play a more specific role in acquisition and storage of aversive learning and memory, while CB1 blocking induces general enhancement of cognitive functions. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity.

    Science.gov (United States)

    Duffy, Danielle; Rader, Daniel

    2007-02-01

    Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

  7. Endocannabinoids as Guardians of Metastasis

    Directory of Open Access Journals (Sweden)

    Irmgard Tegeder

    2016-02-01

    Full Text Available Endocannabinoids including anandamide and 2-arachidonoylglycerol are involved in cancer pathophysiology in several ways, including tumor growth and progression, peritumoral inflammation, nausea and cancer pain. Recently we showed that the endocannabinoid profiles are deranged during cancer to an extent that this manifests in alterations of plasma endocannabinoids in cancer patients, which was mimicked by similar changes in rodent models of local and metastatic cancer. The present topical review summarizes the complexity of endocannabinoid signaling in the context of tumor growth and metastasis.

  8. Endocannabinoid signaling in reward and addiction

    Science.gov (United States)

    Parsons, Loren H.; Hurd, Yasmin L.

    2015-01-01

    Brain endocannabinoid signaling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated endocannabinoid signaling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired endocannabinoid signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states, and craving that propel addiction. Understanding the contributions of endocannabinoid disruptions to behavioral and physiological traits provides insight into the endocannabinoid influence on addiction vulnerability. PMID:26373473

  9. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    Directory of Open Access Journals (Sweden)

    Daniela eLaricchiuta

    2014-05-01

    Full Text Available Rewarding effects have been related to enhanced dopamine (DA release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS (URB597, AM251 or DAergic system (haloperidol were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597 or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner.

  10. The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation

    Directory of Open Access Journals (Sweden)

    B. M. Fonseca

    2013-01-01

    Full Text Available Although the detrimental effects of cannabis consumption during gestation are known for years, the vast majority of studies established a link between cannabis consumption and foetal development. The complex maternal-foetal interrelationships within the placental bed are essential for normal pregnancy, and decidua definitively contributes to the success of this process. Nevertheless, the molecular signalling network that coordinates strategies for successful decidualization and placentation are not well understood. The discovery of the endocannabinoid system highlighted new signalling mediators in various physiological processes, including reproduction. It is known that endocannabinoids present regulatory functions during blastocyst development, oviductal transport, and implantation. In addition, all the endocannabinoid machinery was found to be expressed in decidual and placental tissues. Additionally, endocannabinoid’s plasmatic levels were found to fluctuate during normal gestation and to induce decidual cell death and disturb normal placental development. Moreover, aberrant endocannabinoid signalling during the period of placental development has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the endocannabinoid system in these critical processes is explored and discussed.

  11. Rutin as a Mediator of Lipid Metabolism and Cellular Signaling Pathways Interactions in Fibroblasts Altered by UVA and UVB Radiation

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    Agnieszka Gęgotek

    2017-01-01

    Full Text Available Background. Rutin is a natural nutraceutical that is a promising compound for the prevention of UV-induced metabolic changes in skin cells. The aim of this study was to examine the effects of rutin on redox and endocannabinoid systems, as well as proinflammatory and proapoptotic processes, in UV-irradiated fibroblasts. Methods. Fibroblasts exposed to UVA and UVB radiation were treated with rutin. The activities and levels of oxidants/antioxidants and endocannabinoid system components, as well as lipid, DNA, and protein oxidation products, and the proinflammatory and pro/antiapoptotic proteins expression were measured. Results. Rutin reduced UV-induced proinflammatory response and ROS generation and enhanced the activity/levels of antioxidants (SOD, GSH-Px, vitamin E, GSH, and Trx. Rutin also normalized UV-induced Nrf2 expression. Its biological activity prevented changes in the levels of the lipid mediators: MDA, 4-HNE, and endocannabinoids, as well as the endocannabinoid receptors CB1/2, VR1, and GPR55 expression. Furthermore, rutin prevented the protein modifications (tyrosine derivatives formation in particular and decreased the levels of the proapoptotic markers—caspase-3 and cytochrome c. Conclusion. Rutin prevents UV-induced inflammation and redox imbalance at protein and transcriptional level which favors lipid, protein, and DNA protection. In consequence rutin regulates endocannabinoid system and apoptotic balance.

  12. Involvement of the endocannabinoid system in periodontal healing

    Energy Technology Data Exchange (ETDEWEB)

    Kozono, Sayaka [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Matsuyama, Takashi, E-mail: takashi@dent.kagoshima-u.ac.jp [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Biwasa, Kamal Krishna [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi 6205 (Bangladesh); Kawahara, Ko-ichi [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tancharoen, Salunya [Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok 10400 (Thailand); Hashiguchi, Teruto [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Noguchi, Kazuyuki [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Maruyama, Ikuro [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2010-04-16

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  13. Involvement of the endocannabinoid system in periodontal healing

    International Nuclear Information System (INIS)

    Kozono, Sayaka; Matsuyama, Takashi; Biwasa, Kamal Krishna; Kawahara, Ko-ichi; Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi; Tancharoen, Salunya; Hashiguchi, Teruto; Noguchi, Kazuyuki; Maruyama, Ikuro

    2010-01-01

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  14. Endocannabinoids and cardiovascular prevention: real progress?

    Directory of Open Access Journals (Sweden)

    Livio Dei Cas

    2009-08-01

    Full Text Available ABSTRACT: The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc. Therefore, the antagonism of the endocannabinoid (EC system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1-3. Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a “major modifiable risk factor” for coronary heart disease (4, 5. Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7. (Heart International 2007; 3: 27-34

  15. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system

    Science.gov (United States)

    Okine, Bright N; Norris, Leonie M; Woodhams, Stephen; Burston, James; Patel, Annie; Alexander, Stephen PH; Barrett, David A; Kendall, David A; Bennett, Andrew J; Chapman, Victoria

    2012-01-01

    BACKGROUND AND PURPOSE Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour. EXPERIMENTAL APPROACH Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined. KEY RESULTS Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction. CONCLUSION AND IMPLICATIONS Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain. PMID:22595021

  16. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    International Nuclear Information System (INIS)

    Wohlman, Irene M.; Composto, Gabriella M.; Heck, Diane E.; Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D.; Casillas, Robert P.; Croutch, Claire R.; Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B.; Laskin, Jeffrey D.

    2016-01-01

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  17. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Wohlman, Irene M.; Composto, Gabriella M. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D. [Department of Chemistry, Lehigh University, Bethlehem, PA (United States); Casillas, Robert P.; Croutch, Claire R. [MRIGlobal, Kansas City, MO (United States); Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ (United States)

    2016-07-15

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  18. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

    Science.gov (United States)

    Grant, Igor; Cahn, B. Rael

    2008-01-01

    The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886

  19. Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

    Science.gov (United States)

    Maldonado, Rafael; Robledo, Patricia; Berrendero, Fernando

    2013-08-01

    The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Causal mediation analysis with multiple mediators in the presence of treatment noncompliance.

    Science.gov (United States)

    Park, Soojin; Kürüm, Esra

    2018-05-20

    Randomized experiments are often complicated because of treatment noncompliance. This challenge prevents researchers from identifying the mediated portion of the intention-to-treated (ITT) effect, which is the effect of the assigned treatment that is attributed to a mediator. One solution suggests identifying the mediated ITT effect on the basis of the average causal mediation effect among compliers when there is a single mediator. However, considering the complex nature of the mediating mechanisms, it is natural to assume that there are multiple variables that mediate through the causal path. Motivated by an empirical analysis of a data set collected in a randomized interventional study, we develop a method to estimate the mediated portion of the ITT effect when both multiple dependent mediators and treatment noncompliance exist. This enables researchers to make an informed decision on how to strengthen the intervention effect by identifying relevant mediators despite treatment noncompliance. We propose a nonparametric estimation procedure and provide a sensitivity analysis for key assumptions. We conduct a Monte Carlo simulation study to assess the finite sample performance of the proposed approach. The proposed method is illustrated by an empirical analysis of JOBS II data, in which a job training intervention was used to prevent mental health deterioration among unemployed individuals. Copyright © 2018 John Wiley & Sons, Ltd.

  1. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

    Science.gov (United States)

    Fuss, Johannes; Bindila, Laura; Wiedemann, Klaus; Auer, Matthias K; Briken, Peer; Biedermann, Sarah V

    2017-11-01

    Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. Our data indicate that the

  2. Endocannabinoid involvement in reward and impulsivity in addiction

    NARCIS (Netherlands)

    van Hell, H.H.

    2011-01-01

    Addiction is one of the most disabling diseases in the world. An important neurotransmitter system that has recently been implicated in addiction is the endocannabinoid system. The endocannabinoid system consists of cannabinoid receptors and endocannabinoid ligands that work on these receptors.

  3. Endocannabinoids

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Petersen, G.; Artmann, A.

    2006-01-01

    The endocannabinoid system embraces a group of lipid molecules, enzymes and receptor proteins. This system appears to be involved in the modulation of neurotransmitter release thereby modifying learning and memory, in the regulation of food intake, and in the modulation of inflammation and pain...

  4. Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

    Science.gov (United States)

    Navarro, Gemma; Borroto-Escuela, Dasiel; Angelats, Edgar; Etayo, Íñigo; Reyes-Resina, Irene; Pulido-Salgado, Marta; Rodríguez-Pérez, Ana I; Canela, Enric I; Saura, Josep; Lanciego, José Luis; Labandeira-García, José Luis; Saura, Carlos A; Fuxe, Kjell; Franco, Rafael

    2018-01-01

    Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB 1 and CB 2 receptors, which may form heteromeric complexes (CB 1 -CB 2 Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB 1 and circa 20 fold for CB 2 ), whereas receptor levels were similar for CB 1 and markedly upregulated for CB 2 ; CB 1 -CB 2 Hets were also upregulated. Unlike in resting cells, CB 2 receptors became robustly coupled to G i in activated cells, in which CB 1 -CB 2 Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß 1-42 ). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP Sw,Ind ) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP Sw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB 1 -CB 2 Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB 1 -CB 2 Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB 1 -CB 2 heteroreceptor complex in activated microglia have potential as targets in the

  5. Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

    Science.gov (United States)

    Dyall, Simon C

    2017-11-01

    The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

  6. Fabp1 gene ablation inhibits high-fat diet-induced increase in brain endocannabinoids.

    Science.gov (United States)

    Martin, Gregory G; Landrock, Danilo; Chung, Sarah; Dangott, Lawrence J; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2017-01-01

    The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet (HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein (FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation (LKO) on the effect of high-fat diet (HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. © 2016 International Society for Neurochemistry.

  7. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations

    DEFF Research Database (Denmark)

    Benzinou, Michael; Chèvre, Jean-Claude; Ward, Kirsten J

    2008-01-01

    The therapeutic effects of cannabinoid receptor blockade on obesity-associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and body mass ind...... variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders....

  8. Dynamic changes to the endocannabinoid system in models of chronic pain

    Science.gov (United States)

    Rani Sagar, Devi; Burston, James J.; Woodhams, Stephen G.; Chapman, Victoria

    2012-01-01

    The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling. PMID:23108548

  9. The skeletal endocannabinoid system: clinical and experimental insights.

    Science.gov (United States)

    Raphael, Bitya; Gabet, Yankel

    2016-05-01

    Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research. Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system. This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others. Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.

  10. A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice.

    Science.gov (United States)

    Wei, Don; Lee, DaYeon; Li, Dandan; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele

    2016-05-01

    The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex. The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

  11. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

    Science.gov (United States)

    Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

    2018-01-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  12. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    Science.gov (United States)

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  13. Effect of biliary cirrhosis on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum: Role of nitric oxide pathway and endocannabinoid system

    Directory of Open Access Journals (Sweden)

    Dehpour A.R.

    2008-06-01

    Full Text Available Background: Relaxation of the corpus cavernosum plays a major role in penile erection. Nitric oxide (NO is known to be the most important factor mediating relaxation of corpus cavernosum, which is mainly derived from nonadrenergic noncholinergic (NANC nerves. The aim of the present study was to investigate the effect of biliary cirrhosis on nonadrenergic noncholinergic (NANC-mediated relaxation of rat corpus cavernosum as well as the possible relevant roles of endocannabinoid and nitric oxide systems.Methods: Corporal strips from sham-operated and biliary cirrhotic rats were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 µM and atropine (1 µM to induce adrenergic and cholinergic blockade. The strips were precontracted with phenylephrine hydrochloride (7.5 µM and electrical field stimulation was applied at different frequencies (2, 5, 10, 15 Hz to obtain NANC-mediated relaxation. In separate precontracted strips of the sham and cirrhotic groups, the concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1mM, as an NO donor, were assessed.  Results: The NANC-mediated relaxation was significantly enhanced in cirrhotic animals (P<0.01. Anandamide potentiated the relaxations in both groups (P<0.05. The cannabinoid CB1 receptor antagonist AM251 (10 µM and the vanilloid receptor antagonist capsazepine (10 µM each significantly prevented the enhanced relaxations in cirrhotic rats (P<0.01. The CB2 receptor antagonist AM630 had no effect on relaxations in the cirrhotic group. In a concentration-dependent manner, L-NAME (30-1000 nM inhibited relaxations in both the sham and cirrhotic groups, although cirrhotic groups were more resistant to the inhibitory effects of L-NAME. The degree of relaxation induced by sodium nitroprusside (10 nM-1 mM was similar in the two groups.Conclusions: Biliary cirrhosis enhances the neurogenic relaxation in rat corpus cavernosum probably via the NO pathway and

  14. Endocannabinoid system: Role in depression, reward and pain control (Review).

    Science.gov (United States)

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-10-01

    Depression and pain co-exist in almost 80% of patients and are associated with impaired health-related quality of life, often contributing to high mortality. However, the majority of patients who suffer from the comorbid depression and pain are not responsive to pharmacological treatments that address either pain or depression, making this comorbidity disorder a heavy burden on patients and society. In ancient times, this depression-pain comorbidity was treated using extracts of the Cannabis sativa plant, known now as marijuana and the mode of action of Δ9‑tetrahydrocannabinol, the active cannabinoid ingredient of marijuana, has only recently become known, with the identification of cannabinoid receptor type 1 (CB1) and CB2. Subsequent investigations led to the identification of endocannabinoids, anandamide and 2-arachidonoylglycerol, which exert cannabinomimetic effects through the CB1 and CB2 receptors, which are located on presynaptic membranes in the central nervous system and in peripheral tissues, respectively. These endocannabinoids are produced from membrane lipids and are lipohilic molecules that are synthesized on demand and are eliminated rapidly after their usage by hydrolyzing enzymes. Clinical studies revealed altered endocannabinoid signaling in patients with chronic pain. Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. However, the precise mode of action of endocannabinoids on different targets in the body and whether their effects on pain and depression follow the same or different pathways, remains to be determined.

  15. Preventive Effects of Resveratrol on Endocannabinoid System and Synaptic Protein Modifications in Rat Cerebral Cortex Challenged by Bilateral Common Carotid Artery Occlusion and Reperfusion

    Directory of Open Access Journals (Sweden)

    Gianfranca Carta

    2018-01-01

    Full Text Available This study aims to evaluate the putative roles of a single acute dose of resveratrol (RVT in preventing cerebral oxidative stress induced by bilateral common carotid artery occlusion, followed by reperfusion (BCCAO/R and to investigate RVT’s ability to preserve the neuronal structural integrity. Frontal and temporal-occipital cortices were examined in two groups of adult Wistar rats, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half the rats were gavage-fed with a single dose of RVT (40 mg/per rat in 300 µL of sunflower oil as the vehicle, while the second half received the vehicle alone. In the frontal cortex, RVT pre-treatment prevented the BCCAO/R-induced increase of lipoperoxides, augmented concentrations of palmitoylethanolamide and docosahexaenoic acid, increased relative levels of the cannabinoid receptors type 1 (CB1 and 2 (CB2, and peroxisome-proliferator-activated-receptor (PPAR-α proteins. Increased expression of CB1/CB2 receptors mirrored that of synaptophysin and post-synaptic density-95 protein. No BCCAO/R-induced changes occurred in the temporal-occipital cortex. Collectively, our results demonstrate that, in the frontal cortex, RVT pre-treatment prevents the BCCAO/R-induced oxidative stress and modulates the endocannabinoid and PPAR-α systems. The increased expression of synaptic structural proteins further suggests the possible efficacy of RVT as a dietary supplement to preserve the nervous tissue metabolism and control the physiological response to the hypoperfusion/reperfusion challenge.

  16. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Directory of Open Access Journals (Sweden)

    Jessica Freundt-Revilla

    Full Text Available Endocannabinoids (ECs are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS. Activation of cannabinoid type 2 receptors (CB2 is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA and Intraspinal Spirocercosis (IS. The two main endocannabinoids, anandamide (AEA and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A, SRMA under treatment with prednisolone (SRMA Tr, intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC. Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05. Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05. CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular

  17. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Science.gov (United States)

    Freundt-Revilla, Jessica; Heinrich, Franciska; Zoerner, Alexander; Gesell, Felix; Beyerbach, Martin; Shamir, Merav; Oevermann, Anna; Baumgärtner, Wolfgang; Tipold, Andrea

    2018-01-01

    Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of

  18. Mediation designs for tobacco prevention research

    Science.gov (United States)

    MacKinnon, David P.; Taborga, Marcia P.; Morgan-Lopez, Antonio A.

    2010-01-01

    This paper describes research designs and statistical analyses to investigate how tobacco prevention programs achieve their effects on tobacco use. A theoretical approach to program development and evaluation useful for any prevention program guides the analysis. The theoretical approach focuses on action theory for how the program affects mediating variables and on conceptual theory for how mediating variables are related to tobacco use. Information on the mediating mechanisms by which tobacco prevention programs achieve effects is useful for the development of efficient programs and provides a test of the theoretical basis of prevention efforts. Examples of these potential mediating mechanisms are described including mediated effects through attitudes, social norms, beliefs about positive consequences, and accessibility to tobacco. Prior research provides evidence that changes in social norms are a critical mediating mechanism for successful tobacco prevention. Analysis of mediating variables in single group designs with multiple mediators are described as well as multiple group randomized designs which are the most likely to accurately uncover important mediating mechanisms. More complicated dismantling and constructive designs are described and illustrated based on current findings from tobacco research. Mediation analysis for categorical outcomes and more complicated statistical methods are outlined. PMID:12324176

  19. Biomarkers of endocannabinoid system activation in severe obesity.

    Directory of Open Access Journals (Sweden)

    Jack C Sipe

    2010-01-01

    Full Text Available Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs, combined with genotyping for mutations in fatty acid amide hydrolase (FAAH would identify circulating biomarkers of ECS activation in severe obesity.Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI of > or = 40 kg/m(2, and 48 normal weight subjects with BMI of A (P129T mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1+/-1.4 pmol/ml and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml with wild-type FAAH genotype (p = 0.04, and significance was maintained after controlling for BMI.Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

  20. Classical endocannabinoid-like compounds and their regulation by nutrients

    DEFF Research Database (Denmark)

    Kleberg, Karen; Hassing, Helle A.; Hansen, Harald S.

    2014-01-01

    Endocannabinoid-like compounds are structurally related to the true endocannabinoids but do not contain highly unsaturated fatty acids, and they do not bind the cannabinoid receptors. The classical endocannabinoid-like compounds include N-acylethanolamines and 2-monoacylglycerols......, which are particularly interesting in a nutritional and metabolic context. Exogenously supplied oleoylethanolamide, palmitoylethanolamide, and linoleoylethanolamide have anorexic effects, and the endogenous formation of these N-acylethanolamines in the small intestine may serve an important role...

  1. Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

    Directory of Open Access Journals (Sweden)

    Lichtman Aron H

    2011-01-01

    Full Text Available Abstract Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.

  2. Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli.

    Science.gov (United States)

    Rea, Kieran; Olango, Weredeselam M; Okine, Bright N; Madasu, Manish K; McGuire, Iseult C; Coyle, Kathleen; Harhen, Brendan; Roche, Michelle; Finn, David P

    2014-01-01

    Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  3. The endocannabinoid system and spermatogenesis

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    Paola eGrimaldi

    2013-12-01

    Full Text Available AbstractSpermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis is under the control of gonadotropins, steroid hormones and it is modulated by a complex network of autocrine and paracrine factors. These modulators ensure the correct progression of germ cell differentiation to form mature spermatozoa. Recently, it has been pointed out the relevance of endocannabinoids as critical modulators of male reproduction. Endocannabinoids are natural lipids able to bind to cannabinoid receptors and whose levels are regulated by specific biosynthetic and degradative enzymes. Together with their receptors and metabolic enzymes, they form the endocannabinoid system (ECS. In male reproductive tracts, they affect Sertoli cell activities, Leydig cell proliferation, germ cell differentiation, sperm motility, capacitation and acrosome reaction. The ECS interferes with the pituitary-gonadal axis, and an intricate crosstalk between ECS and steroid hormones has been highlighted. This mini-review will focus on the involvement of the ECS in the control of spermatogenesis and on the interaction between ECS and steroid hormones.

  4. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system

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    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-01-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. PMID:27903595

  5. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    Science.gov (United States)

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187

  6. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

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    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-04-17

    Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

  7. The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction

    Directory of Open Access Journals (Sweden)

    Francisco-Javier Bermúdez-Silva

    2011-08-01

    Full Text Available The endocannabinoid system (ECS has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses. We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the Gi/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN and bulimia nervosa (BN are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug

  8. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

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    Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

    2017-01-01

    indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Endocannabinoids and the processing of value-related signals

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    Miriam eMelis

    2012-02-01

    Full Text Available Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA neurons in the ventral tegmental area (VTA make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.

  10. Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

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    Monteleone, Alessio Maria; Di Marzo, Vincenzo; Aveta, Teresa; Piscitelli, Fabiana; Dalle Grave, Riccardo; Scognamiglio, Pasquale; El Ghoch, Marwan; Calugi, Simona; Monteleone, Palmiero; Maj, Mario

    2015-02-01

    A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy

  11. The endocannabinoid system: emotion, learning and addiction.

    Science.gov (United States)

    Moreira, Fabrício A; Lutz, Beat

    2008-06-01

    The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named anandamide after the Sanskrit word 'ananda', meaning 'bliss'. However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses three properties of the endocannabinoid system as an attempt to understand these diverse effects. First, this system typically functions 'on-demand', depending on environmental stimuli and on the emotional state of the organism. Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli. Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate. Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.

  12. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids.

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    Pataky, Zoltan; Carrard, Isabelle; Gay, Valerie; Thomas, Aurélien; Carpentier, Anne; Bobbioni-Harsch, Elisabetta; Golay, Alain

    2018-04-10

    To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Among completers (n = 87), body weight decreased in 35 patients (-9.1 ± 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL. © 2018 The Author(s) Published by S. Karger GmbH, Freiburg.

  13. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids?

    Directory of Open Access Journals (Sweden)

    Zoltan Pataky

    2018-04-01

    Full Text Available Objective: To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED as well as quality of life (QoL and to elucidate the role of endocannabinoids in metabolic syndrome (MS. Methods: In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Results: Among completers (n = 87, body weight decreased in 35 patients (-9.1 ± 8.6 kg, remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg. 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08, fasting glucose (p 2 = 0.12, total cholesterol (p = 0.001, R2 = 0.11, triglycerides (p = 0.001, R2 = 0.11, LDL-cholesterol (p = 0.03, R2 = 0.05 as well as depression score (p = 0.002, R2 = 0.29. Conclusion: Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL.

  14. Astrocytes in endocannabinoid signalling.

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    Navarrete, Marta; Díez, Adolfo; Araque, Alfonso

    2014-10-19

    Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  15. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation.

    Science.gov (United States)

    Gouveia-Figueira, Sandra; Späth, Jana; Zivkovic, Angela M; Nording, Malin L

    2015-01-01

    Bioactive lipids, including oxylipins, endocannabinoids, and related compounds may function as specific biochemical markers of certain aspects of inflammation. However, the postprandial responsiveness of these compounds is largely unknown; therefore, changes in the circulating oxylipin and endocannabinoid metabolome in response to a challenge meal were investigated at six occasions in a subject who freely modified her usual diet. The dietary change, and especially the challenge meal itself, represented a modification of precursor fatty acid status, with expectedly subtle effects on bioactive lipid levels. To detect even the slightest alteration, highly sensitive ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS/MS) methods for bioactive lipid profiling was employed. A previously validated UPLC-ESI-MS/MS method for profiling the endocannabinoid metabolome was used, while validation of an UPLC-ESI-MS/MS method for oxylipin analysis was performed with acceptable outcomes for a majority of the parameters according to the US Food and Drug Administration guidelines for linearity (0.9938 metabolome, caused by changes in diet and ii) responsiveness to a challenge meal for a subset of the oxylipin and endocannabinoid metabolome. To summarize, we have shown proof-of-concept of our UPLC-ESI-MS/MS bioactive lipid protocols for the purpose of monitoring subtle shifts, and thereby useful to address lipid-mediated postprandial inflammation.

  16. Dynamic regulation of the endocannabinoid system: implications for analgesia

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    Wong Amy

    2009-10-01

    Full Text Available Abstract The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

  17. Effects of activation of endocannabinoid system on myocardial metabolism

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    Agnieszka Polak

    2016-05-01

    Full Text Available Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.

  18. Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction.

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    Austin R Jackson

    Full Text Available Endogenous cannabinoids [endocannabinoids] are lipid signaling molecules that have been shown to modulate immune functions. However, their role in the regulation of Th17 cells has not been studied previously. In the current study, we used methylated Bovine Serum Albumin [mBSA]-induced delayed type hypersensitivity [DTH] response in C57BL/6 mice, mediated by Th17 cells, as a model to test the anti-inflammatory effects of endocannabinoids. Administration of anandamide [AEA], a member of the endocannabinoid family, into mice resulted in significant mitigation of mBSA-induced inflammation, including foot pad swelling, cell infiltration, and cell proliferation in the draining lymph nodes [LN]. AEA treatment significantly reduced IL-17 and IFN-γ production, as well as decreased RORγt expression while causing significant induction of IL-10 in the draining LNs. IL-10 was critical for the AEA-induced mitigation of DTH response inasmuch as neutralization of IL-10 reversed the effects of AEA. We next analyzed miRNA from the LN cells and found that 100 out of 609 miRNA species were differentially regulated in AEA-treated mice when compared to controls. Several of these miRNAs targeted proinflammatory mediators. Interestingly, many of these miRNA were also upregulated upon in vitro treatment of LN cells with IL-10. Together, the current study demonstrates that AEA may suppress Th-17 cell-mediated DTH response by inducing IL-10 which in turn triggers miRNA that target proinflammatory pathways.

  19. Individual differences in response to positive and negative stimuli: endocannabinoid-based insight on approach and avoidance behaviors

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    Daniela eLaricchiuta

    2014-12-01

    Full Text Available Approach and avoidance behaviors - the primary responses to the environmental stimuli of danger, novelty and reward - are associated with the brain structures that mediate cognitive functionality, reward sensitivity and emotional expression. Individual differences in approach and avoidance behaviors are modulated by the functioning of amygdaloid-hypothalamic-striatal and striatal-cerebellar networks implicated in action and reaction to salient stimuli. The nodes of these networks are strongly interconnected and by acting on them the endocannabinoid and dopaminergic systems increase the intensity of appetitive or defensive motivation. This review analyzes the approach and avoidance behaviors in humans and rodents, addresses neurobiological and neurochemical aspects of these behaviors, and proposes a possible synaptic plasticity mechanism, related to endocannabinoid-dependent long-term potentiation and depression that allows responding to salient positive and negative stimuli.

  20. The endocannabinoid system and its relevance for nutrition

    DEFF Research Database (Denmark)

    Maccarrone, Mauro; Gasperi, Valeria; Catani, Maria Valeria

    2010-01-01

    Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS......). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features...... of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed...

  1. Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

    Science.gov (United States)

    Clark, Amy L; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F; Piston, David W; Urano, Fumihiko

    2017-07-17

    Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

  2. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

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    Ibrahim Knani

    2016-12-01

    Full Text Available Objective: Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS. Among numerous metabolic regulators, the endocannabinoid (eCB system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods: We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS. Author Video: Author Video Watch what authors say about their articles Keywords: Endocannabinoids, PWS, Magel2, Peripheral CB1 blockade, Metabolic syndrome

  3. The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder

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    Viviana eTrezza

    2013-08-01

    Full Text Available Posttraumatic stress disorder (PTSD is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors.

  4. Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals.

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    Vlachou, S; Panagis, G

    2014-01-01

    The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of reward-related disorders.

  5. Translating genetic research into preventive intervention: The baseline target moderated mediator design

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    George W. Howe

    2016-01-01

    Full Text Available In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We end with a discussion of some of the advantages and limitations of this approach.

  6. Endocannabinoid System: A Multi-Facet Therapeutic Target.

    Science.gov (United States)

    Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

    2016-01-01

    Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve "protective role" in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish

  7. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; Fornari, Raquel V; Roozendaal, Benno

    2015-05-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

  8. Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design.

    Science.gov (United States)

    Howe, George W; Beach, Steven R H; Brody, Gene H; Wyman, Peter A

    2015-01-01

    In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach.

  9. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

    Science.gov (United States)

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2016-01-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

  10. ENDOCANNABINOIDS AND EICOSAMOIDS: BIOSYNTHESIS AND INTERACTIONS WITH IMMUNE RESPONSE

    Directory of Open Access Journals (Sweden)

    Yu. K. Karaman

    2013-01-01

    Full Text Available The review is dedicated to modern concepts of arachidonic acid metabolites, i.e., endocannabinoids and eicosanoids, their biosynthetic pathways, cross-talk mechanisms and participation in immune response. New information from literature and own results include data concerning overlapping enzymatic pathways controlling biosynthesis of endocannabinoids and eicosanoids. Impact of synthetic cannabinoid receptor ligands upon production rates of proinflammatory cytokines and eicosanoids is discussed, as like as relationships among immune system reactivity and expression levels of cannabinoid receptors.

  11. Gestation Related Gene Expression of the Endocannabinoid Pathway in Rat Placenta

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    Kanchan Vaswani

    2015-01-01

    Full Text Available Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglα, and Ptgs2 was studied (cohort 1, microarray. Biological replication of the results was performed by qPCR (cohort 2. Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1, from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.

  12. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

    OpenAIRE

    Solbrig, MV; Adrian, R; Baratta, J; Piomelli, D; Giuffrida, A

    2005-01-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endoca...

  13. The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice

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    Rose Chesworth

    2018-02-01

    Full Text Available The use of cannabis is a well-established component risk factor for schizophrenia, particularly in adolescent individuals with genetic predisposition for the disorder. Alterations to the endocannabinoid system have been found in the prefrontal cortex of patients with schizophrenia. Thus, we assessed whether molecular alterations exist in the endocannabinoid signalling pathway during brain development in a mouse model for the schizophrenia risk gene neuregulin 1 (Nrg1. We analysed transcripts encoding key molecules of the endocannabinoid system in heterozygous transmembrane domain Nrg1 mutant mice (Nrg1 TM HET, which is known to have increased sensitivity to cannabis exposure. Tissue from the prelimbic cortex and hippocampus of male and female Nrg1 TM HET mice and wild type-like littermates was collected at postnatal days (PNDs 7, 10, 14, 21, 28, 35, 49, and 161. Quantitative polymerase chain reaction was conducted to assess mRNA levels of cannabinoid receptor 1 (CB1R and enzymes for the synthesis and breakdown of the endocannabinoid 2-arachidonoylglycerol [i.e., diacylglycerol lipase alpha (DAGLα, monoglyceride lipase (MGLL, and α/β-hydrolase domain-containing 6 (ABHD6]. No sex differences were found for any transcripts in either brain region; thus, male and female data were pooled. Hippocampal and cortical mRNA expression of DAGLα, MGLL, and ABHD6 increased until PND 21–35 and then decreased and stabilised for the rest of postnatal development. Hippocampal CB1R mRNA expression increased until PND 21 and decreased after this age. Expression levels of these endocannabinoid markers did not differ in Nrg1 TM HET compared to control mice at any time point. Here, we demonstrate dynamic changes in the developmental trajectory of several key endocannabinoid system transcripts in the mouse brain, which may correspond with periods of endocannabinoid system maturation. Nrg1 TM HET mutation did not alter the developmental trajectory of the

  14. Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG on Executive Functions in Humans.

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    Ana B Fagundo

    Full Text Available Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG and executive functions (decision making, response inhibition and cognitive flexibility in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = -.37; p<.05. A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05 and decision making performance (r = .23; P<.05. There was no significant correlation between either 2-AG (r = -.17 or AEA (r = -.08 concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders. Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.

  15. Antibody-Mediated Rejection: Pathogenesis, Prevention, Treatment, and Outcomes

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    Olivia R. Blume

    2012-01-01

    Full Text Available Antibody-mediated rejection (AMR is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA typing including well-designed studies to determine anti-MHC-class-I-related chain A (MICA and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP is effective in removing alloantibodies (DSAs from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively.

  16. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

    Science.gov (United States)

    Coleman, Jonathan R. I.; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L.; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M.; Schneider, Silvia; Silverman, Wendy K.; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H.; Eley, Thalia C.

    2016-01-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27346075

  17. Beyond Cannabis: Plants and the Endocannabinoid System.

    Science.gov (United States)

    Russo, Ethan B

    2016-07-01

    Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain

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    Jean-François Bouchard

    2016-01-01

    Full Text Available Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

  19. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Science.gov (United States)

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

  20. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

    Science.gov (United States)

    Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  1. Anticipatory and consummatory effects of (hedonic chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Directory of Open Access Journals (Sweden)

    Antonello E. Rigamonti

    2015-11-01

    Full Text Available Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods: To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1, peptide YY (PYY, anandamide (AEA, 2-AG, palmitoylethanolamide (PEA, and oleoylethanolamide (OEA in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results: The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions: When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  2. Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

    Science.gov (United States)

    MacDowell, Karina S; Sayd, Aline; García-Bueno, Borja; Caso, Javier R; Madrigal, José L M; Leza, Juan Carlos

    2017-09-01

    Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

  3. Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity.

    Science.gov (United States)

    Lovelace, Jonathan W; Vieira, Philip A; Corches, Alex; Mackie, Ken; Korzus, Edward

    2014-06-01

    In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7-11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.

  4. Song-associated reward correlates with endocannabinoid-related gene expression in male European starlings (Sturnus vulgaris).

    Science.gov (United States)

    Hahn, Allison H; Merullo, Devin P; Spool, Jeremy A; Angyal, Caroline S; Stevenson, Sharon A; Riters, Lauren V

    2017-03-27

    Vocal communication is required for successful social interactions in numerous species. During the breeding season, songbirds produce songs that are reinforced by behavioral consequences (e.g., copulation). However, some songbirds also produce songs not obviously directed at other individuals. The consequences maintaining or reinforcing these songs are less obvious and the neural mechanisms associated with undirected communication are not well-understood. Previous studies indicate that undirected singing is intrinsically rewarding and mediated by opioid or dopaminergic systems; however, endocannabinoids are also involved in regulating reward and singing behavior. We used a conditioned place preference paradigm to examine song-associated reward in European starlings and quantitative real-time PCR to measure expression of endocannabinoid-related neural markers (CB 1 , FABP7, FABP5, FAAH, DAGLα), in brain regions involved in social behavior, reward and motivation (ventral tegmental area [VTA], periaqueductal gray [PAG], and medial preoptic nucleus [POM]), and a song control region (Area X). Our results indicate that starlings producing high rates of song developed a conditioned place preference, suggesting that undirected song is associated with a positive affective state. We found a significant positive relationship between song-associated reward and CB 1 receptors in VTA and a significant negative relationship between song-associated reward and CB 1 in PAG. There was a significant positive relationship between reward and the cannabinoid transporter FABP7 in POM and a significant negative relationship between reward and FABP7 in PAG. In Area X, FABP5 and DAGLα correlated positively with singing. These results suggest a role for endocannabinoid signaling in vocal production and reward associated with undirected communication. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

    Science.gov (United States)

    Silveira, Mason M.; Arnold, Jonathon C.; Laviolette, Steven R.; Hillard, Cecilia J.; Celorrio, Marta; Aymerich, María S.; Adams, Wendy K.

    2016-01-01

    Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications. PMID:27639448

  6. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Toczek, Marek [Department of Experimental Physiology and Pathophysiology Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok (Poland); Bielawska, Katarzyna [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Skrzydlewska, Elżbieta, E-mail: elzbieta.skrzydlewska@umb.edu.pl [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland)

    2016-06-15

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the

  7. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    International Nuclear Information System (INIS)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta

    2016-01-01

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB 1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB 1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the liver of

  8. Differential Regulation of Eicosanoid and Endocannabinoid Production by Inflammatory Mediators in Human Choriodecidua.

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    M D Mitchell

    Full Text Available An increase in intrauterine prostaglandin production is critical for the onset and progression of labor in women and indeed all mammalian species studied. Endocannabinoids can act as substrates for enzymes of the prostaglandin biosynthetic pathways and can be utilized to generate other related compounds such as prostamides. The end products are indistinguishable by radioimmunoassay. We have separated such compounds by mass spectrometry. We now show that inflammatory stimuli such as LPS and proinflammatory cytokines act differentially on these pathways in human choriodecidua and preferentially create drive through to prostaglandin end products. These findings create doubt about the interpretation of data on prostaglandin biosynthesis in intrauterine tissues from pregnant women especially in the presence of an infection. The possibility is raised that separation of these products might reduce variability in results and lead to potential uses for their measurement in the diagnosis of preterm labor.

  9. Endocannabinoids and Human Sperm Cells

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    Giovanna Zolese

    2010-10-01

    Full Text Available N-acylethanolamides (NAEs are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA, the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA and oleylethanolamide (OEA in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1 and type-2 (CB2 cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1, while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs. This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility.

  10. Prevention and Treatment of Bone Metastases in Breast Cancer

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    Ripamonti Carla

    2013-09-01

    Full Text Available In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression. Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach.

  11. Updates in Reproduction Coming from the Endocannabinoid System

    Science.gov (United States)

    Bradshaw, Heather B.

    2014-01-01

    The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. PMID:24550985

  12. Updates in Reproduction Coming from the Endocannabinoid System

    Directory of Open Access Journals (Sweden)

    Rosaria Meccariello

    2014-01-01

    Full Text Available The endocannabinoid system (ECS is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility.

  13. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

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    Brian C. Shonesy

    2014-12-01

    Full Text Available Summary: Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.

  14. Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

    Science.gov (United States)

    Achterberg, E J Marijke; van Swieten, Maaike M H; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-08-01

    Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. A Preliminary Model for the Protective Role of the Endocannabinoid 2-Arachydonylglycerol in Neuroinflammation

    Science.gov (United States)

    2015-09-30

    Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy . J Pharmacol Exp Ther, 307:129-137. Zhang M, Chen C. 2008. Endocannabinoid 2... Disorders . Brain Res Rev, 52(2):201-43. Pope C, Mechoulam R, Parsons L. 2010. Endocannabinoid Signaling in Neurotoxicity and Neuroprotection

  16. The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

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    Francesca Rossi

    Full Text Available Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

  17. Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

    Science.gov (United States)

    Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

    2017-05-09

    Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1 -/- or CB2 -/- mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

  18. Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

    Science.gov (United States)

    Oleson, Erik B; Beckert, Michael V; Morra, Joshua T; Lansink, Carien S; Cachope, Roger; Abdullah, Rehab A; Loriaux, Amy L; Schetters, Dustin; Pattij, Tommy; Roitman, Mitchell F; Lichtman, Aron H; Cheer, Joseph F

    2012-01-26

    Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats.

    Science.gov (United States)

    Zubrzycki, Marek; Janecka, Anna; Liebold, Andreas; Ziegler, Mechthild; Zubrzycka, Maria

    2017-11-01

    Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. The study objectives were realized on rats using a method that allows the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation. The amplitude of ETJ was a measure of the effect of neurotransmitters on neural structures. Perfusion of cerebral ventricles with anandamide (AEA), endomorphin-2 (EM-2), URB597, an inhibitor of fatty acid amide hydrolase (FAAH) and JZL195, a dual inhibitor of FAAH and monoacylglycerol lipase (MAGL) reduced the ETJ amplitude. The antinociceptive effect of AEA, EM-2, URB597 and JZL195 was blocked by CB 1 receptor antagonist, AM251 and by μ receptor-antagonist, β-funaltrexamine. In contrast to AEA, 2-arachidonoylglycerol alone did not decrease ETJ amplitude. We demonstrated that in the orofacial area, analgesic activity is modulated by AEA and that EM-2-induced antinociception was mediated by μ and CB 1 receptors. The action of AEA and EM-2 is tightly regulated by FAAH and FAAH/MAGL, by preventing the breakdown of endogenous cannabinoids in regions where they are produced on demand. Therefore, the current findings support the therapeutic potential of FAAH and FAAH/MAGL inhibitors as novel pharmacotherapeutic agents for orofacial pain. © 2017 The British Pharmacological Society.

  20. Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism

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    Shaan S. Naughton

    2013-01-01

    Full Text Available Endocannabinoids and their G-protein coupled receptors (GPCR are a current research focus in the area of obesity due to the system’s role in food intake and glucose and lipid metabolism. Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β-oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain.

  1. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity.

    Science.gov (United States)

    Monteleone, A M; Di Marzo, V; Monteleone, P; Dalle Grave, R; Aveta, T; Ghoch, M El; Piscitelli, F; Volpe, U; Calugi, S; Maj, M

    2016-06-01

    Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2-AG, OEA and PEA to hedonic eating in obese individuals. Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non-favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity.

  2. Preventive Migraine Treatment

    Science.gov (United States)

    Silberstein, Stephen D.

    2015-01-01

    Purpose of Review: This article reviews the evidence base for the preventive treatment of migraine. Recent Findings: Evidence-based guidelines for the preventive treatment of migraine have recently been published by the American Academy of Neurology (AAN) and the Canadian Headache Society (CHS), providing valuable guidance for clinicians. Strong evidence exists to support the use of metoprolol, timolol, propranolol, divalproex sodium, sodium valproate, and topiramate for migraine prevention, according to the AAN. Based on best available evidence, adverse event profile, and expert consensus, topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, Petasites (butterbur), riboflavin, coenzyme Q10, and magnesium citrate received a strong recommendation for use from the CHS. Summary: Migraine preventive drug treatments are underutilized in clinical practice. Principles of preventive treatment are important to improve compliance, minimize side effects, and improve patient outcomes. Choice of preventive treatment of migraine should be based on the presence of comorbid and coexistent illness, patient preference, reproductive potential and planning, and best available evidence. PMID:26252585

  3. Targeting the endocannabinoid system : future therapeutic strategies

    NARCIS (Netherlands)

    Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-01-01

    The endocannabinoid system (ECS) is involved in many physiological regulation pathways in the human body, which makes this system the target of many drugs and therapies. In this review, we highlight the latest studies regarding the role of the ECS and the drugs that target it, with a particular

  4. Moderate-vigorous physical activity across body mass index in females: moderating effect of endocannabinoids and temperament.

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    Fernando Fernández-Aranda

    Full Text Available Endocannabinoids and temperament traits have been linked to both physical activity and body mass index (BMI however no study has explored how these factors interact in females. The aims of this cross-sectional study were to 1 examine differences among distinct BMI groups on daytime physical activity and time spent in moderate-vigorous physical activity (MVPA, temperament traits and plasma endocannabinoid concentrations; and 2 explore the association and interaction between MVPA, temperament, endocannabinoids and BMI.Physical activity was measured with the wrist-worn accelerometer Actiwatch AW7, in a sample of 189 female participants (43 morbid obese, 30 obese, and 116 healthy-weight controls. The Temperament and Character Inventory-Revised questionnaire was used to assess personality traits. BMI was calculated by bioelectrical impedance analysis via the TANITA digital scale. Blood analyses were conducted to measure levels of endocannabinoids and endocannabinoid-related compounds. Path-analysis was performed to examine the association between predictive variables and MVPA.Obese groups showed lower MVPA and dysfunctional temperament traits compared to healthy-weight controls. Plasma concentrations of 2-arachidonoylglyceryl (2-AG were greater in obese groups. Path-analysis identified a direct effect between greater MVPA and low BMI (b = -0.13, p = .039 and high MVPA levels were associated with elevated anandamide (AEA levels (b = 0.16, p = .049 and N-oleylethanolamide (OEA levels (b = 0.22, p = .004, as well as high Novelty seeking (b = 0.18, p<.001 and low Harm avoidance (b = -0.16, p<.001.Obese individuals showed a distinct temperament profile and circulating endocannabinoids compared to controls. Temperament and endocannabinoids may act as moderators of the low MVPA in obesity.

  5. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  6. The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.

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    Randall G Krug

    Full Text Available The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld, enzymes that degrade (faah, faah2a, faah2b, and receptors that bind (cnr1, cnr2, gpr55-like endocannabinoids are expressed in zebrafish (Danio rerio. These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.

  7. Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

    Science.gov (United States)

    Sagheddu, Claudia; Muntoni, Anna Lisa; Pistis, Marco; Melis, Miriam

    2015-01-01

    Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. © 2015 Elsevier Inc. All rights reserved.

  8. From Fertilisation to Implantation in Mammalian Pregnancy—Modulation of Early Human Reproduction by the Endocannabinoid System

    Directory of Open Access Journals (Sweden)

    Justin C. Konje

    2010-09-01

    Full Text Available There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol in early reproduction.

  9. Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats

    Directory of Open Access Journals (Sweden)

    Valentina Satta

    2018-02-01

    Full Text Available Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED. Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats. For this purpose, brain levels of the endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG, as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus. The brain density of cannabinoid type-1 receptors (CB1 was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain. To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD (margarine. Three experimental groups were used, all with ad libitum access to chow: control (CTRL, with no access to margarine; low restriction (LR, with 2 h margarine access 7 days/week; high restriction (HR, with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group. Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both

  10. The endocannabinoid system within the dorsal lateral geniculate nucleus of the vervet monkey

    DEFF Research Database (Denmark)

    Javadi, P.; Bouskila, J.; Bouchard, J. -F.

    2015-01-01

    The endocannabinoid system mainly consists of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), their endogenous ligands termed endocannabinoids (eCBs), and the enzymes responsible for the synthesis and degradation of eCBs. These cannabinoid receptors have been well characterized in rodent a...... layers may explain some of the behavioral effects of cannabinoids associated with the integrity of the dorsal visual pathway that plays a role in visual-spatial localization and motion perception....

  11. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

    Science.gov (United States)

    du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun

    2015-11-01

    Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

  12. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    Energy Technology Data Exchange (ETDEWEB)

    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  13. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    International Nuclear Information System (INIS)

    Frampton, Gabriel; Coufal, Monique; Li, Huang; Ramirez, Jonathan; DeMorrow, Sharon

    2010-01-01

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the γ-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-γ-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the γ-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  14. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    International Nuclear Information System (INIS)

    Ito, Yuki; Tomizawa, Motohiro; Suzuki, Himiko; Okamura, Ai; Ohtani, Katsumi; Nunome, Mari; Noro, Yuki; Wang, Dong; Nakajima, Tamie; Kamijima, Michihiro

    2014-01-01

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity

  15. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Yuki, E-mail: yukey@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Tomizawa, Motohiro [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502 (Japan); Suzuki, Himiko [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Okamura, Ai [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ohtani, Katsumi [National Institute of Occupational Safety and Health, Kanagawa 214-8585 (Japan); Nunome, Mari; Noro, Yuki [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Wang, Dong; Nakajima, Tamie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Kamijima, Michihiro, E-mail: kamijima@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan)

    2014-09-15

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity.

  16. 5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells.

    Science.gov (United States)

    Park, Seok-Woo; Hah, J Hun; Oh, Sang-Mi; Jeong, Woo-Jin; Sung, Myung-Whun

    2016-07-13

    Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA. DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.

  17. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa.

    Science.gov (United States)

    Monteleone, Palmiero; Matias, Isabelle; Martiadis, Vassilis; De Petrocellis, Luciano; Maj, Mario; Di Marzo, Vincenzo

    2005-06-01

    The endocannabinoid system, consisting of two cannabinoid receptors (CB1 and CB2) and the endogenous ligands anandamide (arachidonoylethanolamide (AEA)) and 2-arachidonoylglycerol (2-AG), has been shown to control food intake in both animals and humans, modulating either rewarding or quantitative aspects of the eating behavior. Moreover, hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis. Therefore, alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders, where a deranged leptin signalling has been also reported. In order to verify this hypothesis, we measured plasma levels of AEA, 2-AG, and leptin in 15 women with anorexia nervosa (AN), 12 women with bulimia nervosa (BN), 11 women with binge-eating disorder (BED), and 15 healthy women. Plasma levels of AEA resulted significantly enhanced in both anorexic and BED women, but not in bulimic patients. No significant change occurred in the plasma levels of 2-AG in all the patients' groups. Moreover, circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women. These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED. Although the pathophysiological significance of this alteration awaits further studies to be clarified, it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED.

  18. The endocannabinoid system and appetite: relevance for food reward

    NARCIS (Netherlands)

    Jager, G.; Witkamp, R.F.

    2014-01-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the

  19. Cannabinoids for treatment of Alzheimer’s disease: moving towards the clinic

    Directory of Open Access Journals (Sweden)

    Isidro eFerrer

    2014-03-01

    Full Text Available The limited effectiveness of current therapies against Alzheimer’s disease highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful A peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of Alzheimer’s disease, which together encourage progress towards a clinical trial.

  20. Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance.

    Science.gov (United States)

    Claeson, Anna-Sara; Gouveia-Figueira, Sandra; Häggström, Jenny; Fowler, Christopher J; Nording, Malin L

    2017-06-01

    Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Cancer treatment - preventing infection

    Science.gov (United States)

    ... Radiation - preventing infection; Bone marrow transplant - preventing infection; Cancer treatment - immunosuppression ... this is a short-lived side effect of cancer treatment. Your provider may give you medicines to help ...

  2. The endocannabinoid anandamide regulates the peristaltic reflex by reducing neuro-neuronal and neuro-muscular neurotransmission in ascending myenteric reflex pathways in rats.

    Science.gov (United States)

    Sibaev, Andrei; Yuece, Birol; Allescher, Hans Dieter; Saur, Dieter; Storr, Martin; Kurjak, Manfred

    2014-04-01

    Endocannabinoids (EC) and the cannabinoid-1 (CB1) receptor are involved in the regulation of motility in the gastrointestinal (GI) tract. However, the underlying physiological mechanisms are not completely resolved. The purpose of this work was to study the physiological influence of the endocannabinoid anandamide, the putative endogenous CB1 active cannabinoid, and of the CB1 receptor on ascending peristaltic activity and to identify the involved neuro-neuronal, neuro-muscular and electrophysiological mechanisms. The effects of anandamide and the CB1 receptor antagonist SR141716A were investigated on contractions of the circular smooth muscle of rat ileum and in longitudinal rat ileum segments where the ascending myenteric part of the peristaltic reflex was studied in a newly designed organ bath. Additionally intracellular recordings were performed in ileum and colon. Anandamide significantly reduced cholinergic twitch contractions of ileum smooth muscle whereas SR141716A caused an increase. Anandamide reduced the ascending peristaltic contraction by affecting neuro-neuronal and neuro-muscular neurotransmission. SR141716A showed opposite effects and all anandamide effects were antagonized by SR141716A (1 μM). Anandamide reduced excitatory junction potentials (EJP) and inhibitory junction potentials (IJP), whereas intestinal slow waves were not affected. CB1 receptors regulate force and timing of the intestinal peristaltic reflex and these actions involve interneurons and motor-neurons. The endogenous cannabinoid anandamide mediates these effects by activation of CB1 receptors. The endogenous cannabinoid system is permanently active, suggesting the CB1 receptor being a possible target for the treatment of motility related disorders. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Science.gov (United States)

    Karlsson, Jessica; Fowler, Christopher J

    2014-01-01

    In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  4. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Directory of Open Access Journals (Sweden)

    Jessica Karlsson

    Full Text Available In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG and anandamide (AEA by cyclooxygenase-2 (COX-2 and fatty acid amide hydrolase (FAAH, respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen.COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1 and arachidonic acid and 2-AG (for COX-2. FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds.It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  5. Antioxidant status and endocannabinoid concentration in postpartum depressive women

    Directory of Open Access Journals (Sweden)

    Mina Ranjbaran

    2015-02-01

    Conclusion: Women’s Job, husband’s job, wanted or unwanted pregnancy from husbands and marital period are associated to postpartum depression. In postpartum depression, TAC, AEA and 2-AG are reduced. So it can be concluded that both antioxidant system and endocannabinoid concentration involved in the development of postpartum depression.

  6. Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Hai-Jing Sun

    2017-01-01

    Full Text Available Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA and 2-arachidonoylglycerol (2-AG detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS, malonaldehyde (MDA, and MPO (myeloperoxidase and increased superoxide dismutase (SOD production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

  7. 5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    Park, Seok-Woo; Hah, J. Hun; Oh, Sang-Mi; Jeong, Woo-Jin; Sung, Myung-Whun

    2016-01-01

    Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA. DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it. The online version of this article (doi:10.1186/s12885-016-2499-3) contains supplementary material, which is available to authorized users

  8. Exposure to a highly caloric palatable diet during pregestational and gestational periods affects hypothalamic and hippocampal endocannabinoid levels at birth and induces adiposity and anxiety-like behaviors in male rat offspring

    Directory of Open Access Journals (Sweden)

    Maria Teresa eRamírez-López

    2016-01-01

    Full Text Available Exposure to unbalanced diets during pre-gestational and gestational periods may result in long-term alterations in metabolism and behavior. The contribution of the endocannabinoid system to these long-term adaptive responses is unknown. In the present study, we investigated the impact of female rat exposure to a hypercaloric-hypoproteic palatable diet during pre-gestational, gestational and lactational periods on the development of male offspring. In addition, the hypothalamic and hippocampal endocannabinoid contents at birth and the behavioral performance in adulthood were investigated. Exposure to a palatable diet resulted in low weight offspring who exhibited low hypothalamic contents of arachidonic acid and the two major endocannabinoids (anandamide and 2-arachidonoylglycerol at birth. Palmitoylethanolamide, but not oleoylethanolamide, also decreased. Additionally, pups from palatable diet-fed dams displayed lower levels of anandamide and palmitoylethanolamide in the hippocampus. The low-weight male offspring, born from palatable diet exposed mothers, gained less weight during lactation and, although they recovered weight during the post-weaning period, they developed abdominal adiposity in adulthood. These animals exhibited anxiety-like behavior in the elevated plus-maze and open field test and a low preference for a chocolate diet in a food preference test, indicating that maternal exposure to a hypercaloric diet induces long-term behavioral alterations in male offspring. These results suggest that maternal diet alterations in the function of the endogenous cannabinoid system can mediate the observed phenotype of the offspring, since both hypothalamic and hippocampal endocannabinoids regulate feeding, metabolic adaptions to caloric diets, learning, memory and emotions.

  9. Oxyradical Stress, Endocannabinoids, and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Anberitha T. Matthews

    2015-12-01

    Full Text Available Atherosclerosis is responsible for most cardiovascular disease (CVD and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG. Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

  10. Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

    Science.gov (United States)

    Cedernaes, Jonathan; Fanelli, Flaminia; Fazzini, Alessia; Pagotto, Uberto; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Schiöth, Helgi B; Benedict, Christian

    2016-12-01

    Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, pexercise (+44%, pexercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (pexercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  11. Ratio-of-Mediator-Probability Weighting for Causal Mediation Analysis in the Presence of Treatment-by-Mediator Interaction

    Science.gov (United States)

    Hong, Guanglei; Deutsch, Jonah; Hill, Heather D.

    2015-01-01

    Conventional methods for mediation analysis generate biased results when the mediator--outcome relationship depends on the treatment condition. This article shows how the ratio-of-mediator-probability weighting (RMPW) method can be used to decompose total effects into natural direct and indirect effects in the presence of treatment-by-mediator…

  12. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    Science.gov (United States)

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

  13. Stroke Prevention & Treatment: Diet & Nutrition

    Science.gov (United States)

    ... Prevention & Treatment: Diet & Nutrition Stroke Prevention & Treatment: Diet & Nutrition A healthy diet can reduce your risk for ... Treatment How does a stroke affect eating and nutrition? Stroke can devastate a person's nutritional health because ...

  14. Exploração farmacológica do sistema endocanabinoide: novas perspectivas para o tratamento de transtornos de ansiedade e depressão? Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?

    Directory of Open Access Journals (Sweden)

    Viviane M. Saito

    2010-05-01

    analogues. Research on their pharmacological profile led to the discovery of the endocannabinoid system in the mammalian brain. This system comprises at least two G-protein coupled receptors, CB1 and CB2, their endogenous ligands (endocannabinoids; e.g. the fatty acid derivatives anandamide and 2-arachydonoyl glycerol, and the enzymes responsible for endocannabinoid synthesis and catabolism. Endocannabinoids represent a class of neuromessengers, which are synthesized on demand and released from post-synaptic neurons to restrain the release of classical neurotransmitters from pre-synaptic terminals.This retrograde signalling modulates a variety of brain functions, including anxiety, fear and mood, whereby activation of CB1 receptors was shown to exert anxiolytic-and antidepressant-like effects in preclinical studies. CONCLUSION: Animal experiments suggest that drugs promoting endocannabinoid action may represent a novel strategy for the treatment of depression and anxiety disorders.

  15. Mediation Analysis of an Adolescent HIV/STI/Pregnancy Prevention Intervention

    Science.gov (United States)

    Glassman, Jill R.; Franks, Heather M.; Baumler, Elizabeth R.; Coyle, Karin K.

    2014-01-01

    Most interventions designed to prevent HIV/STI/pregnancy risk behaviours in young people have multiple components based on psychosocial theories (e.g. social cognitive theory) dictating sets of mediating variables to influence to achieve desired changes in behaviours. Mediation analysis is a method for investigating the extent to which a variable…

  16. Nutritional status-dependent endocannabinoid signalling regulates the integration of rat visceral information.

    Science.gov (United States)

    Khlaifia, Abdessattar; Matias, Isabelle; Cota, Daniela; Tell, Fabien

    2017-06-01

    Vagal sensory inputs transmit information from the viscera to brainstem neurones located in the nucleus tractus solitarii to set physiological parameters. These excitatory synapses exhibit a CB1 endocannabinoid-induced long-term depression (LTD) triggered by vagal fibre stimulation. We investigated the impact of nutritional status on long-term changes in this long-term synaptic plasticity. Food deprivation prevents LTD induction by disrupting CB1 receptor signalling. Short-term refeeding restores the capacity of vagal synapses to express LTD. Ghrelin and cholecystokinin, respectively released during fasting and refeeding, play a key role in the control of LTD via the activation of energy sensing pathways such as AMPK and the mTOR and ERK pathways. Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarii, a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB)-induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reversed by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding, restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and

  17. CA1 Pyramidal Cell Theta-Burst Firing Triggers Endocannabinoid-Mediated Long-Term Depression at Both Somatic and Dendritic Inhibitory Synapses

    Science.gov (United States)

    Younts, Thomas J.; Chevaleyre, Vivien

    2013-01-01

    Endocannabinoids (eCBs) are retrograde lipid messengers that, by targeting presynaptic type 1 cannabinoid receptors (CB1Rs), mediate short- and long-term synaptic depression of neurotransmitter release throughout the brain. Short-term depression is typically triggered by postsynaptic, depolarization-induced calcium rises, whereas long-term depression is induced by synaptic activation of Gq/11 protein-coupled receptors. Here we report that a physiologically relevant pattern of postsynaptic activity, in the form of theta-burst firing (TBF) of hippocampal CA1 pyramidal neurons, can trigger long-term depression of inhibitory transmission (iLTD) in rat hippocampal slices. Paired recordings between CA1 interneurons and pyramidal cells, followed by post hoc morphological reconstructions of the interneurons' axon, revealed that somatic and dendritic inhibitory synaptic inputs equally expressed TBF-induced iLTD. Simultaneous recordings from neighboring pyramidal cells demonstrated that eCB signaling triggered by TBF was highly restricted to only a single, active cell. Furthermore, pairing submaximal endogenous activation of metabotropic glutamate or muscarinic acetylcholine receptors with submaximal TBF unmasked associative iLTD. Although CB1Rs are also expressed at Schaffer-collateral excitatory terminals, long-term plasticity under various recording conditions was spared at these synapses. Consistent with this observation, TBF also shifted the balance of excitation and inhibition in favor of excitatory throughput, thereby altering information flow through the CA1 circuit. Given the near ubiquity of burst-firing activity patterns and CB1R expression in the brain, the properties described here may be a general means by which neurons fine tune the strength of their inputs in a cell-wide and cell-specific manner. PMID:23966696

  18. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  19. Potential role of the endocannabinoid receptor antagonist rimonabant in the management of cardiometabolic risk: a narrative review of available data

    Directory of Open Access Journals (Sweden)

    Kirk A Bronander

    2007-05-01

    Full Text Available Kirk A Bronander1, Michael J Bloch21Division of General Internal Medicine, 2Divisions of Cardiology and General Internal Medicine, Department of Medicine, University of Nevada School of Medicine, Reno, NV, USAAbstract: The endocannabinoid system (ECS is an endogenous physiological system composed of two cannabinoid receptors and several endogenous ligands. The ECS is intimately involved in appetite regulation and energy homeostasis, which makes it an intriguing target for pharmacological treatment of obesity, diabetes, and the metabolic syndrome. Rimonabant is the first cannabinoid receptor (CB-1 antagonist being studied and utilized to treat obesity (it is approved in Europe but is currently under review in the United States. Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight and obese individuals with weight loss significantly greater than a reduced calorie diet alone. In addition, multiple other cardiometabolic parameters were improved in the treatment groups including increased levels of high density lipoprotein cholesterol, reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in glycosylated hemoglobin percentage. There was an increase in the adverse effects of depression, anxiety, irritability, and nausea in rimonabant-treated groups. This novel medication may become an important therapeutic option in the fight to reduce cardiovascular disease worldwide through its unique action on cardiometabolic risk.Keywords: rimonabant, endocannabinoid, metabolic syndrome, obesity

  20. Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

    2017-11-01

    Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

  1. Novel preventive treatment options

    DEFF Research Database (Denmark)

    Longbottom, C; Ekstrand, K; Zero, D

    2009-01-01

    A number of novel preventive treatment options which, as with traditional methods, can be differentiated into 3 categories of prevention (primary, secondary and tertiary), have been and are being currently investigated. Those reviewed are either commercially available or appear relatively close...... of these techniques show considerable promise and dentists should be aware of these developments and follow their progress, the evidence for each of these novel preventive treatment options is currently insufficient to make widespread recommendations. Changes in dental practice should be explored to see how oral...

  2. Preventing and De-Escalating Ethical Conflict: A Communication-Training Mediation Model.

    Science.gov (United States)

    Levin, Tomer T; Parker, Patricia A

    2015-01-01

    While ethical conflicts in the provision of healthcare are common, the current third-party mediator model is limited by a lack of expert ethical mediators, who are often not on site when conflict escalates. In order to improve clinical outcomes in situations such as conflicts at the end of life, we suggest that clinicians-physicians, nurses and social workers-be trained to prevent and de-escalate emerging conflicts. This can be achieved using a mediation model framed by a communication-training approach. A case example is presented and the model is discussed. The implication of this preventative/early intervention model for improving clinical outcomes, in particular end-of life conflict, is considered. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

  3. Processing cardiovascular information in the vlPAG during electroacupuncture in rats: roles of endocannabinoids and GABA

    Science.gov (United States)

    Tjen-A-Looi, Stephanie C.; Li, Peng; Longhurst, John C.

    2009-01-01

    A long-loop pathway, involving the hypothalamic arcuate nucleus (ARC), ventrolateral periaqueductal gray (vlPAG), and the rostral ventrolateral medulla (rVLM), is essential in electroacupuncture (EA) attenuation of sympathoexcitatory cardiovascular reflex responses. The ARC provides excitatory input to the vlPAG, which, in turn, inhibits neuronal activity in the rVLM. Although previous studies have shown that endocannabinoid CB1 receptor activation modulates γ-aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission in the dorsolateral PAG in stress-induced analgesia, an important role for endocannabinoids in the vlPAG has not yet been observed. We recently have shown (Fu LW, Longhurst JC. J Appl Physiol; doi:10.1152/japplphysiol.91648.2008) that EA reduces the local vlPAG concentration of GABA, but not glutamate, as measured with high-performance liquid chromatography from extracellular samples collected by microdialysis. We, therefore, hypothesized that, during EA, endocannabinoids, acting through CB1 receptors, presynaptically inhibit GABA release to disinhibit the vlPAG and ultimately modulate excitatory reflex blood pressure responses. Rats were anesthetized, ventilated, and instrumented to measure heart rate and blood pressure. Gastric distention-induced blood pressure responses of 18 ± 5 mmHg were reduced to 6 ± 1 mmHg by 30 min of low-current, low-frequency EA applied bilaterally at pericardial P 5–6 acupoints overlying the median nerves. Like EA, microinjection of the fatty acid amide hydrolase inhibitor URB597 (0.1 nmol, 50 nl) into the vlPAG to increase endocannabinoids locally reduced the gastric distention cardiovascular reflex response from 21 ± 5 to 3 ± 4 mmHg. This inhibition was reversed by pretreatment with the GABAA antagonist gabazine (27 mM, 50 nl), suggesting that endocannabinoids exert their action through a GABAergic receptor mechanism in the vlPAG. The EA-related inhibition from 18 ± 3 to 8 ± 2 mmHg was reversed to 14

  4. Food Allergy: Our Evolving Understanding of Its Pathogenesis, Prevention, and Treatment.

    Science.gov (United States)

    Iweala, Onyinye I; Burks, A Wesley

    2016-05-01

    Food allergy is defined as an IgE-mediated hypersensitivity response to ingested food with allergic symptoms ranging from urticaria to life-threatening anaphylaxis. Food allergy is thought to develop because of (1) failed induction of tolerance upon initial exposure to food antigen or (2) breakdown of established tolerance to food antigen. We review current understanding of the pathogenesis, epidemiology, and natural history of food allergy, including the unconventional IgE-mediated food allergy to mammalian meat known as alpha-gal food allergy. We highlight emerging data on food allergy treatment and prevention, emphasizing the growing appeal of manipulating the gut microenvironment using probiotics and helminth products to blunt systemic allergic responses to food.

  5. Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum.

    Science.gov (United States)

    Liu, Jing; Parsons, Loren; Pope, Carey

    2015-09-01

    Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes

    Czech Academy of Sciences Publication Activity Database

    Vignali, M.; Benfenati, V.; Caprini, M.; Anděrová, Miroslava; Nobile, M.; Ferroni, S.

    2009-01-01

    Roč. 57, č. 7 (2009), s. 791-806 ISSN 0894-1491 R&D Projects: GA ČR GA305/06/1316; GA ČR GA305/06/1464; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : cortical astroglia * potassium conductance * endocannabinoids Subject RIV: FH - Neurology Impact factor: 4.932, year: 2009

  7. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

    Science.gov (United States)

    Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

    2017-07-01

    The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Western Blotting of the Endocannabinoid System.

    Science.gov (United States)

    Wager-Miller, Jim; Mackie, Ken

    2016-01-01

    Measuring expression levels of G protein-coupled receptors (GPCRs) is an important step for understanding the distribution, function, and regulation of these receptors. A common approach for detecting proteins from complex biological systems is Western blotting. In this chapter, we describe a general approach to Western blotting protein components of the endocannabinoid system using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and nitrocellulose membranes, with a focus on detecting type 1 cannabinoid (CB1) receptors. When this technique is carefully used, specifically with validation of the primary antibodies, it can provide quantitative information on protein expression levels. Additional information can also be inferred from Western blotting such as potential posttranslational modifications that can be further evaluated by specific analytical techniques.

  10. Traditional preventive treatment options

    DEFF Research Database (Denmark)

    Longbottom, C; Ekstrand, K; Zero, D

    2009-01-01

    Preventive treatment options can be divided into primary, secondary and tertiary prevention techniques, which can involve patient- or professionally applied methods. These include: oral hygiene (instruction), pit and fissure sealants ('temporary' or 'permanent'), fluoride applications (patient...... options....

  11. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction.

    Directory of Open Access Journals (Sweden)

    Stéphanie eOlière

    2013-09-01

    Full Text Available Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamine. Interestingly, recent accumulating evidence points toward the involvement of the endocannabinoid system (ECBS in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep-insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. The aims of this article are to: 1 review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and 2 evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoid in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

  12. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System

    Science.gov (United States)

    Gomes, Felipe V.; Silva, Andréia L.; Uliana, Daniela L.; Camargo, Laura H. A.; Guimarães, Francisco S.; Cunha, Fernando Q.; Joca, Sâmia R. L.; Resstel, Leonardo B. M.

    2015-01-01

    Background: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. Methods: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Results: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in

  13. Role of the endocannabinoid system in human brain functions relevant for psychiatric disorders

    NARCIS (Netherlands)

    Bossong, M.G.

    2012-01-01

    Impaired cognitive function is a fundamental characteristic of many psychiatric and neurological disorders such as schizophrenia or Alzheimer’s disease. The endocannabinoid (eCB) system, consisting of cannabinoid receptors and accompanying ligands, has been implicated in these disorders. In

  14. Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.

    Science.gov (United States)

    Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E; Cravatt, Benjamin F; Lichtman, Aron H; Kinsey, Steven G

    2015-06-01

    Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.

  15. Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.

    Directory of Open Access Journals (Sweden)

    Gonzalo E Yévenes

    Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.

  16. Causal mediation analysis with multiple causally non-ordered mediators.

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    Taguri, Masataka; Featherstone, John; Cheng, Jing

    2018-01-01

    In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

  17. Prevention of Incisional Hernias after Open Abdomen Treatment

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    Frederik Berrevoet

    2018-02-01

    Full Text Available Management of a patient with an open abdomen is difficult, and the primary closure of the fascial edges is essential to obtain the best patient outcome, regardless of the initial etiology of the open abdomen. The use of temporary abdominal closure devices is nowadays the gold standard to have the highest closure rates with mesh-mediated fascial traction as the proposed standard of care. However, the incidence of incisional hernias, although much more controlled than when leaving an abdomen open, is high and reaches up to 65%. As shown for other high-risk patient subgroups, such as obese patients, patients with an abdominal aneurysm, and patients with former -ostomy sites, the prevention of incisional hernias might be key to further optimize patient outcomes after open abdomen treatment. In this overview, current available modalities to decrease the incidence of incisional hernia are discussed. Most of these preventive options have been shown effective in giant ventral hernia repair and might work effectively in this patient cohort with open abdomen as well.

  18. Postpartum haemorrhage: prevention and treatment.

    Science.gov (United States)

    Sentilhes, Loïc; Merlot, Benjamin; Madar, Hugo; Sztark, François; Brun, Stéphanie; Deneux-Tharaux, Catherine

    2016-11-01

    Postpartum hemorrhage (PPH) is one of the leading causes of maternal death and severe maternal morbidity worldwide and strategies to prevent and treat PPH vary among international authorities. Areas covered: This review seeks to provide a global overview of PPH (incidence, causes, risk factors), prevention (active management of the third stage of labor and prohemostatic agents), treatment (first, second and third-line measures to control PPH), by also underlining recommendations elaborated by international authorities and using algorithms. Expert commentary: When available, oxytocin is considered the drug of first choice for both prevention and treatment of PPH, while peripartum hysterectomy remains the ultimate life-saving procedure if pharmacological and resuscitation measures fail. Nevertheless, the level of evidence for preventing and treating PPH is globally low. The emergency nature of PPH makes randomized controlled trials (RCT) logistically difficult. Population-based observational studies should be encouraged as they can usefully strengthen the evidence base, particularly for components of PPH treatment that are difficult or impossible to assess through RCT.

  19. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

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    Shenglong Zou

    2018-03-01

    Full Text Available The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R and 2. The CB1R is the prominent subtype in the central nervous system (CNS and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

  20. Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

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    Hu, Wen; Zhang, Mingyue; Czéh, Boldizsár; Zhang, Weiqi; Flügge, Gabriele

    2011-07-15

    Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise

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    Yang Rongze

    2011-10-01

    Full Text Available Abstract Background Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1 and fatty acid amide hydrolase (FAAH are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods Thirty overweight or obese, middle-aged women (BMI = 34.3 ± 0.8 kg/m2, age = 59 ± 1 years underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N = 9, caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N = 13, or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N = 8. Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08 ± 0.11 vs. 1.78 ± 0.10, expressed as target gene/β-actin mRNA ratio × 10-3, P Conclusions There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue endocannabinoid-related gene expression during dietary weight loss. Trial Registration ClinicalTrials.gov: NCT00664729.

  2. Peripheral Endocannabinoid Responses to Hedonic Eating in Binge-Eating Disorder

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    Alessio Maria Monteleone

    2017-12-01

    Full Text Available Reward mechanisms are likely implicated in the pathophysiology of binge-eating behaviour, which is a key symptom of binge-eating disorder (BED. Since endocannabinoids modulate food-related reward, we aimed to investigate the responses of anandamide (AEA and 2-arachidonoylglycerol (2-AG to hedonic eating in patients with BED. Peripheral levels of AEA and 2-AG were measured in 7 obese BED patients before and after eating favorite (hedonic eating and non-favorite (non-hedonic eating foods. We found that plasma levels of AEA progressively decreased after eating the non-favorite food and significantly increased after eating the favorite food, whereas plasma levels of 2-AG did not differ significantly between the two test conditions, although they showed a trend toward significantly different time patterns. The changes in peripheral AEA levels were positively correlated to the subjects’ sensations of the urge to eat and the pleasantness while eating the presented food, while changes in peripheral 2-AG levels were positively correlated to the subjects’ sensation of the pleasantness while eating the presented food and to the amount of food they would eat. These results suggest the occurrence of distinctive responses of endocannabinoids to food-related reward in BED. The relevance of such findings to the pathophysiology of BED remains to be elucidated.

  3. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes

    NARCIS (Netherlands)

    Eyk, van H.J.; Schinkel, van L.D.; Kantae, V.; Dronkers, C.E.A.; Westenberg, J.J.M.; Roos, de A.; Lamb, H.J.; Jukema, J.W.; Harms, A.C.; Hankemeier, T.; Stelt, van der M.; Jazet, I.M.; Rensen, P.C.N.; Smit, J.W.A.

    2018-01-01

    Background/ObjectivesEndocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac

  4. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.

    Science.gov (United States)

    Bowen, T Scott; Eisenkolb, Sophia; Drobner, Juliane; Fischer, Tina; Werner, Sarah; Linke, Axel; Mangner, Norman; Schuler, Gerhard; Adams, Volker

    2017-01-01

    Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (∼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice. © FASEB.

  5. The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

    NARCIS (Netherlands)

    Witkamp, R.F.

    2014-01-01

    The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management

  6. The endocannabinoid system and appetite: relevance for food reward.

    Science.gov (United States)

    Jager, Gerry; Witkamp, Renger F

    2014-06-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the functioning of the ECS, the present review specifically addresses its role in the modulation of hedonic eating. Humans possess strong motivational systems triggered by rewarding aspects of food. Food reward is comprised of two components: one appetitive (orienting towards food); the other consummatory (hedonic evaluation), also referred to as 'wanting' and 'liking', respectively. Endocannabinoid tone seems to influence both the motivation to feed and the hedonic value of foods, probably by modifying palatability. Human physiology underlying hedonic eating is still not fully understood. A better understanding of the role of the ECS in the rewarding value of specific foods or diets could offer new possibilities to optimise the balance between energy and nutrient intake for different target groups. These groups include the obese and overweight, and potentially individuals suffering from malnutrition. Examples for the latter group are patients with disease-related anorexia, as well as the growing population of frail elderly suffering from persistent loss of food enjoyment and appetite resulting in malnutrition and involuntary weight loss. It has become clear that the psychobiology of food hedonics is extremely complex and the clinical failure of CB1 inverse agonists including rimonabant (Accomplia®) has shown that 'quick wins' in this field are unlikely.

  7. The multiple functions of the endocannabinoid system: a focus on the regulation of food intake

    Directory of Open Access Journals (Sweden)

    Tibiriça Eduardo

    2010-01-01

    Full Text Available Abstract Background Cannabis sativa (also known as marijuana has been cultivated by man for more than 5,000 years. However, there was a rise in its use in the 20th century for recreational, religious or spiritual, and medicinal purposes. The main psychoactive constituent of cannabis, whose structure was identified in the 1960's, is Δ9-tetrahydrocannabinol. On the other hand, the discovery of cannabinoid receptors and their endogenous agonists took place only very recently. In fact, the first cannabinoid receptor (CB1 was cloned in 1990, followed 3 years later by the characterization of a second cannabinoid receptor (CB2. Since the 19th century, the use of cannabis has been reported to stimulate appetite and increase the consumption of sweet and tasty food, sometimes resulting in significant weight gain. The recent description of the endocannabinoid system, not only in the central nervous system but also in peripheral tissues, points to its involvement in the regulation of appetite, food intake and energy metabolism. Consequently, the pharmacological modulation of the over-activity of this system could be useful in the treatment of the metabolic syndrome. Conclusions The endocannabinoid system has important physiological functions not only in the central nervous system but also in peripheral tissues. The activation of central CB1 receptors, particularly in hypothalamic nuclei and in the limbic system, is involved in the regulation of feeding behavior, and especially in the control of the intake of palatable food. In the periphery, cannabinoid receptors are present in adipocytes, skeletal muscle, gastrointestinal tract and liver, modulating energy metabolism.

  8. Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.

    Science.gov (United States)

    Killinger, Bryan A; Moszczynska, Anna

    2016-02-01

    Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter, and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to a destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague-Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed 3 days after the treatments for the levels of several DAergic markers as well as for the levels of tubulins and their post-translational modifications (PMTs). Binge METH induced a loss of stable long-lived MTs within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include

  9. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

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    Douglas R Smith

    Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  10. Prevention, not just treatment.

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    Connors, G L; Hilling, L

    1998-03-01

    A tragic burden of disease, disability, and death has resulted from smoking. The role of pulmonary rehabilitation is not only in treatment and rehabilitation of lung disease but in the prevention of lung disease. The skills of the pulmonary rehabilitation specialist should be used in the earlier detection and prevention of lung disease through primary and secondary prevention. The spirometer must gain acceptance in the medical community as the early tool to evaluate lung health, not the chest radiograph or the stethoscope. The lung age formula and sputum pap smears are just a few of the evaluation tools used to detect and motivate susceptible individuals. Prevention is the key to enhancing lung health.

  11. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    Science.gov (United States)

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  12. Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back

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    Roberto Coccurello

    2018-04-01

    Full Text Available Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin, and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin

  13. Understanding how pain education causes changes in pain and disability: protocol for a causal mediation analysis of the PREVENT trial.

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    Lee, Hopin; Moseley, G Lorimer; Hübscher, Markus; Kamper, Steven J; Traeger, Adrian C; Skinner, Ian W; McAuley, James H

    2015-07-01

    Pain education is a complex intervention developed to help clinicians manage low back pain. Although complex interventions are usually evaluated by their effects on outcomes, such as pain or disability, most do not directly target these outcomes; instead, they target intermediate factors that are presumed to be associated with the outcomes. The mechanisms underlying treatment effects, or the effect of an intervention on an intermediate factor and its subsequent effect on outcome, are rarely investigated in clinical trials. This leaves a gap in the evidence for understanding how treatments exert their effects on outcomes. Mediation analysis provides a method for identifying and quantifying the mechanisms that underlie interventions. To determine whether the effect of pain education on pain and disability is mediated by changes in self-efficacy, catastrophisation and back pain beliefs. Causal mediation analysis of the PREVENT randomised controlled trial. Two hundred and two participants with acute low back pain from primary care clinics in the Sydney metropolitan area. Participants will be randomised to receive either 'pain education' (intervention group) or 'sham education' (control group). All outcome measures (including patient characteristics), primary outcome measures (pain and disability), and putative mediating variables (self-efficacy, catastrophisation and back pain beliefs) will be measured prior to randomisation. Putative mediators and primary outcome measures will be measured 1 week after the intervention, and primary outcome measures will be measured 3 months after the onset of low back pain. Causal mediation analysis under the potential outcomes framework will be used to test single and multiple mediator models. A sensitivity analysis will be conducted to evaluate the robustness of the estimated mediation effects on the influence of violating sequential ignorability--a critical assumption for causal inference. Mediation analysis of clinical trials can

  14. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

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    Justin R. Piro

    2012-06-01

    Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

  15. Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance

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    Viviana eTrezza

    2012-01-01

    Full Text Available The endocannabinoid system shows functional activity from early stages of brain development: it plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation, thus shaping brain organization during pre- and postnatal life. Cannabis sativa preparations are among the illicit drugs most commonly used by young people, including pregnant women. The developing brain can be therefore exposed to cannabis preparations during two critical periods: first, in offspring of cannabis-using mothers through perinatal and/or prenatal exposure; second, in adolescent cannabis users during neural maturation. In the last decade, it has become clear that the endocannabinoid system critically modulates memory processing and emotional responses. Therefore, it is well possible that developmental exposure to cannabinoid compounds induces enduring changes in behaviors and neural processes belonging to the cognitive and emotional domains. We address this issue by focusing on rodent studies, in order to provide a framework for understanding the impact of cannabinoid exposure on the developing brain.

  16. Immune system modulation in the central nervous system: A possible role for endocannabinoids

    International Nuclear Information System (INIS)

    Abd-Allah, Adel R.A.

    2007-01-01

    The immune system is designed to protect the body from infection and tumor formation. To perform this function, cells of the immune system can be dangerous for the survival and function of the neuronal network in the brain under the influence of infection or immune imbalance. An attack of immune cells inside the brain includes the potential for severe neuronal damage or cell death and therefore impairment of the CNS function. To avoid such undesirable action of the immune system, the CNS performs a cascade of cellular and molecular mechanisms enabling strict control of immune reactions i mmune privilege . Under inflammatory and patholological conditions, uncontrolled immune system results in the activation of neuronal damage that is frequently associated with neurological diseases. On the other hand, processes of neuroprotection and neurorepair after neuronal damage depend on a steady and tightly controlled immunesurvelliance. Many immunoprotectants play a role to imbalance the immune reactions in the CNS and other organs which presents an important therapeutic target. It has been reported recently that endocannabinoids are secreted in abundance in the CNS following neuronal insult, probably for its protection. There are at least two types of cannabinoid receptors, CB1 and CB2. Both are coupled to G proteins. CB1 receptors exist primarily on central and peripheral neurons. CB2 receptors are present mainly on immune cells. Endogenous agonists for cannabinoid receptors (endocannabinoids), have been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2AG), and 2-archidonyl glyceryl ether. Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis. Therapeutic uses of cannabinoid receptor agonists/antagonists include the management of many disease conditions. They are also involved in immune system suppression and in cell to cell communication

  17. Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.

    Science.gov (United States)

    Monteleone, P; Bifulco, M; Di Filippo, C; Gazzerro, P; Canestrelli, B; Monteleone, F; Proto, M C; Di Genio, M; Grimaldi, C; Maj, M

    2009-10-01

    Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.

  18. Endocannabinoid system in cardiovascular disorders - new pharmacotherapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Pedro Cunha

    2011-01-01

    Full Text Available The long history of Cannabis sativa had its development stimulated and oriented for medicine after the discovery and chemical characterization of its main active ingredient, the 9-tetrahydrocannabinol (9-THC. Consequently, a binding site for 9-THC was identified in rat brains and the first cannabinoid receptor (CB1 was cloned, followed by the CB2 and by the discover of two endogenous agonists: anandamide and 2-arachidonoyl glycerol. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze its synthesis and degradation constitute the endocannabinoid system (ECS, which plays an important role in the cardiovascular system. In vivo experiments with rats have demonstrated the action of anandamide and 2-AG on the development of atherosclerotic plaque, as well as an effect on heart rate, blood pressure, vasoactivity and energy metabolism (action in dyslipidemia and obesity. Recent studies with an antagonist of CB1 receptors showed that the modulation of ECS can play an important role in reducing cardiovascular risk in obese and dyslipidemic patients. Similarly, studies in rats have demonstrated the action of CB2 receptors in adhesion, migration, proliferation and function of immune cells involved in the atherosclerotic plaque formation process. The evidence so far gathered shows that the modulation of ECS (as agonism or antagonism of its receptors is an enormous potential field for research and intervention in multiple areas of human pathophysiology. The development of selective drugs for the CB1 and CB2 receptors may open a door to new therapeutic regimens.This review article aims to address the key findings and evidences on the modulation of ECS, in order to prospect future forms of therapeutic intervention at the cardiovascular level. A recent, emerging, controversial and of undoubted scientific interest subject, which states as a potential therapeutic target to reach in the 21 st century.

  19. Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

    Science.gov (United States)

    Manduca, Antonia; Morena, Maria; Campolongo, Patrizia; Servadio, Michela; Palmery, Maura; Trabace, Luigia; Hill, Matthew N; Vanderschuren, Louk J M J; Cuomo, Vincenzo; Trezza, Viviana

    2015-08-01

    To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  20. Treatment and prevention of acute radiation dermatitis

    International Nuclear Information System (INIS)

    Benomar, S.; Hassam, B.; Boutayeb, S.; Errihani, H.; Lalya, I.; El Gueddari, B.K.

    2010-01-01

    Acute radiation dermatitis is a common side-effect of radiotherapy which often necessitates interruption of the therapy. Currently, there is no general consensus about its prevention or about the treatment of choice. The goal of this work was to focus on optimal methods to prevent and manage acute skin reactions related to radiation therapy and to determine if there are specific topical or oral agents for the prevention of this acute skin reaction. The prevention and the early treatment are the two focus points of the management of the acute radiation dermatitis. (authors)

  1. Uncoupling of sarcoplasmic reticulum Ca²⁺-ATPase by N-arachidonoyl dopamine. Members of the endocannabinoid family as thermogenic drugs

    DEFF Research Database (Denmark)

    Mahmmoud, Yasser Ahmed; Gaster, Michel

    2013-01-01

    BACKGROUND AND PURPOSE: The sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) plays a role in thermogenesis. The exogenous compound capsaicin increased SERCA-mediated ATP hydrolysis not coupled to Ca²⁺ transport. Here, we have sought to identify endogenous compounds that may function as SERCA uncoupling...... agents. EXPERIMENTAL APPROACH: Using isolated SR vesicles from rabbits, we have screened for endogenous compounds that uncouple SERCA. We have also studied their ability to deplete cytoplasmic ATP from human skeletal muscle cells in culture. KEY RESULTS: Studies on SR vesicles showed that the endogenous......, regardless of the presence of glucose. CONCLUSIONS AND IMPLICATIONS: NADA is an endogenous molecule that may function as SERCA uncoupling agent in vivo. Members of the endocannabinoid family exert concerted actions on several Ca²⁺-handling proteins. Uncoupling of SERCA by exogenous compounds could be a novel...

  2. Considerations for a Human Rights Impact Assessment of a Population Wide Treatment for HIV Prevention Intervention.

    Science.gov (United States)

    Hanefeld, Johanna; Bond, Virginia; Seeley, Janet; Lees, Shelley; Desmond, Nicola

    2015-12-01

    Increasing attention is being paid to the potential of anti-retroviral treatment (ART) for HIV prevention. The possibility of eliminating HIV from a population through a universal test and treat intervention, where all people within a population are tested for HIV and all positive people immediately initiated on ART, as part of a wider prevention intervention, was first proposed in 2009. Several clinical trials testing this idea are now in inception phase. An intervention which relies on universally testing the entire population for HIV will pose challenges to human rights, including obtaining genuine consent to testing and treatment. It also requires a context in which people can live free from fear of stigma, discrimination and violence, and can access services they require. These challenges are distinct from the field of medical ethics which has traditionally governed clinical trials and focuses primarily on patient researcher relationship. This paper sets out the potential impact of a population wide treatment as prevention intervention on human rights. It identifies five human right principles of particular relevance: participation, accountability, the right to health, non-discrimination and equality, and consent and confidentiality. The paper proposes that explicit attention to human rights can strengthen a treatment as prevention intervention, contribute to mediating likely health systems challenges and offer insights on how to reach all sections of the population. © 2013 John Wiley & Sons Ltd.

  3. Exposure Plus Response-Prevention Treatment of Bulimia Nervosa.

    Science.gov (United States)

    Leitenberg, Harold; And Others

    1988-01-01

    Evaluated exposure plus response-prevention treatment of bulimia nervosa among 47 women. Subjects were assigned to either exposure plus response-prevention in one setting, exposure plus response-prevention in multiple settings, cognitive-behavioral therapy, or waiting-list control conditions. Found three treatment groups improved significantly on…

  4. Prevention and treatment of allergic asthma in pregnancy: from conventional drugs to new therapeutical approaches.

    Science.gov (United States)

    Cadavid, Angela P; Bannenberg, Gérard L; Arck, Petra C; Fitzgerald, Justine S; Markert, Udo R

    2011-05-01

    Different conventional anti-asthmatic and anti-allergic drugs are commonly used in pregnancy, including inhaled corticosteroids, long- and short-acting β-agonists, leukotriene modifiers, cromolyn, and theophylline. Alternatively, immunotherapy with allergens before and during pregnancy is accepted as a causal treatment of allergies, but the allergy specifity and severity in combination with a variety of application protocols and procedures cause wide heterogenity of this treatment principle. Furthermore, the pharmacokinetic characteristics and the US Food and Drug Administration (FDA) classification of conventional anti-allergic drugs and immunological implications of immunotherapy are summarized in this review, and insights on fetal programming of allergies are introduced. We propose a potential perspective of treatment with anti-inflammatory and pro-resolving mediators, such as lipoxins, resolvins and protectins; these are lipid mediators physiologically generated during the immune response from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. This proposal fits with the recently appreciated approaches to allergy prevention for the newborn child by a balanced maternal nutrition and omega-3 long-chain polyunsaturated fatty acid consumption.

  5. Attitudes towards preventive tuberculosis treatment among hospital staff

    Directory of Open Access Journals (Sweden)

    Vidya Pathak

    2016-02-01

    Full Text Available Background. Healthcare workers have an increased risk of latent tuberculosis infection (LTBI, but previous studies suggested that they might be reluctant to accept preventive tuberculosis (TB treatment. We aimed to examine doctors’ and nurses’ experience of TB screening and to explore their attitudes towards preventive TB treatment. Methods. We conducted a survey among randomly selected healthcare workers at a tertiary hospital in Sydney, Australia, using a paper-based questionnaire. Results. A total of 1,304 questionnaires were distributed and 311 (24% responses were received. The majority of hospital staff supported preventive TB treatment in health care workers with evidence of latent TB infection (LTBI in general (74%, 164/223 and for them personally (81%, 198/244 while 80 and 53 healthcare workers respectively had no opinion on the topic. Staff working in respiratory medicine were significantly less likely to support preventive TB treatment in health care workers in general or for them personally if they would have evidence of LTBI compared to other specialties (p = 0.001. Only 13% (14/106 of respondents with evidence of LTBI indicated that they had been offered preventive TB treatment. Twenty-one percent (64/306 of respondents indicated that they did not know the difference between active and latent TB. Among staff who had undergone testing for LTBI, only 33% (75/230 felt adequately informed about the meaning of their test results. Discussion. Hospital staff in general had positive attitudes towards preventive TB treatment, but actual treatment rates were low and perceived knowledge about LTBI was insufficient among a significant proportion of staff. The gap between high support for preventive TB treatment among staff and low treatment rates needs to be addressed. Better education on the concept of LTBI and the meaning of screening test results is required.

  6. Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    W. Todd Penberthy

    2009-01-01

    Full Text Available Acute attacks of multiple sclerosis (MS are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA is now known to involve induction of indoleamine 2,3-dioxygenase (IDO and interleukin-10 (IL-10, where IL-10 requires subsequent heme oxygenase-1 (HMOX-1 induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2 can prevent demyelination in experimental autoimmune encephalomyelitis (EAE animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ12,14-PGJ2. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD, without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPAR-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic

  7. Exosomes: A Novel Strategy for Treatment and Prevention of Diseases

    Directory of Open Access Journals (Sweden)

    Jiaqi Wang

    2017-06-01

    Full Text Available An “exosome” is a nanoscale membrane vesicle derived from cell endocytosis that functions as an important intercellular communication mediator regulating the exchange of proteins and genetic materials between donor and surrounding cells. Exosomes secreted by normal and cancer cells participate in tumor initiation, progression, invasion, and metastasis. Furthermore, immune cells and cancer cells exert a two-way bidirectional regulatory effect on tumor immunity by exchanging exosomes. Current studies on exosomes have further expanded their known functions in physiological and pathological processes. The purpose of this review is to describe their discovery and biological functions in the context of their enormous potential in the clinical diagnosis, prevention, and treatment of cancer as well as bacterial and viral infectious diseases.

  8. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems.

    Science.gov (United States)

    Edwards, Alexander; Abizaid, Alfonso

    2016-07-01

    Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients

    Directory of Open Access Journals (Sweden)

    Verde Roberta

    2010-04-01

    Full Text Available Abstract Background The endocannabinoids, anandamide and 2-AG, are produced by adipocytes, where they stimulate lipogenesis via cannabinoid CB1 receptors and are under the negative control of leptin and insulin. Endocannabinoid levels are elevated in the blood of obese individuals and nonobese type 2 diabetes patients. To date, no study has evaluated endocannabinoid levels in subcutaneous adipose tissue (SAT of subjects with both obesity and type 2 diabetes (OBT2D, characterised by similar adiposity and whole body insulin resistance and lower plasma leptin levels as compared to non-diabetic obese subjects (OB. Design and Methods The levels of anandamide and 2-AG, and of the anandamide-related PPARα ligands, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, in the SAT obtained by abdominal needle biopsy in 10 OBT2D, 11 OB, and 8 non-diabetic normal-weight (NW subjects, were measured by liquid chromatography-mass spectrometry. All subjects underwent a hyperinsulinaemic euglycaemic clamp. Results As compared to NW, anandamide, OEA and PEA levels in the SAT were 2-4.4-fold elevated (p Conclusions The observed alterations emphasize, for the first time in humans, the potential different role and regulation of adipose tissue anandamide (and its congeners and 2-AG in obesity and type 2 diabetes.

  10. Interrupting violence: how the CeaseFire Program prevents imminent gun violence through conflict mediation.

    Science.gov (United States)

    Whitehill, Jennifer M; Webster, Daniel W; Frattaroli, Shannon; Parker, Elizabeth M

    2014-02-01

    Cities are increasingly adopting CeaseFire, an evidence-based public health program that uses specialized outreach workers, called violence interrupters (VIs), to mediate potentially violent conflicts before they lead to a shooting. Prior research has linked conflict mediation with program-related reductions in homicides, but the specific conflict mediation practices used by effective programs to prevent imminent gun violence have not been identified. We conducted case studies of CeaseFire programs in two inner cities using qualitative data from focus groups with 24 VIs and interviews with eight program managers. Study sites were purposively sampled to represent programs with more than 1 year of implementation and evidence of program effectiveness. Staff with more than 6 months of job experience were recruited for participation. Successful mediation efforts were built on trust and respect between VIs and the community, especially high-risk individuals. In conflict mediation, immediate priorities included separating the potential shooter from the intended victim and from peers who may encourage violence, followed by persuading the parties to resolve the conflict peacefully. Tactics for brokering peace included arranging the return of stolen property and emphasizing negative consequences of violence such as jail, death, or increased police attention. Utilizing these approaches, VIs are capable of preventing gun violence and interrupting cycles of retaliation.

  11. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME; analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors.The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  12. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Science.gov (United States)

    McPartland, John M

    2009-01-01

    Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor. A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME); analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors. The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  13. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects

    Directory of Open Access Journals (Sweden)

    Eva M Marco

    2011-10-01

    Full Text Available Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e. anxiety disorders, depression and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD, the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.

  14. Efficacy of osmoprotectants on prevention and treatment of murine dry eye.

    Science.gov (United States)

    Chen, Wei; Zhang, Xin; Li, Jinyang; Wang, Yu; Chen, Qi; Hou, Chao; Garrett, Qian

    2013-09-19

    To evaluate the efficacy of osmoprotectants on prevention and treatment of dry eye in a murine model. Dry eye was induced in mice by using an intelligently controlled environmental system (ICES). Osmoprotectants betaine, L-carnitine, erythritol, or vehicle (PBS) were topically administered to eyes four times daily following two schedules: schedule 1 (modeling prevention): dosing started at the beginning of housing in ICES and lasted for 21 or 35 days; schedule 2 (modeling treatment): dosing started after ICES-housed mice developed dry eye (day 21), continuing until day 35. Treatment efficacy was evaluated for corneal fluorescein staining; corneal epithelial apoptosis by TUNEL and caspase-3 assays; goblet cell numbers by PAS staining; and expression of inflammatory mediators, TNF-α, IL-17, IL-6, or IL-1β by using RT-PCR on days 0, 14, 21, and/or 35. Compared with vehicle, prophylactic administration of betaine, L-carnitine, or erythritol significantly decreased corneal staining and expression of TNF-α and IL-17 on day 21 (schedule 1). Treatment of mouse dry eye with osmoprotectants significantly reduced corneal staining on day 35 compared with day 21 (schedule 2). Relative to vehicle, L-carnitine treatment of mouse dry eye for 14 days (days 21 to 35) resulted in a significant reduction in corneal staining, number of TUNEL-positive cells, and expression of TNF-α, IL-17, IL-6, or IL-1β, as well as significantly increased the number of goblet cells. Topical application of betaine, L-carnitine, or erythritol systematically limited progression of environmentally induced dry eye. L-carnitine can also reduce the severity of such dry-eye conditions.

  15. Corneal allograft rejection: Risk factors, diagnosis, prevention, and treatment

    Directory of Open Access Journals (Sweden)

    Dua Harminder

    1999-01-01

    Full Text Available Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID and probably, conjunctiva associated lymphoid tissue (CALT induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506 are of proven benefit, both for treatment and prevention of rejection.

  16. Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

    Science.gov (United States)

    2017-10-01

    Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

  17. The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

    Science.gov (United States)

    Berardi, Andrea; Schelling, Gustav; Campolongo, Patrizia

    2016-09-01

    Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Garlic for Cardiovascular Disease: Prevention or Treatment?

    Science.gov (United States)

    Alali, Feras Q; El-Elimat, Tamam; Khalid, Lila; Hudaib, Reema; Al-Shehabi, Tuqa Saleh; Eid, Ali H

    2017-01-01

    Cardiovascular disease (CVD) is the leading cause of global mortality with a substantial economic impact. The annual deaths are expected to increase in the next decade. An array of dietary supplements is being used by people worldwide to ameliorate cardiovascular risk factors. Garlic (Allium sativum L.), a top-selling herbal dietary supplement, is renowned for its wide range beneficial effects, particularly in the treatment and prevention of CVD. This review aims to present a thorough discussion of the available evidence-based data which support the use of garlic in the treatment or prevention of cardiovascular diseases, including atherosclerosis, hypertension, and hyperlipidemia. The molecular mechanisms underlying these effects are dissected as well. This review supports the notion that garlic has the potential to treat mild hypertension, to decrease hypercholesterolemia, and to prevent atherosclerosis. More clinical studies are essential to unequivocally understand the mechanisms underlying treatment or prevention of these cardiovascular conditions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Pressure ulcer prevention and treatment knowledge of Jordanian nurses.

    Science.gov (United States)

    Saleh, Mohammad Y N; Al-Hussami, Mahmoud; Anthony, Denis

    2013-02-01

    The aims of the study were to determine: (1) Jordanian nurses' level of knowledge of pressure ulcer prevention and treatment of hospitalized patients based on guidelines for pressure ulcer prevention and treatment. (2) Frequency of utilization of pressure ulcer prevention and treatment interventions in clinical practice. (3) Variables that are associated with nurses' utilization of pressure ulcer prevention and treatment interventions. Pressure ulcers are common and previous studies have shown education, knowledge and attitude affect implementation of interventions. A cross-sectional survey design was used to collect data from 460 nurses between June 2010 and November 2010. We used a questionnaire, which was informed by earlier work and guidelines, to collect data about nurses' knowledge and practice of pressure ulcer prevention and treatment. Knowledge and education show an association with implementation of prevention, and demographic variables do not. Similarly knowledge and type of hospital showed an association with implementing treatment. Of concern the use of "donuts" and massage are reported in use. Although pressure ulcer care is well known by nurses, inappropriate pressure ulcer interventions were reported in use. Copyright © 2013 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

  20. Probiotics: their role in the treatment and prevention of disease.

    Science.gov (United States)

    Doron, Shira; Gorbach, Sherwood L

    2006-04-01

    A probiotic is a "live microbial food ingredients that, when ingested in sufficient quantities, exerts health benefits on the consumer". Probiotics exert their benefits through several mechanisms; they prevent colonization, cellular adhesion and invasion by pathogenic organisms, they have direct antimicrobial activity and they modulate the host immune response. The strongest evidence for the clinical effectiveness of probiotics has been in their use for the prevention of symptoms of lactose intolerance, treatment of acute diarrhea, attenuation of antibiotic-associated gastrointestinal side effects and the prevention and treatment of allergy manifestations. More research needs to be carried out to clarify conflicting findings on the use of probiotics for prevention of travelers' diarrhea, infections in children in daycare and dental caries, and elimination of nasal colonization with potentially pathogenic bacteria. Promising ongoing research is being conducted on the use of probiotics for the treatment of Clostridium difficile colitis, treatment of Helicobacter pylori infection, treatment of inflammatory bowel disease and prevention of relapse, treatment of irritable bowel syndrome, treatment of intestinal inflammation in cystic fibrosis patients, and prevention of necrotizing enterocolitis in premature infants. Finally, areas of future research include the use of probiotics for the treatment of rheumatoid arthritis, prevention of cancer and the treatment of graft-versus-host disease in bone marrow transplant recipients.

  1. Moderators and mediators of treatments for youth with ADHD

    NARCIS (Netherlands)

    van der Oord, S.; Daley, D.; Maric, M.; Prins, P.J.M.; Ollendick, T.H.

    2015-01-01

    There are few studies assessing moderation and mediation of behavioral treatment and cognitive training outcome in children with ADHD. Only two studies have assessed moderation of treatment outcome. For behavioral treatment outcome, comorbid anxiety, parental self-efficacy, paternal ADHD, and no or

  2. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

    Science.gov (United States)

    Dawson, Alison J; Kilpatrick, Eric S; Coady, Anne-Marie; Elshewehy, Abeer M M; Dakroury, Youssra; Ahmed, Lina; Atkin, Stephen L; Sathyapalan, Thozhukat

    2017-07-14

    Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p weight. There was a significant reduction of weight with orlistat (p weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

  3. Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer

    Directory of Open Access Journals (Sweden)

    Bharat B. Aggarwal

    2010-10-01

    Full Text Available Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”.

  4. Nanotechnology for the Prevention and Treatment of Cataract.

    Science.gov (United States)

    Cetinel, Sibel; Montemagno, Carlo

    2015-01-01

    The purpose of this article was to review recent advances in the applications of nanotechnology in cataract treatment and prevention strategies. A literature review on the use of nanotechnology for the prevention and treatment of cataract was done. Research articles about nanotechnology-based treatments and prevention technologies for cataract were searched on Web of Science, and the most recent advances were reported. Nonsteroid anti-inflammatory drugs, natural antioxidants, biologic and chemical chaperones, and chaperones such as molecules have found great application in preventing and treating cataracts. Current scientific research on new treatment strategies, which focuses on the biochemical basis of the disease, will likely result in new anticataract agents. However, none of the drug formulations will be approved for use unless efficient delivery is promised. Nanoparticle engineering together with biomimetic strategies enable the development of next-generation, more efficient, less complex, and personalized treatments. The only currently available treatment for cataracts, surgical replacement of the opacified lens, is not an easily accessible option in developing countries. New treatment strategies based on topical drugs would enable treatment to reach massive populations facing the threat of blindness and more effectively deal with the postsurgical complications. Nanotechnology plays a key role in improving drug delivery systems with enhanced controlled release, targeted delivery, and bioavailability to overcome diffusion limitations in the eye.

  5. [Prevention and treatment of obesity in children].

    Science.gov (United States)

    Togashi, Kenji; Iguchi, Kosei; Masuda, Hidenari

    2013-02-01

    The prevalence of childhood obesity and its comorbidities is high in Japan. Increasing prevalence of obesity among children emphasizes the importance of focusing on primary prevention to avoid health complications later in life. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. Treatment interventions include behavioral therapy, reduction in sedentary behavior, and dietary and exercise education. After dietary treatment combined with exercise treatment, the areas of subcutaneous and visceral fat decreased significantly. These data suggest that dietary treatment combined with exercise treatment in obese children normalizes the distribution of abdominal fat and reduces the risk factors for chronic disease.

  6. The Potential Role of Contraction-Induced Myokines in the Regulation of Metabolic Function for the Prevention and Treatment of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Brian P. Carson

    2017-05-01

    Full Text Available Skeletal muscle represents the largest organ in the body, comprises 36–42% of body weight, and has recently been recognized as having an endocrine function. Proteins expressed and released by muscle that have autocrine, paracrine, and endocrine bioactivities have been termed myokines. It is likely that muscle contraction represents the primary stimulus for the synthesis and secretion of myokines to enable communication with other organs such as the liver, adipose tissue, brain, and auto-regulation of muscle metabolism. To date, several hundred myokines in the muscle secretome have been identified, a sub-population of which are specifically induced by skeletal muscle contraction. However, the bioactivity of many of these myokines and the mechanism through which they act has either not yet been characterized or remains poorly understood. Physical activity and exercise are recognized as a central tenet in both the prevention and treatment of type 2 diabetes (T2D. Recent data suggest humoral factors such as muscle-derived secretory proteins may mediate the beneficial effects of exercise in the treatment of metabolic diseases. This mini-review aims to summarize our current knowledge on the role of contraction-induced myokines in mediating the beneficial effects of physical activity and exercise in the prevention and treatment of T2D, specifically glucose and lipid metabolism. Future directions as to how we can optimize contraction-induced myokine secretion to inform exercise protocols for the prevention and treatment of T2D will also be discussed.

  7. Dietary Agents and Phytochemicals in the Prevention and Treatment of Experimental Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Arpit Saxena

    2014-10-01

    Full Text Available Inflammatory bowel diseases (IBDs, consisting mainly of ulcerative colitis (UC and Crohn's disease (CD, are important immune-mediated diseases of the gastrointestinal tract. The etiology of the disease includes environmental and genetic factors. Its management presents a constant challenge for gastroenterologists and conventional surgeon. 5-Amninosalicylates, antibiotics, steroids, and immune modulators have been used to reduce the symptoms and for maintenance of remission. Unfortunately, long-term usage of these agents has been found to lead to severe toxicities, which are deterrent to the users. Pre-clinical studies carried out in the recent past have shown that certain dietary agents, spices, oils, and dietary phytochemicals that are consumed regularly possess beneficial effects in preventing/ameliorating UC. For the first time, this review addresses the use of these dietary agents and spices in the treatment and prevention of IBD and also emphasizes on the mechanisms responsible for their effects.

  8. The acute and preventative treatment of episodic migraine

    Directory of Open Access Journals (Sweden)

    Sarah Miller

    2012-01-01

    Full Text Available Episodic migraine is a common debilitating condition with significant worldwide impact. An effective management plan must include acute treatment to relieve the pain and potential disability associated with the attacks and may also include preventative treatments with an aim of decreasing attack frequency and severity in the longer term. Acute treatments must be limited to a maximum of 2-3 days a week to prevent medication overuse headache and focus on simple analgesia, non-steroidal anti-inflammatory drugs and triptans. Preventative treatments are numerous and should be considered when migraine attacks are frequent and or disabling, acute medication is failing, in special circumstances such as hemiplegic migraines or if the patient requests them. All preventative medications must be given at therapeutic doses for at least 6-8 weeks before an adequate trial can be judged ineffective. The most important factor in choosing drugs is the patient and the clinical features of their attack and treatment should be tailored to these. Relative co-morbidities will influence drug choice, as will the side effect profile and the efficacy of the drug. First line preventative drugs include ß-blockers, amitriptyline and anti-epileptic drugs such as topiramate and valproate. Drugs with lower efficacy or poorer side effect profiles include selective serotonin reuptake inhibitors (SSRIs, calcium channel antagonists, gabapentin and herbal medicines.

  9. Diagnosis, Treatment, and Prevention of Hemodialysis Emergencies.

    Science.gov (United States)

    Saha, Manish; Allon, Michael

    2017-02-07

    Given the high comorbidity in patients on hemodialysis and the complexity of the dialysis treatment, it is remarkable how rarely a life-threatening complication occurs during dialysis. The low rate of dialysis emergencies can be attributed to numerous safety features in modern dialysis machines; meticulous treatment and testing of the dialysate solution to prevent exposure to trace elements, toxins, and pathogens; adherence to detailed treatment protocols; and extensive training of dialysis staff to handle medical emergencies. Most hemodialysis emergencies can be attributed to human error. A smaller number are due to rare idiosyncratic reactions. In this review, we highlight major emergencies that may occur during hemodialysis treatments, describe their pathogenesis, offer measures to minimize them, and provide specific interventions to prevent catastrophic consequences on the rare occasions when such emergencies arise. These emergencies include dialysis disequilibrium syndrome, venous air embolism, hemolysis, venous needle dislodgement, vascular access hemorrhage, major allergic reactions to the dialyzer or treatment medications, and disruption or contamination of the dialysis water system. Finally, we describe root cause analysis after a dialysis emergency has occurred to prevent a future recurrence. Copyright © 2017 by the American Society of Nephrology.

  10. Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

    Directory of Open Access Journals (Sweden)

    Farnaz Fekri

    Full Text Available Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR, and distinct mechanism(s that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may

  11. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Frost, M; Nielsen, T L; Wraae, K

    2010-01-01

    Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1...... receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution....

  12. Cardiac Cachexia: Perspectives for Prevention and Treatment.

    Science.gov (United States)

    Okoshi, Marina Politi; Capalbo, Rafael Verardino; Romeiro, Fernando G; Okoshi, Katashi

    2017-01-01

    Cachexia is a prevalent pathological condition associated with chronic heart failure. Its occurrence predicts increased morbidity and mortality independent of important clinical variables such as age, ventricular function, or heart failure functional class. The clinical consequences of cachexia are dependent on both weight loss and systemic inflammation, which accompany cachexia development. Skeletal muscle wasting is an important component of cachexia; it often precedes cachexia development and predicts poor outcome in heart failure. Cachexia clinically affects several organs and systems. It is a multifactorial condition where underlying pathophysiological mechanisms are not completely understood making it difficult to develop specific prevention and treatment therapies. Preventive strategies have largely focused on muscle mass preservation. Different treatment options have been described, mostly in small clinical studies or experimental settings. These include nutritional support, neurohormonal blockade, reducing intestinal bacterial translocation, anemia and iron deficiency treatment, appetite stimulants, immunomodulatory agents, anabolic hormones, and physical exercise regimens. Currently, nonpharmacological therapy such as nutritional support and physical exercise are considered central to cachexia prevention and treatment.

  13. Spices for Prevention and Treatment of Cancers.

    Science.gov (United States)

    Zheng, Jie; Zhou, Yue; Li, Ya; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin

    2016-08-12

    Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action.

  14. Lifestyle and Sarcopenia—Etiology, Prevention, and Treatment

    Directory of Open Access Journals (Sweden)

    Oren Rom

    2012-10-01

    Full Text Available The term sarcopenia describes the loss of skeletal muscle mass, strength, and function in old age. As the world population continues to grow older, more attention is given to the phenomena of sarcopenia and the search for strategies of prevention and treatment. The progression of sarcopenia is affected by age-related physiological and systemic changes in the body, including alterations in skeletal muscle tissue, hormonal changes, increased inflammatory activities, and oxidative stress. Sarcopenia progression is also affected by lifestyle factors which are far more controllable. These factors include various aspects of nutrition, physical activity, exercise, alcohol intake, and tobacco use. Raising the public awareness regarding the impact of these factors, as causes of sarcopenia and potential strategies of prevention and treatment, is of great importance. In this review we aim to describe various lifestyle factors that affect the etiology, prevention, and treatment of sarcopenia.

  15. Spices for Prevention and Treatment of Cancers

    Science.gov (United States)

    Zheng, Jie; Zhou, Yue; Li, Ya; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin

    2016-01-01

    Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action. PMID:27529277

  16. Cost-effectiveness of root caries preventive treatments.

    Science.gov (United States)

    Schwendicke, Falk; Göstemeyer, Gerd

    2017-01-01

    With a growing number of individuals retaining their teeth lifelong, often with periodontitis-induced root surface exposure, there is the need for cost-effective management strategies for root caries lesions. The present study aimed to assess the cost-effectiveness of root caries preventive treatments. Patients were simulated over 10 years using a Markov model. Four treatments were compared: No treatment, daily 225-800ppm fluoride rinses, chlorhexidine (CHX) varnish (2×/year), silver diamine fluoride (SDF) varnish (2×/year). Data from a systematic review were submitted to network meta-analysis for inferring relative efficacies of treatments. The health outcome was years of teeth being free of root caries. A mixed public-private payer perspective within 2016 German healthcare was taken, with costs being estimated from fee item catalogues or based on market prices. Populations with different numbers of teeth and tooth-level risks were modelled. Monte-Carlo microsimulations, univariate- and probabilistic sensitivity analyses were performed. In populations with 16 teeth at risk and low tooth-level risk for root caries, providing no preventive treatment was least costly, but also least effective (130 Euro, 144 years). SDF ranked next, being more costly (180 Euro), but also more effective (151 years). Payers willing to invest 8.30 Euro per root caries-free tooth-year found SDF most cost-effective. CHX varnish and fluoride rinse were not cost-effective. In populations with more teeth and high tooth-level risk, SDF was the most effective and least costly option. Root caries preventive treatments (like SDF) are effective and might even be cost-saving in high risk populations. Application of SDF can be recommended as a cost-saving treatment for prevention of root caries in patients with high risk of root caries. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Three Depression Prevention Programs

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Seeley, John R.; Gau, Jeff M.

    2010-01-01

    Objective: Evaluate a new 5-step method for testing mediators hypothesized to account for the effects of depression prevention programs. Method: In this indicated prevention trial, at-risk teens with elevated depressive symptoms were randomized to a group cognitive-behavioral (CB) intervention, group supportive expressive intervention, CB…

  18. Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: Influence on cholinergic toxicity

    International Nuclear Information System (INIS)

    Liu, Jing; Parsons, Loren; Pope, Carey

    2013-01-01

    Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6–7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89–90%) and CPF (78–83%) exposure. FAAH activity was also markedly reduced (88–91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35–50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3 mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear. - Highlights: • Chlorpyrifos and parathion both extensively inhibited hippocampal cholinesterase. • Functional signs were only noted with parathion. • Chlorpyrifos and parathion increased hippocampal extracellular anandamide levels. • 2-Arachidonoylglycerol levels were

  19. Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: Influence on cholinergic toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jing [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK (United States); Parsons, Loren [Committee on Neurobiology of Affective Disorders, The Scripps Research Institute, La Jolla, CA (United States); Pope, Carey, E-mail: carey.pope@okstate.edu [Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK (United States)

    2013-11-01

    Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6–7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89–90%) and CPF (78–83%) exposure. FAAH activity was also markedly reduced (88–91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35–50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3 mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear. - Highlights: • Chlorpyrifos and parathion both extensively inhibited hippocampal cholinesterase. • Functional signs were only noted with parathion. • Chlorpyrifos and parathion increased hippocampal extracellular anandamide levels. • 2-Arachidonoylglycerol levels were

  20. Role of Nutrition in the Prevention and Treatment of Stroke

    Science.gov (United States)

    ... Prevention & Treatment: Diet & Nutrition Stroke Prevention & Treatment: Diet & Nutrition A healthy diet can reduce your risk for ... Treatment How does a stroke affect eating and nutrition? Stroke can devastate a person's nutritional health because ...

  1. Developing an acceptability assessment of preventive dental treatments.

    Science.gov (United States)

    Hyde, Susan; Gansky, Stuart A; Gonzalez-Vargas, Maria J; Husting, Sheila R; Cheng, Nancy F; Millstein, Susan G; Adams, Sally H

    2009-01-01

    Early childhood caries (ECC) is very prevalent among young Hispanic children. ECC is amenable to a variety of preventive procedures, yet many Hispanic families underutilize dental services. Acceptability research may assist in health care planning and resource allocation by identifying patient preferences among efficacious treatments with the goal of improving their utilization. The purposes of this study were (a) to develop a culturally competent acceptability assessment instrument, directed toward the caregivers of young Hispanic children, for five preventive dental treatments for ECC and (b) to test the instrument's reliability and validity. An instrument of five standard treatments known to prevent ECC was developed, translated, reviewed by focus groups, and pilot tested, then tested for reliability The instrument included illustrated cards, brief video clips, and samples of the treatments and was culturally appropriate for low-income Hispanic caregivers. In addition to determining the acceptability of the five treatments individually, the treatments were also presented as paired comparisons. Focus groups and debriefing interviews following the pilot tests established that the instrument has good face validity. The illustrated cards, product samples, and video demonstrations of the five treatments resulted in an instrument possessing good content validity. The instrument has good to excellent test-retest reliability, with identical time 1-time 2 responses for each of the five treatments 92 percent of the time (range 87 to 97 percent), and the same treatment of the paired comparisons preferred 75 percent of the time (range 61 to 90 percent). The acceptability instrument described is reliable and valid and may be useful in program planning efforts to identify and increase the utilization of preferred ECC preventive treatments for target populations.

  2. Endocannabinoid release modulates electrical coupling between CCK cells connected via chemical and electrical synapses in CA1

    Directory of Open Access Journals (Sweden)

    Jonathan eIball

    2011-11-01

    Full Text Available Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholesystokinin (CCK interneurons which co-express cannbinoid type-1 (CB1 receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labelling in acute slices of rat hippocampus at P18-20 days. CA1 stratum radiatum CCK Schaffer collateral associated (SCA cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released IPSPs that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5M resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI, maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.

  3. Antibody-mediated Prevention of Fusarium Mycotoxins in the Field

    Directory of Open Access Journals (Sweden)

    Yu-Cai Liao

    2008-10-01

    Full Text Available Fusarium mycotoxins directly accumulated in grains during the infection of wheat and other cereal crops by Fusarium head blight (FHB pathogens are detrimental to humans and domesticated animals. Prevention of the mycotoxins via the development of FHB-resistant varieties has been a challenge due to the scarcity of natural resistance against FHB pathogens. Various antibodies specific to Fusarium fungi and mycotoxins are widely used in immunoassays and antibody-mediated resistance in planta against Fusarium pathogens has been demonstrated. Antibodies fused to antifungal proteins have been shown to confer a very significantly enhanced Fusarium resistance in transgenic plants. Thus, antibody fusions hold great promise as an effective tool for the prevention of mycotoxin contaminations in cereal grains. This review highlights the utilization of protective antibodies derived from phage display to increase endogenous resistance of wheat to FHB pathogens and consequently to reduce mycotoxins in field. The role played by Fusarium-specific antibody in the resistance is also discussed.

  4. [Treatment and prevention of cancer treatment related oral mucositis].

    Science.gov (United States)

    Ruiz-Esquide, Gonzalo; Nervi, Bruno; Vargas, Alex; Maíz, Alberto

    2011-03-01

    One of the most common and troublesome complications of modern intensive anticancer treatments is oral mucositis. The purpose of this review is to summarize current evidence and clinical guidelines regarding its prevention and therapy. The use of keratinocyte growth factor-1, supplementary glutamine and other recently developed treatment modalities are discussed. The injury of the oral mucosa caused by antineoplastic agents promotes the local expression of multiple pro-inflammatory and pro-apoptotic molecules and eventually leads to the development of ulcers. Such lesions predispose patients to several infectious and nutritional complications. Also, they lead to modification of treatment schedules, potentially affecting overall prognosis. Local cryotherapy with ice chips and phototherapy with low energy laser may be useful as preventive measures. Mouthwashes with allopurinol and phototherapy with low energy laser can be used as treatment. In radiotherapy, special radiation administration techniques should be used to minimize mucosal injury. Pain control should always be optimized, with the use of patient controlled analgesia and topical use of morphine. Supplemental glutamine should not be used outside of research protocols. Lastly, thorough attention should be paid to general care and hygiene measures.

  5. Intravenous immunoglobulin prevents murine antibody-mediated acute lung injury at the level of neutrophil reactive oxygen species (ROS production.

    Directory of Open Access Journals (Sweden)

    John W Semple

    Full Text Available Transfusion-related acute lung injury (TRALI is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature and respiratory distress (dyspnea were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage.

  6. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH neurons in an estrous cycle and endocannabinoid signaling dependent manner.

    Directory of Open Access Journals (Sweden)

    Imre Farkas

    Full Text Available The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+-imaging revealed a ghrelin-triggered increase of the Ca(2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM suggesting direct action of ghrelin. Estradiol (1nM eliminated the ghrelin-evoked rise of Ca(2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1 antagonist AM251 (1µM and the intracellularly applied DAG-lipase inhibitor THL (10 µM, indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

  7. Attitudes to malaria, prevention, treatment and management ...

    African Journals Online (AJOL)

    SERVER

    2007-11-05

    Nov 5, 2007 ... consequences of malaria treatment pattern and management strategies in an urban center. Questionnaires were issued ... anopheles mosquitoes as malaria vector are some of the factors militating against prevention and proper management of the .... bush clearing, drainage and gutter control in preventing.

  8. Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

    Science.gov (United States)

    Miao, Lu; Holley, Aaron K.; Zhao, Yanming; St. Clair, William H.

    2014-01-01

    Abstract Significance: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. Recent Advances: Ionizing radiation (IR)–generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. Critical Issues: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. Future Directions: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues. Antioxid. Redox Signal. 20, 1481–1500. PMID:24093432

  9. Emerging nanotechnology approaches for HIV/AIDS treatment and prevention

    Science.gov (United States)

    Mamo, Tewodros; Moseman, E Ashley; Kolishetti, Nagesh; Salvador-Morales, Carolina; Shi, Jinjun; Kuritzkes, Daniel R; Langer, Robert; von Andrian, Ulrich

    2010-01-01

    Currently, there is no cure and no preventive vaccine for HIV/AIDS. Combination antiretroviral therapy has dramatically improved treatment, but it has to be taken for a lifetime, has major side effects and is ineffective in patients in whom the virus develops resistance. Nanotechnology is an emerging multidisciplinary field that is revolutionizing medicine in the 21st century. It has a vast potential to radically advance the treatment and prevention of HIV/AIDS. In this review, we discuss the challenges with the current treatment of the disease and shed light on the remarkable potential of nanotechnology to provide more effective treatment and prevention for HIV/AIDS by advancing antiretroviral therapy, gene therapy, immunotherapy, vaccinology and microbicides. PMID:20148638

  10. Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

    Directory of Open Access Journals (Sweden)

    Mauro Maccarrone

    2017-05-01

    Full Text Available Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB” was identified as N-arachidonoylethanolamine (or anandamide (AEA, and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.

  11. Gut microbiota and obesity: role in aetiology and potential therapeutic target.

    Science.gov (United States)

    Moran, Carthage P; Shanahan, Fergus

    2014-08-01

    Obesity is epidemic; chronic energy surplus is clearly important in obesity development but other factors are at play. Indigenous gut microbiota are implicated in the aetiopathogenesis of obesity and obesity-related disorders. Evidence from murine models initially suggested a role for the gut microbiota in weight regulation and the microbiota has been shown to contribute to the low grade inflammation that characterises obesity. The microbiota and its metabolites mediate some of the alterations of the microbiota-gut-brain axis, the endocannabinoid system, and bile acid metabolism, found in obesity-related disorders. Modulation of the gut microbiota is an attractive proposition for prevention or treatment of obesity, particularly as traditional measures have been sub-optimal. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.

    Science.gov (United States)

    Rubino, Tiziana; Prini, Pamela; Piscitelli, Fabiana; Zamberletti, Erica; Trusel, Massimo; Melis, Miriam; Sagheddu, Claudia; Ligresti, Alessia; Tonini, Raffaella; Di Marzo, Vincenzo; Parolaro, Daniela

    2015-01-01

    Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. The role of life skills promotion in substance abuse prevention: a mediation analysis.

    Science.gov (United States)

    Bühler, Anneke; Schröder, Elke; Silbereisen, Rainer K

    2008-08-01

    Research has shown that life skills programs are the most effective single activity in school-based substance abuse prevention. However, little is known about the processes through which they are effective. This study examines whether an evidence-based prevention program targeting general competence is effective through the promotion of knowledge about life skills and enhanced related behaviors. Based on a sample of 442 fifth graders participating in a quasi-experimental prevention study, as expected, mediation analyses revealed that increased knowledge about life skills paralleled an increase in students' distant attitudes toward alcohol and nicotine use. Unexpectedly, behaviors manifesting enhanced life skills were found not only among program participants who remained experimental/non-smokers or stopped smoking but also among smokers. In general, findings suggest that favorable prevention outcomes may be influenced through building knowledge about general life skills. The notion of uniform mechanisms of effectiveness in prevention programs is discussed.

  14. Polarized cellular patterns of endocannabinoid production and detection shape cannabinoid signaling in neurons

    Directory of Open Access Journals (Sweden)

    Delphine eLadarre

    2015-01-01

    Full Text Available Neurons display important differences in plasma membrane composition between somatodendritic and axonal compartments, potentially leading to currently unexplored consequences in G-protein-coupled-receptor signaling. Here, by using highly-resolved biosensor imaging to measure local changes in basal levels of key signaling components, we explored features of type-1 cannabinoid receptor (CB1R signaling in individual axons and dendrites of cultured rat hippocampal neurons. Activation of endogenous CB1Rs led to rapid, Gi/o-protein- and cAMP-mediated decrease of cyclic-AMP-dependent protein kinase (PKA activity in the somatodendritic compartment. In axons, PKA inhibition was significantly stronger, in line with axonally-polarized distribution of CB1Rs. Conversely, inverse agonist AM281 produced marked rapid increase of basal PKA activation in somata and dendrites, but not in axons, removing constitutive activation of CB1Rs generated by local production of the endocannabinoid 2-arachidonoylglycerol (2-AG. Interestingly, somatodendritic 2-AG levels differently modified signaling responses to CB1R activation by Δ9-THC, the psychoactive compound of marijuana, and by the synthetic cannabinoids WIN55,212-2 and CP55,940. These highly contrasted differences in sub-neuronal signaling responses warrant caution in extrapolating pharmacological profiles, which are typically obtained in non-polarized cells, to predict in vivo responses of axonal (i.e. presynaptic GPCRs. Therefore, our results suggest that enhanced comprehension of GPCR signaling constraints imposed by neuronal cell biology may improve the understanding of neuropharmacological action.

  15. A SIMPLE AND EFFECTIVE TREATMENT FOR PERICHONDRITIS TO PREVENT REACCUMULATION

    Directory of Open Access Journals (Sweden)

    Pampa Pathi Goud

    2015-11-01

    Full Text Available OBJECTIVE: A simple treatment for perichondritis to prevent reaccumulation by using a drain. Existing treatment for this condition is initially medical, surgical (incision and drainage and compression to prevent recurrence with accompanying medical management. However the result is often a failure, resulting in partial or complete cauliflower ear deformity. PROCEDURE: Treatment involves to drain the site of infection and placing a drain to prevent reaccumulation. RESULT: The prescribed treatment avoids reaccumulation of fluid and repeated drainage. CONCLUSION: This method can be implemented for routine minor OT practice.

  16. Circulating Endocannabinoids and Insulin Resistance in Patients with Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Xiaoya Wang

    2016-01-01

    Full Text Available Objectives. The purpose of this study is to investigate the relationship between plasma endocannabinoids and insulin resistance (IR in patients with obstructive sleep apnea (OSA. Methods. A population of 64 with OSA and 24 control subjects was recruited. Body mass index (BMI, waist circumference, lipids, blood glucose and insulin, homeostasis model of assessment for insulin resistance index (HOMA-IR, anandamide (AEA, 1/2-arachidonoylglycerol (1/2-AG, and apnea-hypopnea index (AHI were analyzed. Results. Fasting blood insulin (22.9 ± 7.8 mIU/L versus 18.5 ± 7.2 mIU/L, P<0.05, HOMA-IR (2.9 ± 1.0 versus 2.4 ± 0.9, P<0.01, AEA (3.2 ± 0.7 nmol/L versus 2.5 ± 0.6 nmol/L, P<0.01, and 1/2-AG (40.8 ± 5.7 nmol/L versus 34.3 ± 7.7 nmol/L, P<0.01 were higher in OSA group than those in control group. In OSA group, AEA, 1/2-AG, and HOMA-IR increase with the OSA severity. The correlation analysis showed significant positive correlation between HOMA-IR and AHI (r=0.44, P<0.01, AEA and AHI (r=0.52, P<0.01, AEA and HOMA-IR (r=0.62, P<0.01, and 1/2-AG and HOMA-IR (r=0.33, P<0.01. Further analysis showed that only AEA was significantly correlated with AHI and HOMA-IR after adjusting for confounding factors. Conclusions. The present study indicated that plasma endocannabinoids levels, especially AEA, were associated with IR and AHI in patients with OSA.

  17. Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance.

    Science.gov (United States)

    Huang, Chien-Ning; Wang, Chau-Jong; Yang, Yi-Sun; Lin, Chih-Li; Peng, Chiung-Huei

    2016-01-01

    Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate-stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy.

  18. Cannabinoid Receptors Mediate Methamphetamine Induction of High Frequency Gamma Oscillations in the Nucleus Accumbens

    Science.gov (United States)

    Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

    2012-01-01

    Patients suffering from amphetamine---induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (~ 80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. PMID:22609048

  19. Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

    Science.gov (United States)

    Iball, Jonathan; Ali, Afia B.

    2011-01-01

    Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization. PMID

  20. Potential of the Antibody Against cis-Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury.

    Science.gov (United States)

    Lu, Kun Ping; Kondo, Asami; Albayram, Onder; Herbert, Megan K; Liu, Hekun; Zhou, Xiao Zhen

    2016-11-01

    Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic trans conformation, thereby restoring ptau function. The recent development of antibodies able to distinguish and eliminate both conformations specifically has led to the discovery of cis-ptau as a precursor of tau-induced pathologic change and an early driver of neurodegeneration that directly links TBI to CTE and possibly to AD. Within hours of TBI in mice or neuronal stress in vitro, neurons prominently produce cis-ptau, which causes and spreads cis-ptau pathologic changes, termed cistauosis. Cistauosis eventually leads to widespread tau-mediated neurodegeneration and brain atrophy. Cistauosis is effectively blocked by the cis-ptau antibody, which targets intracellular cis-ptau for proteasome-mediated degradation and prevents extracellular cis-ptau from spreading to other neurons. Treating TBI mice with cis-ptau antibody not only blocks early cistauosis but also prevents development and spreading of tau-mediated neurodegeneration and brain atrophy and restores brain histopathologic features and functional outcomes. Thus, cistauosis is a common early disease mechanism for AD, TBI, and CTE, and cis-ptau and its antibody may be useful for early diagnosis, treatment, and prevention of these devastating diseases.

  1. A Mediation Analysis of a Tobacco Prevention Program for Adolescents in India: How Did Project MYTRI Work?

    Science.gov (United States)

    Stigler, Melissa Harrell; Perry, Cheryl L.; Smolenski, Derek; Arora, Monika; Reddy, K. Srinath

    2011-01-01

    This article presents the results of a mediation analysis of Project MYTRI (Mobilizing Youth for Tobacco Related Initiatives in India), a randomized, controlled trial of a multiple-component, school-based tobacco prevention program for sixth- to ninth-graders (n = 14,085) in Delhi and Chennai, India. A mediation analysis identifies "how"…

  2. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    OpenAIRE

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN5...

  3. Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth.

    Science.gov (United States)

    Bariani, María Victoria; Correa, Fernando; Leishman, Emma; Domínguez Rubio, Ana Paula; Arias, Andreína; Stern, Aníbal; Bradshaw, Heather B; Franchi, Ana María

    2017-08-01

    Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice? Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling. Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor. An in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation. Time of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot. In vivo treatment of 15-day

  4. The role of the cannabinoid system in the pathogenesis and treatment of alcohol dependence

    Directory of Open Access Journals (Sweden)

    Bogusława Pietrzak

    2011-09-01

    Full Text Available The lack of satisfactory results of alcohol dependence treatment force us to search for new directions of research. Recent studies concentrate on endocannabinoid transmission. The results show an interplay between the endocannabinoid and dopaminergic signaling in activation of the limbic reward system. The mechanisms leading to development of dependence are very complex and poorly recognized. Endogenous cannabinoids seem to have an important role in the functioning of this system, both directly and indirectly affecting the level of different neurotransmitters. The effect of alcohol on the endocannabinoid system is also complex and involves changes at the molecular level. Experimental studies have demonstrated an important role of the CB1 receptors in the neurochemical mechanism of alcohol consumption and its regulation. SR141716 (rimonabant, a CB1 receptor antagonist, significantly lowers voluntary alcohol intake and motivation for its consumption in various experimental studies. Very encouraging results of preclinical studies were not completely confirmed in the clinical studies. However, further clinical studies are still necessary.

  5. Global response to HIV: treatment as prevention, or treatment for treatment?

    NARCIS (Netherlands)

    Sigaloff, Kim C. E.; Lange, Joep M. A.; Montaner, Julio

    2014-01-01

    The concept of "treatment as prevention" has emerged as a means to curb the global HIV epidemic. There is, however, still ongoing debate about the evidence on when to start antiretroviral therapy in resource-poor settings. Critics have brought forward multiple arguments against a "test and treat"

  6. Cognitive mediators of treatment outcomes in pediatric functional abdominal pain.

    Science.gov (United States)

    Levy, Rona L; Langer, Shelby L; Romano, Joan M; Labus, Jennifer; Walker, Lynn S; Murphy, Tasha B; Tilburg, Miranda A L van; Feld, Lauren D; Christie, Dennis L; Whitehead, William E

    2014-12-01

    Cognitive-behavioral (CB) interventions improve outcomes for many pediatric health conditions, but little is known about which mechanisms mediate these outcomes. The goal of this study was to identify whether changes in targeted process variables from baseline to 1 week posttreatment mediate improvement in outcomes in a randomized controlled trial of a brief CB intervention for idiopathic childhood abdominal pain. Two hundred children with persistent functional abdominal pain and their parents were randomly assigned to 1 of 2 conditions: a 3-session social learning and CB treatment (N=100), or a 3-session educational intervention controlling for time and attention (N=100). Outcomes were assessed at 3-, 6-, and 12-month follow-ups. The intervention focused on altering parental responses to pain and on increasing adaptive cognitions and coping strategies related to pain in both parents and children. Multiple mediation analyses were applied to examine the extent to which the effects of the social learning and CB treatment condition on child gastrointestinal (GI) symptom severity and pain as reported by children and their parents were mediated by changes in targeted cognitive process variables and parents' solicitous responses to their child's pain symptoms. Reductions in parents' perceived threat regarding their child's pain mediated reductions in both parent-reported and child-reported GI symptom severity and pain. Reductions in children's catastrophic cognitions mediated reductions in child-reported GI symptom severity but no other outcomes. Reductions in parental solicitousness did not mediate outcomes. Results suggest that reductions in reports of children's pain and GI symptoms after a social learning and CB intervention were mediated at least in part by decreasing maladaptive parent and child cognitions.

  7. Attitudes to publicly funded obesity treatment and prevention

    DEFF Research Database (Denmark)

    Lund, Thomas Bøker; Sandøe, Peter; Lassen, Jesper

    2011-01-01

    The aim of this study was to investigate the Danish public’s support for publicly funded obesity treatment and prevention. It was also examined whether levels of support could be explained by dislike of obese people and / or the belief that those who are obese are personally responsible......, the perceived controllability of obesity, self-reported BMI, and additional attitudinal and sociodemographic characteristics. Public funding of some obesity treatments, such as weight-loss surgery, attracted only limited public support. A majority of the Danish public did support ‘softer’ treatment...... interventions and preventive initiatives. Attitudes to the treatment of obesity were clearly best predicted by the belief that individuals are personally responsible for their own obesity. Dislike of obese persons had no direct effect on the preference for collective treatment initiatives and only a small...

  8. Impetigo: Tips for Treatment and Prevention

    Science.gov (United States)

    ... DO Videos Contact Close ‹ Back to Healthy Living Impetigo: Tips for Treatment and Prevention The symptoms of ... to other parts of their bodies. Causes of Impetigo Impetigo usually affects preschool and school-aged children, ...

  9. Identification and Sensitivity Analysis for Average Causal Mediation Effects with Time-Varying Treatments and Mediators: Investigating the Underlying Mechanisms of Kindergarten Retention Policy.

    Science.gov (United States)

    Park, Soojin; Steiner, Peter M; Kaplan, David

    2018-06-01

    Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach.

  10. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

    Science.gov (United States)

    Kolla, Nathan J; Mishra, Achal

    2018-01-01

    Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  11. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Nathan J. Kolla

    2018-03-01

    Full Text Available Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  12. Prevention and Treatment of Noise-Induced Tinnitus

    Science.gov (United States)

    2014-09-01

    Tinnitus PRINCIPAL INVESTIGATOR: Dr. Richard A. Altschuler CONTRACTING ORGANIZATION: University of Michigan REPORT DATE: 2014...3 Ju 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Prevention and Treatment of Noise-Induced Tinnitus 5b. GRANT NUMBER 5c. PROGRAM...prevent or treat noise induced tinnitus . Our studies showed a military relevant small arms fire-like noise will induce tinnitus in approximately 33

  13. Identifying the Average Causal Mediation Effects with Multiple Mediators in the Presence of Treatment Non-Compliance

    Science.gov (United States)

    Park, Soojin

    2015-01-01

    Identifying the causal mechanisms is becoming more essential in social and medical sciences. In the presence of treatment non-compliance, the Intent-To-Treated effect (hereafter, ITT effect) is identified as long as the treatment is randomized (Angrist et al., 1996). However, the mediated portion of effect is not identified without additional…

  14. Patients' preferences for headache acute and preventive treatment.

    Science.gov (United States)

    Mitsikostas, Dimos D; Belesioti, Ioanna; Arvaniti, Chryssa; Mitropoulou, Euthymia; Deligianni, Christina; Kasioti, Elina; Constantinidis, Theodoros; Dermitzakis, Manolis; Vikelis, Michail

    2017-10-06

    We aimed to explore patients' preferences for headache treatments with a self-administered questionnaire including the Q-No questionnaire for nocebo. Questionnaires from 514 outpatients naïve to neurostimulation and monoclonal antibodies were collected. Patients assessed that the efficacy of a treatment is more important than safety or route of administration. They preferred to use an external neurostimulation device for both acute (67.1%) and preventive treatment (62.8%). Most patients preferred to take a pill (86%) than any other drug given parenterally for symptomatic pharmaceutical treatment. For preventive pharmaceutical treatment, most patients preferred to take a pill once per day (52%) compared to an injection either subcutaneously or intravenously each month (9% and 4%), or three months (15% and 11%). 56.6% of all participants scored more than 15 in Q-No questionnaire indicating potential nocebo behaviors that contributed significantly in their choices. These patient preferences along with efficacy and safety data may help physicians better choose the right treatment for the right person.

  15. Endocannabinoids in Alzheimer's disease and their impact on normative cognitive performance: a case-control and cohort study

    Directory of Open Access Journals (Sweden)

    Christen Erica

    2009-01-01

    Full Text Available Abstract Background Neuropathological, animal, and cell culture studies point to a role for the body's own endogenous cannabinoids (eCBs system in Alzheimer's disease (AD pathology and treatment. To date, no published studies have investigated the potential utility of circulating eCBs as diagnostic biomarkers for AD or the impact of central eCBs on cognition. Results In comparison with healthy controls, there were no significant differences in measured eCB concentrations in plasma samples from patients with AD. Detectable eCBs in cerebrospinal fluid (CSF had no relationship to cognitive performance in healthy controls at risk for AD. In pooled plasma samples, an inverse correlation was observed between plasma levels of the eCB 2-AG (2-arachidonoylglycerol and TNF-α (r = -0.41, p Conclusion These results suggest that circulating endocannabinoids do not have utility as diagnostic biomarkers for AD and do not have a robust correlation with cognitive performance. Circulating levels of 2-AG may downregulate TNF-α production.

  16. [Treatment and prevention of venous thromboembolic disease: what's new?].

    Science.gov (United States)

    Rey, Marie-Antoinette; Bron, Cédric; Haesler, Erik; Mazzolai, Lucia

    2009-02-04

    Venous thromboembolic (VTE) disease is frequent and questions regarding its treatment or prevention are numerous. This review is aimed at summarizing and pointing out the novelties on VTE treatment and prevention recently published in the Chest journal earlier this year (8th edition of ACCP guidelines). Generally, the aim of guidelines and of this review as well, is to offer guidance to practictioners in making the most appropriate choice for treating or preventing VTE. They are not intended for strict application and doctors will always have to decide individually case by case taking into account patients preference and the risk-benefit balance.

  17. Nanotechnology and HIV: potential applications for treatment and prevention.

    Science.gov (United States)

    Kim, Peter S; Read, Sarah W

    2010-01-01

    HIV/AIDS is a global pandemic and is the leading infectious cause of death among adults. Although antiretroviral (ARV) therapy has dramatically improved the quality of life and increased the life expectancy of those infected with HIV, life-long suppressive treatment is required and a cure for HIV infection remains elusive; frequency of dosing and drug toxicity as well as the development of viral resistance pose additional limitations. Furthermore, preventative measures such as a vaccine or microbicide are urgently needed to curb the rate of new infections. The capabilities inherent to nanotechnology hold much potential for impact in the field of HIV treatment and prevention. This article reviews the potential for the multidisciplinary field of nanotechnology to advance the fields of HIV treatment and prevention. © 2010 John Wiley & Sons, Inc.

  18. Waste treatment in NUCEF facility with silver mediated electrochemical oxidation technique

    International Nuclear Information System (INIS)

    Umeda, M.; Sugikawa, S.

    2000-01-01

    Silver mediated electrochemical oxidation technique has been considered one of promising candidates for alpha-bearing waste treatment. Destruction tests of organic compounds, such as insoluble tannin, TBP and dodecane, were carried out by this technique and the experimental data such as destruction rates, current efficiencies and intermediates were obtained. These compounds could be completely mineralized without the formation of reactive organic nitrate associated to safety hazards. On the basis of these results, the applicability of silver mediated electrochemical oxidation technique to waste treatment in NUCEF was evaluated. (authors)

  19. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.

    Science.gov (United States)

    Patel, Sachin; Kingsley, Philip J; Mackie, Ken; Marnett, Lawrence J; Winder, Danny G

    2009-12-01

    Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.

  20. Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders.

    Science.gov (United States)

    Capasso, Anna; Milano, Walter; Cauli, Omar

    2018-02-12

    Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long-standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour. The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes. Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. FEMALE MICE ARE RESISTANT TO Fabp1 GENE ABLATION-INDUCED ALTERATIONS IN BRAIN ENDOCANNABINOID LEVELS

    Science.gov (United States)

    Martin, Gregory G.; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K.; Dangott, Lawrence J.; Peng, Xiaoxue; Kaczocha, Martin; Murphy, Eric J.; Kier, Ann B.; Schroeder, Friedhelm

    2017-01-01

    Although liver fatty acid binding protein (FABP1, L-FABP) is not detectable in brain, Fabp1 gene ablation (LKO) markedly increases endocannabinoids (EC) in brains of male mice. Since the brain EC system of females differs significantly from that of males, it was important to determine if LKO differently impacted the brain EC system. LKO did not alter brain levels of arachidonic acid (ARA)-containing ECs, i.e arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), but decreased non-ARA-containing N-acylethanolamides (OEA, PEA) and 2-oleoylglycerol (2-OG) that potentiate the actions of AEA and 2-AG. These changes in brain potentiating EC levels were not associated with: i) a net decrease in levels of brain membrane proteins associated with fatty acid uptake and EC synthesis; ii) a net increase in brain protein levels of cytosolic EC chaperones and enzymes in EC degradation; or iii) increased brain protein levels of EC receptors (CB1, TRVP1). Instead, the reduced or opposite responsiveness of female brain EC levels to loss of FABP1 (LKO) correlated with intrinsically lower FABP1 level in livers of WT females than males. These data show that female mouse brain endocannabinoid levels were unchanged (AEA, 2-AG) or decreased (OEA, PEA, 2-OG) by complete loss of FABP1 (LKO). PMID:27450559

  2. [Preventive treatment of retinal detachment in aphakic eyes].

    Science.gov (United States)

    Regnault, F; Bregeat, P

    1977-01-01

    We have examined 243 cases with retinal detachment occurring within 6 months following cataract surgery. In 92 of them retinal tear was due to lattice degeneration, in 66 to snail track degeneration and in 17 to equatorial degeneration. 290 other patients had preventive treatments. In this group, there were only 10 cases of retinal detachment. 9 out of 22 patients who had no preventive treatment suffered retinal detachments. There are two reasons for the occurrence of this retinal detachment in the 6 months following cataract surgery in eyes where retinal degenerations are found: (1) surgical trauma even with cryoextraction is responsible for traction of the vitreous base, (2) rapid disappearance of the hyaluronic acid in the aphakic vitreous is responsible for the degradation of the vitreous with formation of large zones of liquid vitreous. When adhesion between the vitreous and the retinal degeneration area remains, the traction is responsible for retinal tear or retinal detachment. The importance of the preventive treatment of retinal lesions prior to cataract surgery should be stressed.

  3. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    OpenAIRE

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p.) on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimenta...

  4. Lumbar supports for prevention and treatment of low back pain

    DEFF Research Database (Denmark)

    Van Tulder, M W; Jellema, P; van Poppel, M N

    2000-01-01

    BACKGROUND: Lumbar supports are used in the treatment of low back pain patients to make the impairment and disability vanish or decrease. Lumbar supports are also used to prevent the onset of low back pain (primary prevention) or to prevent recurrences of a low back pain episode (secondary...... 1999, and the Embase database up to September 1998. We also screened references given in relevant reviews and identified controlled trials, and used Science Citation Index to identify additional controlled trials. SELECTION CRITERIA: Controlled clinical trials that reported on any type of lumbar...... types of treatment or no intervention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, while it is still unclear if lumbar...

  5. Food Allergies: Symptoms, Diagnosis, Prevention and Treatment | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Food Allergies Food Allergies: Symptoms, Diagnosis, Prevention and Treatment Past Issues / Spring ... treatments only ease the symptoms. Preventing a food allergy reaction There are no drugs or treatments available ...

  6. Adherence to Technology-Mediated Insomnia Treatment: A Meta-Analysis, Interviews, and Focus Groups

    OpenAIRE

    Horsch, Corine; Lancee, Jaap; Beun, Robbert Jan; Neerincx, Mark A; Brinkman, Willem-Paul

    2015-01-01

    Background: Several technologies have been proposed to support the reduction of insomnia complaints. A user-centered assessment of these technologies could provide insight into underlying factors related to treatment adherence. Objective: Gaining insight into adherence to technology-mediated insomnia treatment as a solid base for improving those adherence rates by applying adherence-enhancing strategies. Methods: Adherence to technology-mediated sleep products was studied in three ways. First...

  7. Pomegranate for Prevention and Treatment of Cancer: An Update

    Directory of Open Access Journals (Sweden)

    Pooja Sharma

    2017-01-01

    Full Text Available Cancer is the second leading cause of death in the United States, and those who survive cancer may experience lasting difficulties, including treatment side effects, as well as physical, cognitive, and psychosocial struggles. Naturally-occurring agents from dietary fruits and vegetables have received considerable attention for the prevention and treatment of cancers. These natural agents are safe and cost efficient in contrast to expensive chemotherapeutic agents, which may induce significant side effects. The pomegranate (Punica granatum L. fruit has been used for the prevention and treatment of a multitude of diseases and ailments for centuries in ancient cultures. Pomegranate exhibits strong antioxidant activity and is a rich source of anthocyanins, ellagitannins, and hydrolysable tannins. Studies have shown that the pomegranate fruit as well as its juice, extract, and oil exert anti-inflammatory, anti-proliferative, and anti-tumorigenic properties by modulating multiple signaling pathways, which suggest its use as a promising chemopreventive/chemotherapeutic agent. This review summarizes preclinical and clinical studies highlighting the role of pomegranate in prevention and treatment of skin, breast, prostate, lung, and colon cancers.

  8. Pomegranate for Prevention and Treatment of Cancer: An Update.

    Science.gov (United States)

    Sharma, Pooja; McClees, Sarah F; Afaq, Farrukh

    2017-01-24

    Cancer is the second leading cause of death in the United States, and those who survive cancer may experience lasting difficulties, including treatment side effects, as well as physical, cognitive, and psychosocial struggles. Naturally-occurring agents from dietary fruits and vegetables have received considerable attention for the prevention and treatment of cancers. These natural agents are safe and cost efficient in contrast to expensive chemotherapeutic agents, which may induce significant side effects. The pomegranate ( Punica granatum L.) fruit has been used for the prevention and treatment of a multitude of diseases and ailments for centuries in ancient cultures. Pomegranate exhibits strong antioxidant activity and is a rich source of anthocyanins, ellagitannins, and hydrolysable tannins. Studies have shown that the pomegranate fruit as well as its juice, extract, and oil exert anti-inflammatory, anti-proliferative, and anti-tumorigenic properties by modulating multiple signaling pathways, which suggest its use as a promising chemopreventive/chemotherapeutic agent. This review summarizes preclinical and clinical studies highlighting the role of pomegranate in prevention and treatment of skin, breast, prostate, lung, and colon cancers.

  9. Marijuana, the Endocannabinoid System and the Female Reproductive System.

    Science.gov (United States)

    Brents, Lisa K

    2016-06-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.

  10. HIV in Indian prisons: Risk behaviour, prevalence, prevention & treatment

    OpenAIRE

    Dolan, Kate; Larney, Sarah

    2010-01-01

    Background & Objectives: HIV is a major health challenge for prison authorities. HIV in prisons has implications for HIV in the general community. The aim of this paper was to gather information on HIV risk, prevalence, prevention and treatment in prisons in India. Methods: Relevant published and unpublished reports and information were sought in order to provide a coherent picture of the current situation relating to HIV prevention, treatment and care in prisons in India. Information covered...

  11. Brief Report: Mediation of Treatment Effect in a Communication Intervention for Pre-School Children with Autism

    Science.gov (United States)

    Aldred, Catherine; Green, Jonathan; Emsley, Richard; McConachie, Helen

    2012-01-01

    Tests of mediation in treatment trials can illuminate processes of change and suggest causal influences in development. We conducted a mediation analysis of a previously published randomised controlled trial of parent-mediated communication-focused treatment for autism against ordinary care, with 28 children aged 2-5 years (Aldred et al. in J…

  12. Mediation and moderation of treatment effects in randomised controlled trials of complex interventions.

    Science.gov (United States)

    Emsley, Richard; Dunn, Graham; White, Ian R

    2010-06-01

    Complex intervention trials should be able to answer both pragmatic and explanatory questions in order to test the theories motivating the intervention and help understand the underlying nature of the clinical problem being tested. Key to this is the estimation of direct effects of treatment and indirect effects acting through intermediate variables which are measured post-randomisation. Using psychological treatment trials as an example of complex interventions, we review statistical methods which crucially evaluate both direct and indirect effects in the presence of hidden confounding between mediator and outcome. We review the historical literature on mediation and moderation of treatment effects. We introduce two methods from within the existing causal inference literature, principal stratification and structural mean models, and demonstrate how these can be applied in a mediation context before discussing approaches and assumptions necessary for attaining identifiability of key parameters of the basic causal model. Assuming that there is modification by baseline covariates of the effect of treatment (i.e. randomisation) on the mediator (i.e. covariate by treatment interactions), but no direct effect on the outcome of these treatment by covariate interactions leads to the use of instrumental variable methods. We describe how moderation can occur through post-randomisation variables, and extend the principal stratification approach to multiple group methods with explanatory models nested within the principal strata. We illustrate the new methodology with motivating examples of randomised trials from the mental health literature.

  13. Hepatorenal syndrome: diagnosis, treatment and prevention

    DEFF Research Database (Denmark)

    Israelsen, Mads Egerod; Gluud, Lise Lotte; Bendtsen, Flemming

    2014-01-01

    Cirrhosis, ascites and renal impairment are associated with high morbidity and mortality. The hepatorenal syndrome (HRS) is a type of renal failure that affects patients with cirrhosis and ascites. This paper provides an update on evidence-based interventions in HRS. A number of factors can...... precipitate HRS. The monitoring, prevention, early detection, and correct treatment of these are essential. Terlipressin combined with albumin is the first-line treatment of type 1 HRS. In type 2 HRS with refractory ascites, liver transplantation and TIPS should be considered....

  14. Epidemiology, treatment and prevention of herpes zoster: A comprehensive review.

    Science.gov (United States)

    Koshy, Elsam; Mengting, Lu; Kumar, Hanasha; Jianbo, Wu

    2018-01-01

    Herpes zoster is a major health burden that can affect individuals of any age. It is seen more commonly among individuals aged ≥50 years, those with immunocompromised status, and those on immunosuppressant drugs. It is caused by a reactivation of varicella zoster virus infection. Cell-mediated immunity plays a role in this reactivation. Fever, pain, and itch are common symptoms before the onset of rash. Post-herpetic neuralgia is the most common complication associated with herpes zoster. Risk factors and complications associated with herpes zoster depend on the age, immune status, and the time of initializing treatment. Routine vaccination for individuals over 60 years has shown considerable effect in terms of reducing the incidence of herpes zoster and post-herpetic neuralgia. Treatment with antiviral drugs and analgesics within 72 hours of rash onset has been shown to reduce severity and complications associated with herpes zoster and post-herpetic neuralgia. This study mainly focuses on herpes zoster using articles and reviews from PubMed, Embase, Cochrane library, and a manual search from Google Scholar. We cover the incidence of herpes zoster, gender distribution, seasonal and regional distribution of herpes zoster, incidence of herpes zoster among immunocompromised individuals, incidence of post-herpetic neuralgia following a zoster infection, complications, management, and prevention of herpes zoster and post-herpetic neuralgia.

  15. Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Rongqing Chen

    2012-11-01

    Full Text Available Alzheimer's disease (AD is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1 in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning, and memory in AD animals. Although the molecular mechanisms underlying the beneficial effects produced by MAGL inhibition remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD, and thus is a promising therapeutic target for the prevention and treatment of AD.

  16. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol.

    Science.gov (United States)

    Hanlon, Erin C; Tasali, Esra; Leproult, Rachel; Stuhr, Kara L; Doncheck, Elizabeth; de Wit, Harriet; Hillard, Cecilia J; Van Cauter, Eve

    2016-03-01

    Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. A commentary on this article appears in this issue on page 495. © 2016 Associated Professional Sleep Societies, LLC.

  17. Restricted vs. unrestricted wheel running in mice: Effects on brain, behavior and endocannabinoids.

    Science.gov (United States)

    Biedermann, Sarah V; Auer, Matthias K; Bindila, Laura; Ende, Gabriele; Lutz, Beat; Weber-Fahr, Wolfgang; Gass, Peter; Fuss, Johannes

    2016-11-01

    Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1 H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    Science.gov (United States)

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 ... No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will test your blood. You ...

  19. Candidiasis: predisposing factors, prevention, diagnosis and alternative treatment.

    Science.gov (United States)

    Martins, Natália; Ferreira, Isabel C F R; Barros, Lillian; Silva, Sónia; Henriques, Mariana

    2014-06-01

    Candidiasis is the most common opportunistic yeast infection. Candida species and other microorganisms are involved in this complicated fungal infection, but Candida albicans continues to be the most prevalent. In the past two decades, it has been observed an abnormal overgrowth in the gastrointestinal, urinary and respiratory tracts, not only in immunocompromised patients, but also related to nosocomial infections and even in healthy individuals. There is a widely variety of causal factors that contribute to yeast infection which means that candidiasis is a good example of a multifactorial syndrome. Due to rapid increase in the incidence in these infections, this is the subject of numerous studies. Recently, the focus of attention is the treatment and, above all, the prevention of those complications. The diagnosis of candidiasis could become quite complicated. Prevention is the most effective "treatment," much more than eradication of the yeast with antifungal agents. There are several aspects to consider in the daily routine that can provide a strength protection. However, a therapeutic approach is necessary when the infection is established, and therefore, other alternatives should be explored. This review provides an overview on predisposition factors, prevention and diagnosis of candidiasis, highlighting alternative approaches for candidiasis treatment.

  20. Increasing the efficacy of cue exposure treatment in preventing relapse of addictive behavior.

    Science.gov (United States)

    Havermans, Remco C; Jansen, Anita T M

    2003-07-01

    Theoretically, cue exposure treatment should be able to prevent relapse by extinguishing conditioned drug responding (e.g. cue-elicited craving). According to contemporary learning theory, though, extinction does not eliminate conditioned responding. Analogous cue exposure with response prevention (CERP) as a treatment of addictive behavior might not eliminate the learned relation between drug-related cues and drug use. This does not necessarily mean that cue exposure cannot successfully prevent relapse. Various suggestions for increasing the efficacy of cue exposure treatment are being discussed from a contemporary learning theory perspective. It is suggested that cue exposure treatment incorporating retrieval cues can be a beneficial treatment in preventing relapse of addictive behavior.

  1. HIV / AIDS: Symptoms, Diagnosis, Prevention and Treatment

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues HIV / AIDS HIV / AIDS: Symptoms , Diagnosis, Prevention and Treatment Past Issues / ... Most people who have become recently infected with HIV will not have any symptoms. They may, however, ...

  2. Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play

    Directory of Open Access Journals (Sweden)

    Antonia Manduca

    2016-11-01

    Full Text Available Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R or mu-opioid receptor (MOR antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC. Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of mediates social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  3. An update in prevention and treatment of pediatric obesity.

    Science.gov (United States)

    Moya, Manuel

    2008-08-01

    Obesity prevalence is growing as well as its severity with increasing morbidity and mortality. This "globesity" also affects developing countries where under nutrition and stunting frequently coexist with overweight and obesity. One third of obese adults began to be so in the pediatric ages. There are two main types of prevention: general one representing greater actions from health authorities and the individual one carried out by the pediatrician and the patient at risk. Once the state of obesity is reached (relative body mass index, rBMI >121%) the longer lasting care becomes more complex and frequently unsuccessful. The treatment of obesity is aimed to care for the present and silent disorders and for preventing its further tracking to adulthood. Identification of pediatric population at risk which is the one with an rBMI of 111%-120% plus other risk factors. Specific individual actions include reduction of food intake, increase of energy expenditure, involvement of parents, and the child-adolescent himself in the prevention. Therapy is based on some principles plus the important medical and emotional approach. A Cochrane study based on only 10 appropriate studies showed a predominant poor efficacy of the undergone preventive action. Treatment guides are presented after our own experience with a group of 400 kids with an average follow-up of 7 years and other individual prevention studies. Involving motivated pediatricians with a minimum of time for visits and better follow-up in the frame of a general national preventive programme could be a rational outcome. Treatment of obesity should never be postponed whatever the clinical care is.

  4. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue

    Directory of Open Access Journals (Sweden)

    Lucie eGeurts

    2011-07-01

    Full Text Available Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system and gut microbiota-derived compounds, namely lipopolysaccharide (LPS. We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the endocannabinoid system and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the endocannabinoid system and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.

  5. Evidence Map of Prevention and Treatment Interventions for Depression in Young People

    Directory of Open Access Journals (Sweden)

    Patrick Callahan

    2012-01-01

    Full Text Available Introduction. Depression in adolescents and young people is associated with reduced social, occupational, and interpersonal functioning, increases in suicide and self-harm behaviours, and problematic substance use. Age-appropriate, evidence-based treatments are required to provide optimal care. Methods. “Evidence mapping” methodology was used to quantify the nature and distribution of the extant high-quality research into the prevention and treatment of depression in young people across psychological, medical, and other treatment domains. Results. Prevention research is dominated by cognitive-behavioral- (CBT- based interventions. Treatment studies predominantly consist of CBT and SSRI medication trials, with few trials of other psychological interventions or complementary/alternative treatments. Quality studies on relapse prevention and treatment for persistent depression are distinctly lacking. Conclusions. This map demonstrates opportunities for future research to address the numerous evidence gaps for interventions to prevent or treat depression in young people, which are of interest to clinical researchers, policy makers, and funding bodies.

  6. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

    2015-01-01

    Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  7. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

    Directory of Open Access Journals (Sweden)

    Eduardo eBlanco Calvo

    2015-11-01

    Full Text Available Perinatal asphyxia (PA is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory and mood. Endocannabinoids, and other acylethanolamides (AEs without endocannabinoid activity, have recently received growing attention as they have potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals that were delivered spontaneously or by caesarean section were employed as controls. At one month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and GFAP, enzymes responsible for synthesis (DAGLα and NAPE-PLD and degradation (FAAH of ECS/AEs and their receptors (CB1 and PPARα in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  8. Principles and approaches to the treatment of immune-mediated movement disorders.

    Science.gov (United States)

    Mohammad, Shekeeb S; Dale, Russell C

    2018-03-01

    Immune mediated movement disorders include movement disorders in the context of autoimmune encephalitis such as anti-NMDAR encephalitis, post-infectious autoimmune movement disorders such as Sydenham chorea, paraneoplastic autoimmune movement disorders such as opsoclonus myoclonus ataxia syndrome, and infection triggered conditions such as paediatric acute neuropsychiatric syndrome. This review focuses on the approach to treatment of immune mediated movement disorders, which requires an understanding of the immunopathogenesis, whether the disease is destructive or 'altering', and the natural history of disease. Factors that can influence outcome include the severity of disease, the delay before starting therapy, use of multimodal therapy and whether the course is monophasic or relapsing. Although the four main conditions listed above have different pathophysiological processes, there are general themes that broadly apply including: early diagnosis and treatment is better, minimise the severity of disease, escalate treatment if the patient is not responding to initial treatments, and minimise relapse. Copyright © 2017. Published by Elsevier Ltd.

  9. Mediators of exposure therapy for youth obsessive-compulsive disorder: specificity and temporal sequence of client and treatment factors.

    Science.gov (United States)

    Chu, Brian C; Colognori, Daniela B; Yang, Guang; Xie, Min-ge; Lindsey Bergman, R; Piacentini, John

    2015-05-01

    Behavioral engagement and cognitive coping have been hypothesized to mediate effectiveness of exposure-based therapies. Identifying which specific child factors mediate successful therapy and which therapist factors facilitate change can help make our evidence-based treatments more efficient and robust. The current study examines the specificity and temporal sequence of relations among hypothesized client and therapist mediators in exposure therapy for pediatric Obsessive Compulsive Disorder (OCD). Youth coping (cognitive, behavioral), youth safety behaviors (avoidance, escape, compulsive behaviors), therapist interventions (cognitive, exposure extensiveness), and youth anxiety were rated via observational ratings of therapy sessions of OCD youth (N=43; ages=8 - 17; 62.8% male) who had received Exposure and Response Prevention (ERP). Regression analysis using Generalized Estimation Equations and cross-lagged panel analysis (CLPA) were conducted to model anxiety change within and across sessions, to determine formal mediators of anxiety change, and to establish sequence of effects. Anxiety ratings decreased linearly across exposures within sessions. Youth coping and therapist interventions significantly mediated anxiety change across exposures, and youth-interfering behavior mediated anxiety change at the trend level. In CLPA, youth-interfering behaviors predicted, and were predicted by, changes in anxiety. Youth coping was predicted by prior anxiety change. The study provides a preliminary examination of specificity and temporal sequence among child and therapist behaviors in predicting youth anxiety. Results suggest that therapists should educate clients in the natural rebound effects of anxiety between sessions and should be aware of the negatively reinforcing properties of avoidance during exposure. Copyright © 2015. Published by Elsevier Ltd.

  10. Prevention and treatment of radiotherapy-induced oral mucositis: a literature review

    International Nuclear Information System (INIS)

    Albuquerque, Ieda Lessa de Souza; Camargo, Teresa Caldas

    2007-01-01

    The prevention and treatment of radiotherapy-induced oral mucositis have still not been fully defined. The current study thus involved a literature search aimed at identifying preventive and therapeutic measures in relation to oral mucositis in patients submitted to radiotherapy, analyzing the level of evidence in the selected studies, identifying which indications for prevention and treatment in the literature pertain to the field of nursing, and critically analyzing the results and their implications for nursing care. This was a systematic literature survey without a meta analysis, consulting the following databases: BIREME, Medline, CancerLit, Scirus, CAPES, Free medical journal, High wire press, SCIELO, and Medscape, from 2000 to 2005. According to observations, nursing care was capable of improving patient's quality of life, promoting education of patients, implementing and supervising oral care programs, and providing guidance on hygiene, prevention, and treatment of oral mucositis, including pain management. However, no Brazilian nursing publications were found on the subject. Research and publications focusing on nursing experience in the prevention and treatment of radiotherapy-related oral mucositis and the implications for patients and nurses are important to provide evidence-based nursing guidelines. (author)

  11. Is parenting the mediator of change in behavioral parent training for externalizing problems of youth?

    Science.gov (United States)

    Forehand, Rex; Lafko, Nicole; Parent, Justin; Burt, Keith B

    2014-12-01

    Change in parenting behavior is theorized to be the mediator accounting for change in child and adolescent externalizing problems in behavioral parent training (BPT). The purpose of this review is to examine this assumption in BPT prevention and intervention programs. Eight intervention and 17 prevention studies were identified as meeting all criteria or all but one criterion for testing mediation. Parenting behaviors were classified as positive, negative, discipline, monitoring/supervision, or a composite measure. Forty-five percent of the tests performed across studies to test mediation supported parenting as a mediator. A composite measure of parenting and discipline received the most support, whereas monitoring/supervision was rarely examined. More support for the mediating role of parenting emerged for prevention than intervention studies and when meeting all criteria for testing mediation was not required. Although the findings do not call BPT into question as an efficacious treatment, they do suggest more attention should be focused on examining parenting as a putative mediator in BPT. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Issues and Challenges of HIV/AIDS Prevention and Treatment Programme in Nepal

    OpenAIRE

    Wasti, Sharada Prasad; Simkhada, Padam; Randall, Julian; Van Teijlingen, Edwin

    2009-01-01

    This paper explores some of the key issues and challenges of government HIV/AIDS prevention and treatment programme in Nepal. Providing HIV/AIDS prevention and treatment services in Nepal is associated with a number of issues and challenges which are shaped mostly on cultural and managerial issues from grass root to policy level.\\ud Numerous efforts have been done and going on by Nepal government and non-government organization but still HIV\\ud prevention and treatment service is not able to ...

  13. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Science.gov (United States)

    McPartland, John M; Guy, Geoffrey W; Di Marzo, Vincenzo

    2014-01-01

    The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  14. Men's Perceptions of Treatment as Prevention in South Africa: Implications for Engagement in HIV Care and Treatment.

    Science.gov (United States)

    Mooney, Alyssa C; Gottert, Ann; Khoza, Nomhle; Rebombo, Dumisani; Hove, Jennifer; Suárez, Aimée Julien; Twine, Rhian; MacPhail, Catherine; Treves-Kagan, Sarah; Kahn, Kathleen; Pettifor, Audrey; Lippman, Sheri A

    2017-06-01

    While South Africa provides universal access to treatment, HIV testing and antiretroviral therapy (ART) uptake remains low, particularly among men. Little is known about community awareness of the effects of treatment on preventing transmission, and how this information might impact HIV service utilization. This qualitative study explored understandings of treatment as prevention (TasP) among rural South African men. Narratives emphasized the know value of ART for individual health, but none were aware of its preventive effects. Many expressed that preventing transmission to partners would incentivize testing, earlier treatment, and adherence in the absence of symptoms, and could reduce the weight of a diagnosis. Doubts about TasP impacts on testing and care included enduring risks of stigma and transmission. TasP information should be integrated into clinic-based counseling for those utilizing services, and community-based education for broader reach. Pairing TasP information with alternative testing options may increase engagement among men reluctant to be seen at clinics.

  15. Are parental self-efficacy and family flexibility mediators of treatment for anorexia nervosa?

    Science.gov (United States)

    Sadeh-Sharvit, Shiri; Arnow, Katherine D; Osipov, Lilya; Lock, James D; Jo, Booil; Pajarito, Sarah; Brandt, Harry; Dodge, Elizabeth; Halmi, Katherine A; Johnson, Craig; Kaye, Walter; Wilfley, Denise; Agras, W Stewart

    2018-03-01

    Family-based treatment (FBT) for adolescent anorexia nervosa (AN) promotes faster weight restoration when compared to other treatments. However, the mechanisms through which this occurs are not clarified. This study explored the trajectories of parental self-efficacy and perceived family flexibility during FBT and systemic family therapy (SyFT). We also explored whether parental self-efficacy mediates the effects of treatment on weight gain early in treatment. 158 adolescents (12-18 years old; 89% girls) and their parents were randomized to FBT or SyFT. Parental self-efficacy as well as adolescents' and parental perceptions of the family's flexibility were collected at baseline and at sessions 2, 4, 6, and 8. Over time, only parents in FBT reported significantly greater self-efficacy. The change in maternal self-efficacy over the first 8 weeks of treatment was a significant mediator of session 10 weight gain. There were no significant group differences in perceived flexibility by session 8. Both parents in FBT and mothers in SyFT understand early the need to change their family's rules and roles. However, the specific strategies of FBT appear to mediate early weight gain in AN. © 2018 Wiley Periodicals, Inc.

  16. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Hansen, Kristian Schultz; Bygbjerg, Ib Christian

    2008-01-01

    The main objective of this study was to assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilisers could administer intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women. The study w...

  17. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

    Directory of Open Access Journals (Sweden)

    Jakub Fichna

    Full Text Available AIMS: Irritable bowel syndrome (IBS is a functional gastrointestinal (GI disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D and constipation-predominant (IBS-C patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

  18. Mediators and Moderators of a School-Based Cognitive-Behavioral Depression Prevention Program.

    Science.gov (United States)

    Duong, Mylien T; Kelly, Brynn M; Haaland, Wren L; Matsumiya, Brandon; Huey, Stanley J; McCarty, Carolyn A

    2016-10-01

    This study tested potential moderators and mediators of an indicated depression prevention program for middle school students, Positive Thoughts and Actions (PTA). Participants were 120 students randomly assigned to PTA, or a brief, individually administered supportive intervention (Individual Support Program, or ISP). Youths completed measures of depressive symptoms at baseline, post-intervention, and 12-month follow-up. Hierarchical regression was used to test three moderators-ethnic minority status, gender, and baseline depressive symptoms-and three mediators representing functional outcomes targeted by PTA-parent-child communication, attitude towards school, and health behavior. Ethnic minority status did not moderate PTA effects at post-intervention but did moderate PTA effects at 12-month follow-up. At 12 months, PTA appeared to be more effective for White participants than ethnic minority youth. Follow-up analyses suggested this moderation effect was due to the tendency of ethnic minority youth, especially those with fewer symptoms at baseline, to drop out by 12 months. Neither gender nor baseline depressive symptoms moderated the effects of PTA. Although PTA improved health behavior and attitudes toward school, there was no evidence that any of these functional outcomes measured mediated the impact of PTA on depressive symptoms. Future directions are discussed.

  19. Reasons for Testing Mediation in the Absence of an Intervention Effect: A Research Imperative in Prevention and Intervention Research.

    Science.gov (United States)

    O'Rourke, Holly P; MacKinnon, David P

    2018-03-01

    Mediation models are used in prevention and intervention research to assess the mechanisms by which interventions influence outcomes. However, researchers may not investigate mediators in the absence of intervention effects on the primary outcome variable. There is emerging evidence that in some situations, tests of mediated effects can be statistically significant when the total intervention effect is not statistically significant. In addition, there are important conceptual and practical reasons for investigating mediation when the intervention effect is nonsignificant. This article discusses the conditions under which mediation may be present when an intervention effect does not have a statistically significant effect and why mediation should always be considered important. Mediation may be present in the following conditions: when the total and mediated effects are equal in value, when the mediated and direct effects have opposing signs, when mediated effects are equal across single and multiple-mediator models, and when specific mediated effects have opposing signs. Mediation should be conducted in every study because it provides the opportunity to test known and replicable mediators, to use mediators as an intervention manipulation check, and to address action and conceptual theory in intervention models. Mediators are central to intervention programs, and mediators should be investigated for the valuable information they provide about the success or failure of interventions.

  20. HIV in Indian prisons: risk behaviour, prevalence, prevention & treatment.

    Science.gov (United States)

    Dolan, Kate; Larney, Sarah

    2010-12-01

    HIV is a major health challenge for prison authorities. HIV in prisons has implications for HIV in the general community. The aim of this paper was to gather information on HIV risk, prevalence, prevention and treatment in prisons in India. Relevant published and unpublished reports and information were sought in order to provide a coherent picture of the current situation relating to HIV prevention, treatment and care in prisons in India. Information covered prison management and population statistics, general conditions in prisons, provision of general medical care and the HIV situation in prison. No data on drug injection in prison were identified. Sex between men was reported to be common in some Indian prisons. A national study found that 1.7 per cent of inmates were HIV positive. Some prisons provided HIV education. Condom provision was considered illegal. A few prisoners received drug treatment for drug use, HIV infection or co-infection with sexually transmitted infections (STIs). HIV prevalence in prisons in India was higher than that in the general community. Regular monitoring of information on HIV risk behaviours and prevalence in Indian prisons is strongly recommended. Evidence based treatment for drug injectors and nation-wide provision of HIV prevention strategies are urgently required. Voluntary counselling, testing and treatment for HIV and STIs should be provided.

  1. Patients' Awareness Of The Prevention And Treatment Of Colorectal Cancer.

    Science.gov (United States)

    Dziki, Łukasz; Puła, Anna; Stawiski, Konrad; Mudza, Barbara; Włodarczyk, Marcin; Dziki, Adam

    2015-09-01

    The aim of the study was to assess patients' awareness of the prevention and treatment of colorectal cancer. Patients diagnosed with colorectal cancer, hospitalised at the Department of General and Colorectal Surgery of the Medical University in Łódź during the period from January 2015 to April 2015, were asked to complete a questionnaire concerning their families' medical case record, factors predisposing them to the development of colorectal cancer, the tests applied in diagnostics, and the treatment process. The questionnaire comprised 42 closed-ended questions with one correct answer. A statistical analysis of all answers was carried out. The study group consisted of 30 men and 20 women aged 27-94 years old. A strong, statistically significant negative correlation between a patient's age and his/her awareness of the prevention and treatment of colorectal cancer was noted (pcancer (p=0.008), and the awareness of the prevention programme. The women's group was characterised by statistically significantly greater awareness of colonoscopy as a screening examination (p=0.004). Patients need more information on colorectal cancer, its risk factors, prevention, the treatment process, and postoperative care. Lack of awareness of the colorectal cancer issue can be one of the major factors contributing to the high incidence of this disease.

  2. Novel Nanotechnology Strategies for the Treatment and Prevention of HIV Infection

    Science.gov (United States)

    Tan, Jian Jun; Sun, Xiao Hui; Ma, Xue Ting; Guan, Jian Qing; Wang, Cun Xin

    2013-09-01

    It is a hard work to develop an hightly effective cure and prevention of HIV/AIDS. The widespread used of some therapy approaches such as highly active anti retroviral therapy (HAART) has improved life quality and span of infected individuals. However, some limitations of these approaches prevent them achieving further advancement. Recent research on drug delivery approaches indicates that engineered nanosystems may bring positive effect on the improvement of current antiretroviral therapy. Furthermore, the basic researches of nanotechnology- based systems which prevent HIV transmission have been started. Therefore, nanotechnology may become a potential approach in the field of HIV/AIDS treatment and prevention. This chapter reviews the latest advancement in the field of nanotechnology-based systems which improve the fields of HIV/AIDS treatment and prevention.

  3. Adherence to Technology-Mediated Insomnia Treatment: A Meta-Analysis, Interviews, and Focus Groups.

    Science.gov (United States)

    Horsch, Corine; Lancee, Jaap; Beun, Robbert Jan; Neerincx, Mark A; Brinkman, Willem-Paul

    2015-09-04

    Several technologies have been proposed to support the reduction of insomnia complaints. A user-centered assessment of these technologies could provide insight into underlying factors related to treatment adherence. Gaining insight into adherence to technology-mediated insomnia treatment as a solid base for improving those adherence rates by applying adherence-enhancing strategies. Adherence to technology-mediated sleep products was studied in three ways. First, a meta-analysis was performed to investigate adherence rates in technology-mediated insomnia therapy. Several databases were queried for technology-mediated insomnia treatments. After inclusion and exclusion steps, data from 18 studies were retrieved and aggregated to find an average adherence rate. Next, 15 semistructured interviews about sleep-support technologies were conducted to investigate perceived adherence. Lastly, several scenarios were written about the usage of a virtual sleep coach that could support adherence rates. The scenarios were discussed in six different focus groups consisting of potential users (n=15), sleep experts (n=7), and coaches (n=9). From the meta-analysis, average treatment adherence appeared to be approximately 52% (95% CI 43%-61%) for technology-mediated insomnia treatments. This means that, on average, half of the treatment exercises were not executed, suggesting there is a substantial need for adherence and room for improvement in this area. However, the users in the interviews believed they adhered quite well to their sleep products. Users mentioned relying on personal commitment (ie, willpower) for therapy adherence. Participants of the focus groups reconfirmed their belief in the effectiveness of personal commitment, which they regarded as more effective than adherence-enhancing strategies. Although adherence rates for insomnia interventions indicate extensive room for improvement, users might not consider adherence to be a problem; they believe willpower to be an

  4. Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism.

    Science.gov (United States)

    García, Carla R; Angelé-Martínez, Carlos; Wilkes, Jenna A; Wang, Hsiao C; Battin, Erin E; Brumaghim, Julia L

    2012-06-07

    Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L-DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L-DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 μM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 μM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 μM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders.

  5. TREATMENT AND VACCINE PREVENTION OF ROTAVIRAL INFECTION AMONG CHILDREN

    Directory of Open Access Journals (Sweden)

    T.V. Kulichenko

    2007-01-01

    Full Text Available Irrespective of the level of healthcare system development rotaviral infection is a serious medical, social and economic problem at all times. Any infant has to undergo rotaviral gastroenteritis. The run of the disease among infants is mostly often aggravated by dehydration and needs intense treatment of exicosis. The standard of treatment is an oral rehydration, which is in most cases contributes to a quicker improvement of the children’s status. In the meantime, according to the metaphor put forward by the who experts «the best solution» to prevent acute rotaviral diarrhea today may become a rotaviral vaccine. Nowadays, in different countries of the world, two vaccines, which showed high efficiency and safety in clinical research, have been registered. Application of these vaccines may contribute to the significant reduction of the acute forms of rotaviral infection among infants, hospitalizations and mortality caused by rotaviral gastroenteritis. This article highlights the principles of treatment and possibility for vaccine prevention of rotaviral infection among children.Key words: rotaviral infection, gastroenteritis, diarrhea, children, rehydration, vaccine prevention, rotaviral vaccine.

  6. Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2017-01-05

    Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Iatrogenic possibilities of orthodontic treatment and modalities of prevention

    Science.gov (United States)

    Meeran, Nazeer Ahmed

    2013-01-01

    The benefits of orthodontic treatment are numerous and in most cases, the benefits outweigh the possible disadvantages. Orthodontic treatment can play an important role in enhancing esthetics, function, and self-esteem in patients. However, it carries with it the risks of enamel demineralization, tissue damage, root resorption, open gingival embrasures in the form of triangular spaces, allergic reactions to nickel, and treatment failure in the form of relapse. These potential complications are easily avoidable by undertaking certain precautions and timely interventions by both the orthodontist and the patient. The orthodontist must ensure that the patient is aware of the associated risks and stress the importance of the patient's role in preventing these untoward outcomes. The decision whether to proceed with the orthodontic treatment is essentially a risk-benefit analysis, where the perceived benefits of commencing treatment outweigh the potential risks. This article provides an overview of the iatrogenic possibilities of orthodontic treatment and the role of the patient as well as the orthodontist in preventing the associated risks. PMID:24987646

  8. Epidermal growth factor prevents thallium(I)- and thallium(III)-mediated rat pheochromocytoma (PC12) cell apoptosis.

    Science.gov (United States)

    Pino, María Teresa Luján; Marotte, Clarisa; Verstraeten, Sandra Viviana

    2017-03-01

    We have reported recently that the proliferation of PC12 cells exposed to micromolar concentrations of Tl(I) or Tl(III) has different outcomes, depending on the absence (EGF - cells) or the presence (EGF + cells) of epidermal growth factor (EGF) added to the media. In the current work, we investigated whether EGF supplementation could also modulate the extent of Tl(I)- or Tl(III)-induced cell apoptosis. Tl(I) and Tl(III) (25-100 μM) decreased cell viability in EGF - but not in EGF + cells. In EGF - cells, Tl(I) decreased mitochondrial potential, enhanced H 2 O 2 generation, and activated mitochondrial-dependent apoptosis. In addition, Tl(III) increased nitric oxide production and caused a misbalance between the anti- and pro-apoptotic members of Bcl-2 family. Tl(I) increased ERK1/2, JNK, p38, and p53 phosphorylation in EGF - cells. In these cells, Tl(III) did not affect ERK1/2 and JNK phosphorylation but increased p53 phosphorylation that was related to the promotion of cell senescence. In addition, this cation significantly activated p38 in both EGF - and EGF + cells. The specific inhibition of ERK1/2, JNK, p38, or p53 abolished Tl(I)-mediated EGF - cell apoptosis. Only when p38 activity was inhibited, Tl(III)-mediated apoptosis was prevented in EGF - and EGF + cells. Together, current results indicate that EGF partially prevents the noxious effects of Tl by preventing the sustained activation of MAPKs signaling cascade that lead cells to apoptosis and point to p38 as a key mediator of Tl(III)-induced PC12 cell apoptosis.

  9. Exercise training prevents the attenuation of anesthetic pre-conditioning-mediated cardioprotection in diet-induced obese rats.

    Science.gov (United States)

    Li, L; Meng, F; Li, N; Zhang, L; Wang, J; Wang, H; Li, D; Zhang, X; Dong, P; Chen, Y

    2015-01-01

    Obesity abolishes anesthetic pre-conditioning-induced cardioprotection due to impaired reactive oxygen species (ROS)-mediated adenosine monophosphate-activated protein kinase (AMPK) pathway, a consequence of increased basal myocardial oxidative stress. Exercise training has been shown to attenuate obesity-related oxidative stress. This study tests whether exercise training could normalize ROS-mediated AMPK pathway and prevent the attenuation of anesthetic pre-conditioning-induced cardioprotection in obesity. Male Sprague-Dawley rats were divided into lean rats fed with control diet and obese rats fed with high-fat diet. After 4 weeks of feeding, lean and obese rats were assigned to sedentary conditions or treadmill exercise for 8 weeks. There was no difference in infarct size between lean sedentary and obese sedentary rats after 25 min of myocardial ischemia followed by 120 min reperfusion. In lean rats, sevoflurane equally reduced infarct size in lean sedentary and lean exercise-trained rats. Molecular studies revealed that AMPK activity, endothelial nitric oxide synthase, and superoxide production measured at the end of ischemia in lean rats were increased in response to sevoflurane. In obese rats, sevoflurane increased the above molecular parameters and reduced infarct size in obese exercise-trained rats but not in obese sedentary rats. Additional study showed that obese exercise-trained rats had decreased basal oxidative stress than obese sedentary rats. The results indicate that exercise training can prevent the attenuation of anesthetic cardioprotection in obesity. Preventing the attenuation of this strategy may be associated with reduced basal oxidative stress and normalized ROS-mediated AMPK pathway, but the causal relationship remains to be determined. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  10. Articulating a rights-based approach to HIV treatment and prevention interventions.

    Science.gov (United States)

    Barr, David; Amon, Joseph J; Clayton, Michaela

    2011-09-01

    Since the beginning of the epidemic, the protection of human rights has been an integral component in the response to Human Immunodeficiency Virus (HIV). The high degree of stigma and discrimination associated with acquired immune deficiency syndrome (AIDS) has made human rights protection not only a priority to ensure the rights of people living with and at-risk for HIV, but to address public health goals as well. Advances in understanding the impact of antiretroviral treatment on HIV prevention provide exciting opportunities and even a paradigm shift in terms of AIDS prevention. However, this potential cannot be reached unless the advancement of human rights is a primary component of treatment and prevention programme and policy development. The use of antiretroviral treatment as prevention reinforces the value of basic principles related to the dignity and agency of people living with HIV to participate in the design and implementation of programmes, to be informed and to make informed decisions about their health and lives, to be protected from harm, and to have opportunities to seek redress and accountability for abuses. The possibility of using HIV treatment as a prevention tool means that now, more than ever, legal reform and community empowerment and mobilisation are necessary to realize the rights and health of people affected by HIV.

  11. Plasma endocannabinoid levels in lean, overweight and obese humans: relationships with intestinal permeability markers, inflammation and incretin secretion.

    Science.gov (United States)

    Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V; Argueta, Donovan A; Rayner, Christopher K; Feinle-Bisset, Christine; Young, Richard L

    2018-02-13

    Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation, however little is known of these effects in humans. This study aimed to: (i) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl-sn-glycerol (2-AG) and OEA in humans, and (ii) examine relationships with intestinal permeability, inflammation markers and incretin hormone secretion. 20 lean, 18 overweight and 19 obese participants underwent intraduodenal Intralipid® infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumour necrosis factor-α (TNF-α), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and toll-like receptor-4 (TLR4) (RT-PCR), were assessed. Fasting plasma AEA was increased in obese, compared with lean and overweight (Plean (Plean and overweight. The relationships between plasma AEA with duodenal ZO-1 and IAP, and GIP, suggest that altered endocannabinoid signalling may contribute to changes in intestinal permeability, inflammation and incretin release in human obesity.

  12. Understanding how pain education causes changes in pain and disability: protocol for a causal mediation analysis of the PREVENT trial

    Directory of Open Access Journals (Sweden)

    Hopin Lee

    2015-07-01

    Discussion and significance: Mediation analysis of clinical trials can estimate how much the total effect of the treatment on the outcome is carried through an indirect path. Using mediation analysis to understand these mechanisms can generate evidence that can be used to tailor treatments and optimise treatment effects. In this study, the causal mediation effects of a pain education intervention for acute non-specific low back pain will be estimated. This knowledge is critical for further development and refinement of interventions for conditions such as low back pain.

  13. Histone deacetylase mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity

    Science.gov (United States)

    Ranganathan, Punithavathi; Hamad, Rania; Mohamed, Riyaz; Jayakumar, Calpurnia; Muthusamy, Thangaraju; Ramesh, Ganesan

    2015-01-01

    Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin up-regulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently up-regulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID:26509586

  14. Development and validation of a quantitative method for the determination of 12 endocannabinoids and related compounds in human plasma using liquid chromatography-tandem mass spectrometry

    NARCIS (Netherlands)

    Balvers, M.G.J.; Verhoeckx, K.C.M.; Witkamp, R.F.

    2009-01-01

    A sensitive and specific LC¿MS/MS method for the quantification of the endocannabinoids and related structures anandamide, 2-arachidonoyl glycerol, 2-arachidonyl glycerol ether, O-arachidonoyl ethanolamide, dihomo-¿-linolenoyl ethanolamide, docosatetraenoyl ethanolamide, N-arachidonoyl dopamine,

  15. Impact of cannabis, cannabinoids and endocannabinoids in the lungs

    Directory of Open Access Journals (Sweden)

    Caroline Turcotte

    2016-09-01

    Full Text Available Since the identification of cannabinoid receptors in the 1990s, a research field has been dedicated to exploring the role of the cannabinoid system in immunity and the inflammatory response in human tissues and animal models. Although the cannabinoid system is present and crucial in many human tissues, studying the impact of cannabinoids on the lungs is particularly relevant because of their contact with exogenous cannabinoids is the context of marijuana consumption. In the past two decades, the scientific community has gathered a large body of evidence supporting that the activation of the cannabinoid system alleviates pain and reduces inflammation. In the context of lung inflammation, exogenous and endogenous cannabinoids have shown therapeutic potential because of their inhibitory effects on immune cell recruitment and functions. On the other hand, cannabinoids were shown to be deleterious to lung function and to impact respiratory pathogen clearance. In this review, we present the existing data on the regulation of lung immunity and inflammation by phytocannabinoids, synthetic cannabinoids and endocannabinoids.

  16. HIV prevention fatigue and HIV treatment optimism among young men who have sex with men

    Science.gov (United States)

    Macapagal, Kathryn; Birkett, Michelle; Janulis, Patrick; Garofalo, Robert; Mustanski, Brian

    2017-01-01

    HIV prevention fatigue (the sense that prevention messages are tiresome) and being overly optimistic about HIV treatments are hypothesized to increase HIV risk behavior. Little research has examined these constructs and their correlates among young men who have sex with men (YMSM), who are at high risk for HIV. YMSM (N = 352; M age = 20; 50% Black) completed measures of prevention fatigue, treatment optimism, HIV risk behaviors, and HIV-related knowledge and attitudes during a longitudinal study. Overall, YMSM reported low levels of HIV prevention fatigue and treatment optimism. Path analysis (n = 307) indicated that greater prevention fatigue and treatment optimism predicted higher rates of condomless sex, but condomless sex did not predict later increases in prevention fatigue or treatment optimism. Results are inconsistent with the hypothesis of high prevention fatigue and treatment optimism among YMSM and point to potential causal relationships among these variables and condomless sex. PMID:28825861

  17. Mediators of Effects of a Selective Family-Focused Violence Prevention Approach for Middle School Students

    Science.gov (United States)

    2013-01-01

    This study examined how parenting and family characteristics targeted in a selective prevention program mediated effects on key youth proximal outcomes related to violence perpetration. The selective intervention was evaluated within the context of a multi-site trial involving random assignment of 37 schools to four conditions: a universal intervention composed of a student social-cognitive curriculum and teacher training, a selective family-focused intervention with a subset of high-risk students, a condition combining these two interventions, and a no-intervention control condition. Two cohorts of sixth-grade students (total N=1,062) exhibiting high levels of aggression and social influence were the sample for this study. Analyses of pre-post change compared to controls using intent-to-treat analyses found no significant effects. However, estimates incorporating participation of those assigned to the intervention and predicted participation among those not assigned revealed significant positive effects on student aggression, use of aggressive strategies for conflict management, and parental estimation of student’s valuing of achievement. Findings also indicated intervention effects on two targeted family processes: discipline practices and family cohesion. Mediation analyses found evidence that change in these processes mediated effects on some outcomes, notably aggressive behavior and valuing of school achievement. Results support the notion that changing parenting practices and the quality of family relationships can prevent the escalation in aggression and maintain positive school engagement for high-risk youth. PMID:21932067

  18. Neonatal pressure ulcers: prevention and treatment

    Directory of Open Access Journals (Sweden)

    García-Molina P

    2017-09-01

    Full Text Available Pablo García-Molina,1,2 Alba Alfaro-López,1 Sara María García-Rodríguez,1 Celia Brotons-Payá,1 Mari Carmen Rodríguez-Dolz,1,2 Evelin Balaguer-López1,2 1Department of Nursing, University of Valencia, 2Research Group of Pediatric Nutrition, INCLIVA Foundation, Valencia, Spain Abstract: Health professionals should be prepared to respond to the needs of hospitalized neonates. The health team must consider multiple situations, where the neonate is at risk of having an adverse effect. One of the main interventions that health professionals must practice when interacting with hospitalized newborns is skin care. Neonates often suffer from diaper rash or intravenous drugs extravasation. Recently, hospitalized neonates and especially those in an unstable clinical situation are also at a risk of developing pressure ulcers. The presence of a pressure ulcer in a neonate can lead to serious problems to survival (eg, sepsis, clinical instability. This is the reason why, with this literature review, we attempt to answer questions from health professionals caring for neonates about the prevention and treatment of pressure ulcers. Keywords: infant, pressure ulcer, treatment, prevention, wound, assessment

  19. Perception and practice of malaria prevention and treatment among ...

    African Journals Online (AJOL)

    McRoy

    and practices related to its prevention and treatment among the women of. Kuje Area ... five in Kuje had poor knowledge of the cause of malaria and its prevention method, and ... serious that every 30 seconds, an under- five child ... Zα = percentage point of normal distribution .... Up to 60 - 70% of the population had either.

  20. Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

    Science.gov (United States)

    Scheggia, D; Zamberletti, E; Realini, N; Mereu, M; Contarini, G; Ferretti, V; Managò, F; Margiani, G; Brunoro, R; Rubino, T; De Luca, M A; Piomelli, D; Parolaro, D; Papaleo, F

    2018-04-01

    The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

  1. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Bygbjerg, Ib Christian; Magnussen, Pascal

    2008-01-01

    OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non-randomized comm......OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non......-randomized community trial was implemented in 21 community clusters (intervention) and four clusters where health units provided routine IPTp (control). The primary outcome measures were access and adherence to IPTp, number of malaria episodes, prevalence of anaemia, and birth weight. Numbers of live births, abortions......, still births, and maternal and child deaths were secondary endpoints. FINDINGS: 1404 (67.5%) of 2081 with the new delivery system received two doses of sulfadoxine-pyrimethamine versus 281 (39.9%) of 704 with health units (P malaria episodes decreased from 906 (49...

  2. Leptin - a link between obesity and osteoarthritis. applications for prevention and treatment.

    Science.gov (United States)

    Vuolteenaho, Katriina; Koskinen, Anna; Moilanen, Eeva

    2014-01-01

    Osteoarthritis (OA) is the most common cause of musculoskeletal disability and pain in the world. The current drug treatment for OA is symptom relieving, and there is an urgent need for treatments that could retard, prevent or repair cartilage destruction in OA. Obesity is a major risk factor for OA. Traditionally, it has been thought to contribute to the development of OA by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, because obesity is also linked to OA in the hand and finger joints. Recent studies have shown that adipocytokine leptin is a possible link between obesity and OA: Leptin levels in synovial fluid are increased in obese patients, leptin receptor (Ob-R) is expressed in cartilage, and leptin induces the production of matrix metalloproteinases (MMPs), pro-inflammatory mediators and nitric oxide (NO) in chondrocytes. Furthermore, according to the very recent findings, not only leptin levels in the joint but also leptin sensitivity in the cartilage are enhanced in obese OA patients. The findings supporting leptin as a causative link between obesity and OA offer leptin as a potential target to the development of disease-modifying drugs for osteoarthritis (DMOAD), especially for obese patients. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

  3. CHALLENGES IN TREATMENT OF RENAL GRAFT ACUTE ANTIBODY-MEDIATED REJECTION

    Directory of Open Access Journals (Sweden)

    A. I. Sushkov

    2016-01-01

    Full Text Available Diagnostic criteria and treatment protocols for acute antibody-mediated rejection (AMR of kidney allograft remain controversial. We report the case of early severe AMR after primary kidney transplantation. The graft removal was considered in the absence of treatment efficacy and in the presence of systemic infl ammatory response syndrome. However, at surgery the graft looked normal and it was not removed. The repeated treatment course (plasmapheresis, antithymocyte globulin, intravenous immunoglobulin and rituximab was effective. The patient has good and stable graft function in 1 year after transplantation. 

  4. Periodontal treatment for preventing adverse pregnancy outcomes

    DEFF Research Database (Denmark)

    Schwendicke, Falk; Karimbux, Nadeem; Allareddy, Veerasathpurush

    2015-01-01

    OBJECTIVES: Periodontal treatment might reduce adverse pregnancy outcomes. The efficacy of periodontal treatment to prevent preterm birth, low birth weight, and perinatal mortality was evaluated using meta-analysis and trial sequential analysis. METHODS: An existing systematic review was updated...... risk of random errors. RESULTS: Thirteen randomized clinical trials evaluating 6283 pregnant women were meta-analyzed. Four and nine trials had low and high risk of bias, respectively. Overall, periodontal treatment had no significant effect on preterm birth (odds ratio [95% confidence interval] 0.......79 [0.57-1.10]) or low birth weight (0.69 [0.43-1.13]). Trial sequential analysis demonstrated that futility was not reached for any of the outcomes. For populations with moderate occurrence (periodontal treatment was not efficacious for any of the outcomes...

  5. Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling

    Directory of Open Access Journals (Sweden)

    Rosanna Chianese

    2013-01-01

    Full Text Available Reproductive functions are regulated both at central (brain and gonadal levels. In this respect, the endocannabinoid system (eCS has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH. Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.

  6. [Advances in the research of prevention and treatment of postburn contractures of hand].

    Science.gov (United States)

    Wang, K A; Wu, G S; Sun, Y; Xia, Z F

    2017-01-20

    Scar contracture deformity, which can lead to dysfunction of hand and low quality of life, is one of the common complication after hand burns. The prevention measures of scar contracture after hand burns include large skin grafting, prevention of infection, insistence on wearing pressure gloves, use of silicone sheets, wearing orthosis, accepting proper physical therapy, and early functional exercise. The primary treatments of postburn contractures of the hand are surgery, drugs, laser treatment, and rehabilitation therapy. Excision of scars, release of muscle, joints or bones, and soft tissue transplantation are the core of surgery. Laser treatment has a bright future but still needs to be further studied. Additionally, some novel treatments such as molecular targeted therapy, cell therapy, fat injection, and botulinum toxin injection will play important roles in prevention and treatment of postburn contractures in the future. The purpose of this article is to review the literature concerning postburn contractures of the hand, and summarize the present situation of prevention and treatment of such disease comprehensively.

  7. HIV treatment as prevention: debate and commentary--will early infection compromise treatment-as-prevention strategies?

    Directory of Open Access Journals (Sweden)

    Myron S Cohen

    Full Text Available Universal HIV testing and immediate antiretroviral therapy for infected individuals has been proposed as a way of reducing the transmission of HIV and thereby bringing the HIV epidemic under control. It is unclear whether transmission during early HIV infection--before individuals are likely to have been diagnosed with HIV and started on antiretroviral therapy--will compromise the effectiveness of treatment as prevention. This article presents two opposing viewpoints by Powers, Miller, and Cohen, and Williams and Dye, followed by a commentary by Fraser.

  8. Electroacupuncture Potentiates Cannabinoid Receptor-Mediated Descending Inhibitory Control in a Mouse Model of Knee Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Xiao-Cui Yuan

    2018-04-01

    Full Text Available Knee osteoarthritis (KOA is a highly prevalent, chronic joint disorder, which can lead to chronic pain. Although electroacupuncture (EA is effective in relieving chronic pain in the clinic, the involved mechanisms remain unclear. Reduced diffuse noxius inhibitory controls (DNIC function is associated with chronic pain and may be related to the action of endocannabinoids. In the present study, we determined whether EA may potentiate cannabinoid receptor-mediated descending inhibitory control and inhibit chronic pain in a mouse model of KOA. We found that the optimized parameters of EA inhibiting chronic pain were the low frequency and high intensity (2 Hz + 1 mA. EA reversed the reduced expression of CB1 receptors and the 2-arachidonoylglycerol (2-AG level in the midbrain in chronic pain. Microinjection of the CB1 receptor antagonist AM251 into the ventrolateral periaqueductal gray (vlPAG can reversed the EA effect on pain hypersensitivity and DNIC function. In addition, CB1 receptors on GABAergic but not glutamatergic neurons are involved in the EA effect on DNIC function and descending inhibitory control of 5-HT in the medulla, thus inhibiting chronic pain. Our data suggest that endocannabinoid (2-AG-CB1R-GABA-5-HT may be a novel signaling pathway involved in the effect of EA improving DNIC function and inhibiting chronic pain.

  9. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available The "classic" endocannabinoid (eCB system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA and 2-arachidonoylglycerol (2-AG, and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis also modulate the eCB system.Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  10. The Modern Approaches to Prevention and Treatment of NSAID-Induced Gastropathy

    OpenAIRE

    S.M. Tkach

    2013-01-01

    The article presents recent data on the different tactics for treatment and prevention of NSAID-induced gastropathy. On the basis of the carried out analysis it has been concluded that the most effective strategies are the use of proton pomp inhibitors and eradication of  infection. The use of double doses of proton pomp inhibitors allows improving the efficacy of prevention and treatment of NSAID-induced gastropathy.

  11. The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers

    DEFF Research Database (Denmark)

    Khademi, M.; Bornsen, L.; Rafatnia, F.

    2009-01-01

    BACKGROUND: Natalizumab affects systemic cytokine expressions and clinical course in relapsing-remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP...... showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. CONCLUSIONS: Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow...... increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy Udgivelsesdato...

  12. Prediabetes Screening and Treatment in Diabetes Prevention: The Impact of Physician Attitudes.

    Science.gov (United States)

    Mainous, Arch G; Tanner, Rebecca J; Scuderi, Christopher B; Porter, Maribeth; Carek, Peter J

    Detection and treatment of prediabetes is an effective strategy in diabetes prevention. However, most patients with prediabetes are not identified. Our objective was to evaluate the relationship between attitudes toward prediabetes as a clinical construct and screening/treatment behaviors for diabetes prevention among US family physicians. An electronic survey of a national sample of academic family physicians (n 1248) was conducted in 2016. Attitude toward prediabetes was calculated using a summated scale assessing agreement with statements regarding prediabetes as a clinical construct. Perceived barriers to diabetes prevention, current strategies for diabetes prevention, and perceptions of peers were also examined. Physicians who have a positive attitude toward prediabetes as a clinical construct are more likely to follow national guidelines for screening (58.4% vs 44.4; P prediabetes (36.4% vs 20.9%; P prediabetes varies significantly, and this variation is related to treatment/screening behaviors for diabetes prevention. © Copyright 2016 by the American Board of Family Medicine.

  13. Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies

    Science.gov (United States)

    Solé, Brisa; Jiménez, Esther; Torrent, Carla; Reinares, Maria; Bonnin, Caterina del Mar; Torres, Imma; Varo, Cristina; Grande, Iria; Valls, Elia; Salagre, Estela; Sanchez-Moreno, Jose; Martinez-Aran, Anabel; Carvalho, André F

    2017-01-01

    Abstract Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients’ psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments. This review provides an overview of the available data from studies examining treatments for cognitive dysfunction in bipolar disorder as well as potential novel treatments, from both pharmacological and psychological perspectives. All these data encourage the development of further studies to find effective strategies to prevent and treat cognitive impairment associated with bipolar disorder. These efforts may ultimately lead to an improvement of psychosocial functioning in these patients. PMID:28498954

  14. Why did soft drink consumption decrease but screen time not? Mediating mechanisms in a school-based obesity prevention program

    OpenAIRE

    Chin A Paw, M.J.M.; Singh, A.S.; Brug, J.; Mechelen, van, W.

    2008-01-01

    Abstract Objectives This paper aims to identify the mediating mechanisms of a school-based obesity prevention program (DOiT). Methods The DOiT-program was implemented in Dutch prevocational secondary schools and evaluated using a controlled, cluster-randomised trial (September 2003 to May 2004). We examined mediators of effects regarding (1) consumption of sugar containing beverages (SCB); (2) consumption of high caloric snacks; (3) screen-viewing behaviour; and (4) active commuting to school...

  15. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

    Science.gov (United States)

    Markworth, James F.; Vella, Luke; Lingard, Benjamin S.; Tull, Dedreia L.; Rupasinghe, Thusitha W.; Sinclair, Andrew J.; Maddipati, Krishna Rao

    2013-01-01

    Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0–3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a

  16. mediation: R package for causal mediation analysis

    OpenAIRE

    Tingley, Dustin; Yamamoto, Teppei; Hirose, Kentaro; Keele, Luke; Imai, Kosuke

    2012-01-01

    In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting su...

  17. The Modern Approaches to Prevention and Treatment of NSAID-Induced Gastropathy

    Directory of Open Access Journals (Sweden)

    S.M. Tkach

    2013-11-01

    Full Text Available The article presents recent data on the different tactics for treatment and prevention of NSAID-induced gastropathy. On the basis of the carried out analysis it has been concluded that the most effective strategies are the use of proton pomp inhibitors and eradication of  infection. The use of double doses of proton pomp inhibitors allows improving the efficacy of prevention and treatment of NSAID-induced gastropathy.

  18. Ciguatera Fish Poisoning: Treatment, Prevention and Management

    Directory of Open Access Journals (Sweden)

    Andrew Reich

    2008-08-01

    Full Text Available Ciguatera Fish Poisoning (CFP is the most frequently reported seafood-toxin illness in the world, and it causes substantial physical and functional impact. It produces a myriad of gastrointestinal, neurologic and/or cardiovascular symptoms which last days to weeks, or even months. Although there are reports of symptom amelioration with some interventions (e.g. IV mannitol, the appropriate treatment for CFP remains unclear to many physicians. We review the literature on the treatments for CFP, including randomized controlled studies and anecdotal reports. The article is intended to clarify treatment options, and provide information about management and prevention of CFP, for emergency room physicians, poison control information providers, other health care providers, and patients.

  19. Ciguatera fish poisoning: treatment, prevention and management.

    Science.gov (United States)

    Friedman, Melissa A; Fleming, Lora E; Fernandez, Mercedes; Bienfang, Paul; Schrank, Kathleen; Dickey, Robert; Bottein, Marie-Yasmine; Backer, Lorraine; Ayyar, Ram; Weisman, Richard; Watkins, Sharon; Granade, Ray; Reich, Andrew

    2008-01-01

    Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world, and it causes substantial physical and functional impact. It produces a myriad of gastrointestinal, neurologic and/or cardiovascular symptoms which last days to weeks, or even months. Although there are reports of symptom amelioration with some interventions (e.g. IV mannitol), the appropriate treatment for CFP remains unclear to many physicians. We review the literature on the treatments for CFP, including randomized controlled studies and anecdotal reports. The article is intended to clarify treatment options, and provide information about management and prevention of CFP, for emergency room physicians, poison control information providers, other health care providers, and patients.

  20. Ciguatera Fish Poisoning: Treatment, Prevention and Management

    Science.gov (United States)

    Friedman, Melissa A.; Fleming, Lora E.; Fernandez, Mercedes; Bienfang, Paul; Schrank, Kathleen; Dickey, Robert; Bottein, Marie-Yasmine; Backer, Lorraine; Ayyar, Ram; Weisman, Richard; Watkins, Sharon; Granade, Ray; Reich, Andrew

    2008-01-01

    Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world, and it causes substantial physical and functional impact. It produces a myriad of gastrointestinal, neurologic and/or cardiovascular symptoms which last days to weeks, or even months. Although there are reports of symptom amelioration with some interventions (e.g. IV mannitol), the appropriate treatment for CFP remains unclear to many physicians. We review the literature on the treatments for CFP, including randomized controlled studies and anecdotal reports. The article is intended to clarify treatment options, and provide information about management and prevention of CFP, for emergency room physicians, poison control information providers, other health care providers, and patients. PMID:19005579

  1. Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

    Science.gov (United States)

    Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

    2016-10-01

    In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

  2. Dental treatment and caries prevention preceding treatment under general anaesthesia in healthy children and adolescents: a retrospective cohort study.

    Science.gov (United States)

    Grindefjord, M; Persson, J; Jansson, L; Tsilingaridis, G

    2018-04-01

    This was to examine healthy children and adolescents treated under general anaesthesia (GA) and a matched control group not receiving GA to compare treatment and preventive care received prior to GA treatment. This retrospective cohort study included 71 healthy subjects and 213 age- and gender-matched control subjects. The treatment group had been consecutively referred from the Public Dental Health Service (PDS) in Stockholm to the Department of Paediatric Dentistry, Eastman Institute, Stockholm during 2006-2007. Data was extracted from the patient records at the PDS, including variables such as number of dental visits, treatment/prophylaxis prior to GA, number of missed and cancelled appointments, and number of decayed teeth. On average, the treatment group had significantly more decayed teeth (p general dentists to paediatric specialists had no behaviour management treatment and nearly half, no preventive treatment, despite receiving significantly more operative treatment compared with matched controls. General dentists should target high caries-risk patients for additional behaviour management and preventive care to reduce the need for treatment under GA.

  3. The Importance of Diet and Gut Health to the Treatment and Prevention of Mental Disorders.

    Science.gov (United States)

    Dawson, S L; Dash, S R; Jacka, F N

    2016-01-01

    The departure from traditional lifestyles and the rising disease burden of mental disorders are increasing global health concerns. Changes in diet around the world mean that populations are now increasingly reliant on highly processed, poor quality foods, which have been linked to increased risk for mental disorder. Conversely, a nutrient-rich diet is understood to be protective of mental health, and researchers are now aiming to understand the biological underpinnings of this relationship. The gut microbiota has been proposed as a key mediator of this link, given its association with both diet and mental health. Importantly, several critical "windows of opportunity" for prevention and intervention have been identified, particularly early life and adolescence; these are periods of rapid development and transition that provide a foundation for future health. Strategies that promote overall diet quality, high in fiber and nutrients, have been linked to increased microbial diversity and gut health. Improving diet quality and subsequent gut health may have benefits for individuals' mental health, as well as the mental health of future generations. Here we discuss specific, targeted dietary and gut focused strategies for the prevention and treatment of mental disorder. © 2016 Elsevier Inc. All rights reserved.

  4. Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.

    Science.gov (United States)

    Smaga, Irena; Bystrowska, Beata; Gawliński, Dawid; Pomierny, Bartosz; Stankowicz, Piotr; Filip, Małgorzata

    2014-08-01

    The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.

  5. Impact of health education on home treatment and prevention

    African Journals Online (AJOL)

    Emmanuel Ameh

    effect on perception (P < .001), knowledge (P < .001), malaria prevention practice ... Caregivers should also be integrated into malaria ... intention (p=0,031) et le type de traitement administré pour fièvre chez l'enfant (p=0,048). .... person consulting and cost of treatment. .... may play a greater role in the choice of treatment.

  6. Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity.

    Directory of Open Access Journals (Sweden)

    Andrei V Derbenev

    Full Text Available Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV. Whole-cell patch-clamp recordings revealed that DEX (1-10 µM rapidly (i.e. within three minutes increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM, and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.

  7. The cost of prevention and treatment of pressure ulcers: A systematic review.

    Science.gov (United States)

    Demarré, Liesbet; Van Lancker, Aurélie; Van Hecke, Ann; Verhaeghe, Sofie; Grypdonck, Maria; Lemey, Juul; Annemans, Lieven; Beeckman, Dimitri

    2015-11-01

    Pressure ulcers impose a substantial financial burden. The need for high-quality health care while expenditures are constrained entails the interest to calculate the cost of preventing and treating pressure ulcers and their impact on patients, healthcare, and society. The aim of this paper is to provide insight into the cost of pressure ulcer prevention and treatment in an adult population. A systematic literature review was performed to conform the Cochrane Collaboration guidelines for systematic reviews. The search strategy contained index terms and key words related to pressure ulcers and cost. The search was performed in Medline, CINAHL, Web of Science, The Cochrane Library, Embase, and EconLit covering articles up to September 2013. Reference lists and conference abstracts were screened. Articles were eligible if they reported on direct medical cost of pressure ulcer prevention or treatment, and provided national cost estimates, cost per patient, or cost per patient per day. The Consensus on Health Economic Criteria checklist was used to assess methodological quality of the included studies. In total, 2542 records were retrieved. After assessing eligibility, 17 articles were included. Five articles reported on both the cost of prevention and treatment, three articles reported on cost of prevention, and nine articles reported on the cost of pressure ulcer treatment. All articles were published between 2001 and 2013. Cost of pressure ulcer prevention per patient per day varied between 2.65 € to 87.57 € across all settings. Cost of pressure ulcer treatment per patient per day ranged from 1.71 € to 470.49 € across different settings. The methodological heterogeneity among studies was considerable, and encompassed differences regarding type of health economic design, perspective, cost components, and health outcomes. Cost of pressure ulcer prevention and treatment differed considerable between studies. Although the cost to provide pressure ulcer prevention

  8. Preventive aspects in children's caries treatments preceding dental care under general anaesthesia.

    Science.gov (United States)

    Savanheimo, Nora; Vehkalahti, Miira M

    2008-03-01

    In Helsinki Public Dental Service (PDS) the Special Oral Health Care Unit (SOHCU) provides comprehensive dental treatments under general anaesthesia (GA). For the present study, all dental treatment given under GA for generally healthy children (n = 102) below 16 years of age (range 2.3-15.8) during a 1-year period and dental treatment and visits of these children in the preceding 2 years in Helsinki PDS was recorded in detail. These children were referred to the SOHCU because of serious difficulties in dental care due to large treatment needs or failures in psychological and chemical management, including sedation. To describe treatments given to generally healthy children under GA and to evaluate preventive aspects of their dental care in the preceding 2 years. The study was cross-sectional and retrospective. Data came from the patients' individual records. Treatments under GA included an average of 6.0 restorations (SD = 2.7, range 0-12) and 1.7 extractions (SD = 2.1, range 0-10). In the 2 preceding years, these children had visited dentist an average of 5.1 times (SD = 2.7, range 1-14) with an average of 2.4 restorations (SD = 1.9, range 0-12) and 0.5 extractions (SD = 1.4, range 0-10). Of the restorations made, 36% were temporary. Of all visits, those with an operative approach accounted for 35%, preventive for 37%, operative and preventive for 5%, and visits with total uncooperation for 23%. Of the children, 90% had at least one preventive visit. Children treated under conscious sedation in the preceding 2 years received less prevention (P = 0.02). Remaining without preventive measures was most likely for those children exhibiting visits with total uncooperation (odds ratio = 4.6; P = 0.004) and for those receiving numerous temporary fillings (odds ratio = 4.1; P = 0.0005). The uncooperative high-caries children pose a demanding challenge to PDS. The early identification of high-caries risk and efforts of intensive preventive care are in key position to

  9. Using therapeutic jurisprudence and preventive law to examine disputants' best interests in mediating cases about physicians' practices: a guide for medical regulators.

    Science.gov (United States)

    Ferris, Lorraine E

    2004-01-01

    Therapeutic jurisprudence (TJ) and preventive law (PL) are used as two theoretical perspectives from which to examine the best interests of parties in mediation because of a dispute about a physician's practice. The focus is mediation provided by and/or for the medical regulator. The paper reviews the literature on TJ and PL, and their relationship to mediation, and demonstrates how medical regulators could benefit by working within a framework reflecting both these perspectives providing it does not involve an egregious matter. A TJ and PL framework would be of particular value in identifying cases for mediation and in evaluating resolutions to mediated disputes.

  10. Unhealthy weight control behaviors mediate the association between weight status and weight-specific health-related quality of life in treatment-seeking youth who are obese.

    Science.gov (United States)

    Lim, Crystal S; Gowey, Marissa A; Cohen, Megan J; Silverstein, Janet; Janicke, David M

    2017-03-01

    Examine whether unhealthy and extreme weight control behaviors (WCBs) mediate the relationship between youth weight status and disease-specific health-related quality of life (HRQOL) in treatment-seeking youth who are overweight and obese (OV/OB). 82 youth 10-17 years of age who were OV/OB and attending an outpatient obesity-related medical appointment completed measures assessing unhealthy and extreme WCBs and disease-specific HRQOL. Parents completed a demographic questionnaire and medical staff measured youth height and weight. Regression analyses revealed that unhealthy WCBs mediated the associations between youth weight status and emotional and social avoidance disease-specific HRQOL, such that higher body mass index (BMI) predicted unhealthy WCBs, which were ultimately associated with poorer emotional and social HRQOL. Mediation analyses were not significant for total, physical, teasing/marginalization, and positive attributes disease-specific HRQOL. In addition, extreme WCBs did not mediate the association between youth weight status and any subscales of the disease-specific HRQOL measure. Weight status is an important predictor of disease-specific HRQOL in OV/OB youth; however, the association with emotional and social HRQOL is partially accounted for by youth engagement in unhealthy WCBs. Clinicians and researchers should assess WCBs and further research should explore and evaluate appropriate intervention strategies to address unhealthy WCBs in pediatric weight management prevention and treatment efforts.

  11. Hippocampal Protein Kinase C Signaling Mediates the Short-Term Memory Impairment Induced by Delta9-Tetrahydrocannabinol.

    Science.gov (United States)

    Busquets-Garcia, Arnau; Gomis-González, Maria; Salgado-Mendialdúa, Victòria; Galera-López, Lorena; Puighermanal, Emma; Martín-García, Elena; Maldonado, Rafael; Ozaita, Andrés

    2018-04-01

    Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

  12. Prevention and treatment of complications following percutaneous nephrolithotomy

    NARCIS (Netherlands)

    Skolarikos, Andreas; de la Rosette, Jean

    2008-01-01

    PURPOSE OF REVIEW: The aim of this article is to identify classification and grading systems of percutaneous nephrolithotomy-related complications and evidence for the prevention and treatment of these complications. RECENT FINDINGS: A total complication rate of up to 83% following percutaneous

  13. [Pain in herpes zoster: Prevention and treatment].

    Science.gov (United States)

    Calvo-Mosquera, G; González-Cal, A; Calvo-Rodríguez, D; Primucci, C Y; Plamenov-Dipchikov, P

    Shingles is a painful rash that results from reactivation of latent varicella-zoster virus in the dorsal root ganglia or cranial nerves. In this article an update is presented on the prevention and pharmacological treatment of the secondary pain from the virus infection. The most effective way to prevent post-herpetic neuralgia and its consequences is the prevention of herpes itself. A live attenuated vaccine (the Oka strain varicella zoster virus) has been available for several years, and is approved in adults aged 50 years old. Although this vaccine has shown to be effective against herpes zoster and post-herpetic neuralgia, its effectiveness decreases with age and is contraindicated in patients with some form of immunosuppression. Today the recombinant vaccines provide an alternative, and may be administered to immunocompromised persons. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  14. mediation: R Package for Causal Mediation Analysis

    Directory of Open Access Journals (Sweden)

    Dustin Tingley

    2014-09-01

    Full Text Available In this paper, we describe the R package mediation for conducting causal mediation analysis in applied empirical research. In many scientific disciplines, the goal of researchers is not only estimating causal effects of a treatment but also understanding the process in which the treatment causally affects the outcome. Causal mediation analysis is frequently used to assess potential causal mechanisms. The mediation package implements a comprehensive suite of statistical tools for conducting such an analysis. The package is organized into two distinct approaches. Using the model-based approach, researchers can estimate causal mediation effects and conduct sensitivity analysis under the standard research design. Furthermore, the design-based approach provides several analysis tools that are applicable under different experimental designs. This approach requires weaker assumptions than the model-based approach. We also implement a statistical method for dealing with multiple (causally dependent mediators, which are often encountered in practice. Finally, the package also offers a methodology for assessing causal mediation in the presence of treatment noncompliance, a common problem in randomized trials.

  15. Therapist-Aided Exposure for Women with Lifelong Vaginismus: Mediators of Treatment Outcome: A Randomized Waiting List Control Trial.

    Science.gov (United States)

    Ter Kuile, Moniek M; Melles, Reinhilde J; Tuijnman-Raasveld, Charlotte C; de Groot, Helen E; van Lankveld, Jacques J D M

    2015-08-01

    Therapist-aided exposure seems an effective treatment for lifelong vaginismus, but mechanisms of action have not yet been established. The purpose of the present study was to investigate whether treatment outcome of a therapist-aided exposure treatment was mediated by changes in positive and negative penetration beliefs or feelings of sexual disgust. Participants with lifelong vaginismus were allocated at random to a 3-month exposure (n = 35) or a waiting list control condition (n = 35). Full intercourse was assessed daily during 12 weeks. Secondary outcome measures (complaints about vaginismus and coital pain) were assessed at baseline and after 12 weeks. Possible mediators: penetration beliefs (catastrophic pain beliefs, genital incompatibility beliefs, perceived control beliefs) and feelings of sexual disgust were assessed at baseline and 6 weeks. Treatment outcome (coital frequency, symptoms of vaginismus, and coital pain) at 12 weeks was mediated by changes in negative and positive penetration beliefs at 6 weeks, in particular by more pronounced reduction of catastrophic pain penetration beliefs. No evidence was found that changes in feelings of sexual disgust mediated treatment outcome. The results strongly suggest that therapist-aided exposure affects negative penetration beliefs and that these changes in negative penetration beliefs mediate treatment outcome in women with lifelong vaginismus. Implications for treatment are discussed. © 2015 International Society for Sexual Medicine.

  16. Challenges in HIV vaccine research for treatment and prevention

    Directory of Open Access Journals (Sweden)

    Barbara eEnsoli

    2014-09-01

    Full Text Available Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug.Further, a residual immune dysregulation associated to chronic immune activation and incomplete restoration of B and T cell subsets, together with HIV DNA persistence in reservoirs, are still unmet needs of the highly active antiretroviral therapy (HAART, causing novel non-AIDS related diseases that account for a higher risk of death even in virologically suppressed patients. These ART unmet needs represent a problem, which is expected to increase by ART roll out. Further, in countries such as South Africa, where 6 millions of individuals are infected, ART appears unable to contain the epidemics. Regretfully, all the attempts at developing a preventative vaccine have been largely disappointing. However, recent therapeutic immunization strategies have opened new avenues for HIV treatment, which might be exploitable also for preventative vaccine approaches. For example, immunization strategies aimed at targeting key viral products responsible of virus transmission, activation and maintenance of virus reservoirs may intensify drug efficacy and lead to a functional cure providing new perspectives also for prevention and future virus eradication strategies. However, this approach imposes new challenges to the scientific community, vaccine developers and regulatory bodies, such as the identification of novel immunological and virological biomarkers to assess efficacy endpoints, taking advantage from the natural history of infection and exploiting lessons from former trials.This review will focus first on recent advancement of therapeutic strategies, then on the progresses made in preventative approaches, discussing concepts and problems for the way ahead for the development of vaccines for HIV treatment

  17. Gene transfection mediated by polyethyleneimine-polyethylene glycol nanocarrier prevents cisplatin-induced spiral ganglion cell damage

    Directory of Open Access Journals (Sweden)

    Guan-gui Chen

    2015-01-01

    Full Text Available Polyethyleneimine-polyethylene glycol (PEI-PEG, a novel nanocarrier, has been used for transfection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein (XIAP in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Auditory brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.

  18. State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

    Science.gov (United States)

    Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

    2011-11-16

    The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

  19. Probiotics for Treatment and Prevention of Urogenital Infections in Women: A Systematic Review.

    Science.gov (United States)

    Hanson, Lisa; VandeVusse, Leona; Jermé, Martha; Abad, Cybéle L; Safdar, Nasia

    2016-05-01

    Probiotics are a complementary and integrative therapy useful in the treatment and prevention of urogenital infections in women. This study extends the work of researchers who systematically investigated the scientific literature on probiotics to prevent or treat urogenital infections. A systematic review was conducted to determine the efficacy of probiotics for prevention and/or treatment of urogenital infections in adult women from January 1, 2008, through June 30, 2015. We searched in CINAHL, MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, Dissertations and Theses, and Alt-HealthWatch. After removing duplicates and studies that did not meet inclusion criteria, 20 studies were reviewed. All included at least one species of Lactobacillus probiotic as an intervention for treatment or prevention of urogenital infections. Data extracted included samples, settings, study designs, intervention types, reported outcomes, follow-up periods, and results. We evaluated all randomized controlled trials for risk of bias and made quality appraisals on all studies. Fourteen of the studies focused on bacterial vaginosis (BV), 3 on urinary tract infections (UTIs), 2 on vulvovaginal candidiasis, and one on human papillomavirus (HPV) as identified on Papanicolaou test. Studies were heterogeneous in terms of design, intervention, and outcomes. Four studies were of good quality, 9 of fair, and 7 poor. Probiotic interventions were effective for treatment and prevention of BV, prevention of recurrences of candidiasis and UTIs, and clearing HPV lesions. No study reported significant adverse events related to the probiotic intervention. The quality of the studies in this systematic review varied. Although clinical practice recommendations were limited by the strength of evidence, probiotic interventions were effective in treatment and prevention of urogenital infections as alternatives or co-treatments. More good quality research is needed to strengthen the body

  20. Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies.

    Science.gov (United States)

    Solé, Brisa; Jiménez, Esther; Torrent, Carla; Reinares, Maria; Bonnin, Caterina Del Mar; Torres, Imma; Varo, Cristina; Grande, Iria; Valls, Elia; Salagre, Estela; Sanchez-Moreno, Jose; Martinez-Aran, Anabel; Carvalho, André F; Vieta, Eduard

    2017-08-01

    Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients' psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments. This review provides an overview of the available data from studies examining treatments for cognitive dysfunction in bipolar disorder as well as potential novel treatments, from both pharmacological and psychological perspectives. All these data encourage the development of further studies to find effective strategies to prevent and treat cognitive impairment associated with bipolar disorder. These efforts may ultimately lead to an improvement of psychosocial functioning in these patients. © The Author 2017. Published by Oxford University Press on behalf of CINP.

  1. Prevention and treatment of complications for thyroid-arterial embolization

    International Nuclear Information System (INIS)

    Yang Jijin; Yuan Min; Tian Jianming; Chen Wei; Yang Chaoai; Hao Qiang; Zou Dajing; Wang Yongchun

    2003-01-01

    Objective: To investigate the complications of thyroid-arterial embolization and their prevention and treatment. Methods: 61 cases of thyroid disorders received the therapy of thyroid-arterial embolization were retrospectively studied. The complications of arterial embolization during or after the procedure were analyzed. How to prevent and deal with these complications were discussed. Results: Sensitivity to contrast media occurred in 1 case and surgical arterial injury in 2. After embolization thyroid storm occurred in 1 patient and all other complications including headache (23 cases), toothache (11 cases), neckache (13 cases), hoarseness (37 cases) were caused by non-target arterial embolization with the most serious one of cerebral infarction (1 case) and another eyelid ptosis (1 case). The cerebral infarct one was treated with some vasodilating drugs and anti-coagulant, all others were given anti-symptomatics or no special treatment. Conclusions: Proper treatment should be ready during thyroid arterial embolization and given in time with occurrence of complications

  2. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    OpenAIRE

    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor...

  3. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats

    Science.gov (United States)

    Vázquez, Mariam; Sánchez, Laura; Rivera, Patricia; Gavito, Ana; Mela, Virginia; Alén, Francisco; Decara, Juan; Suárez, Juan; Giné, Elena; López-Moreno, José Antonio; Chowen, Julie; Rodríguez-de-Fonseca, Fernando; Serrano, Antonia; Viveros, María Paz

    2016-01-01

    Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats

  4. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Pavón

    Full Text Available Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS, which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in

  5. Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis.

    Science.gov (United States)

    Khodoun, Marat V; Kucuk, Zeynep Yesim; Strait, Richard T; Krishnamurthy, Durga; Janek, Kevin; Clay, Corey D; Morris, Suzanne C; Finkelman, Fred D

    2013-12-01

    Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis. We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis. Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which FcγRI, FcγRIII, and/or FcγRIV had been deleted or blocked. Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG(2a)-mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV were probably crucial for its complete inhibition of IgG(2a)-mediated anaphylaxis. IgG(2a)-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils. IgG-mediated anaphylaxis can be induced by ligation of FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology. Published by Mosby, Inc.

  6. Targeting inflammatory pathways by dietary agents for prevention and treatment of cancer

    International Nuclear Information System (INIS)

    Aggarwal, Bharat B.

    2016-01-01

    Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. While acute inflammation that persists for short-term mediates host defense against infections, chronic inflammation that lasts for long-term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors NF-kB and STAT3, two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NFkB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kB; fifth, chemotherapeutic agents and γ-irradiation activate NF-kB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis and metastasis are regulated by NF-kB and STAT3; seventh, suppression of NF-kB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kB and STAT3 activation pathways. Thus, the suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer. We will discuss the potential of nutraceuticals derived from spices and from traditional Indian medicine in suppression of inflammatory pathways and their role inprevention and therapy of cancer. (author)

  7. Strategies for Prevention and Treatment of Trichomonas vaginalis Infections.

    Science.gov (United States)

    Bouchemal, Kawthar; Bories, Christian; Loiseau, Philippe M

    2017-07-01

    The last estimated annual incidence of Trichomonas vaginalis worldwide exceeds that of chlamydia and gonorrhea combined. This critical review updates the state of the art on advances in T. vaginalis diagnostics and strategies for treatment and prevention of trichomoniasis. In particular, new data on treatment outcomes for topical administration of formulations are reviewed and discussed. Copyright © 2017 American Society for Microbiology.

  8. Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

    Science.gov (United States)

    Bedse, Gaurav; Hartley, Nolan D; Neale, Emily; Gaulden, Andrew D; Patrick, Toni A; Kingsley, Philip J; Uddin, Md Jashim; Plath, Niels; Marnett, Lawrence J; Patel, Sachin

    2017-10-01

    Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ 9 -tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis.

    Science.gov (United States)

    Borrelli, Francesca; Aviello, Gabriella; Romano, Barbara; Orlando, Pierangelo; Capasso, Raffaele; Maiello, Francesco; Guadagno, Federico; Petrosino, Stefania; Capasso, Francesco; Di Marzo, Vincenzo; Izzo, Angelo A

    2009-11-01

    Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut. Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically. In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry. Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration. In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.

  10. Prepartum anaemia: prevention and treatment.

    Science.gov (United States)

    Milman, Nils

    2008-12-01

    This review focuses on the occurrence, prevention and treatment of anaemia during pregnancy in Western societies. Iron deficiency anaemia (IDA) is the most prevalent deficiency disorder and the most frequent form of anaemia in pregnant women. Minor causes of anaemia are folate and vitamin B12 deficiency, haemoglobinopathy and haemolytic anaemia. Anaemia is defined as haemoglobin of pregnancy. The prevalence of prepartum anaemia in the third trimester ranges 14-52% in women taking placebo and 0-25% in women taking iron supplements, dependent on the doses of iron. In studies incorporating serum ferritin, the frequency of IDA in placebo-treated women ranges 12-17% and in iron-supplemented women 0-3%. Requirements for absorbed iron increase during pregnancy from 0.8 mg/day in the first trimester to 7.5 mg/day in the third trimester, on the average approximately 4.4 mg/day, and dietary measures are inadequate to reduce the frequency of prepartum IDA. However, IDA is efficiently prevented by oral iron supplements in doses of 30-40 mg ferrous iron taken between meals from early pregnancy to delivery. Treatment of IDA should aim at replenishing body iron deficits by oral and/or intravenous administration of iron. In women with slight to moderate IDA, i.e. haemoglobin of 90-105 g/L, treatment with oral ferrous iron of approximately 100 mg/day between meals is the therapeutic option in the first and second trimester; haemoglobin should be checked after 2 weeks and provided an increase of >or=10 g/L, oral iron therapy has proved effective and should continue. Treatment with intravenous iron is superior to oral iron with respect to the haematological response. Intravenous iron is considered safe in the second and third trimester, while there is little experience in the first trimester. Intravenous iron of 600-1,200 mg should be considered: (1) as second option if oral iron fails to increase haemoglobin within 2 weeks; (2) as first option at profound IDA, i.e. haemoglobin of

  11. Are Graduating Pediatric Residents Prepared to Engage in Obesity Prevention and Treatment?

    Science.gov (United States)

    Frintner, Mary Pat; Liebhart, Janice L; Lindros, Jeanne; Baker, Alison; Hassink, Sandra G

    2016-01-01

    Little information is available to gauge residents' perceived receipt of comprehensive training and preparedness to manage children with obesity in practice. A national, random sample of 1000 graduating pediatric residents were surveyed in 2013 on childhood overweight/obesity and preparedness to prevent and treat obesity. A composite training measure was created by summing the number of areas (10 possible) where training on overweight/obesity was received. Multivariable logistic regression explored relationships of resident and training characteristics to residents' belief that their own counseling on prevention and treatment of overweight/obesity is very effective (vs somewhat/slightly/not effective). Of 625 survey respondents (63% response), most (68-92%) reported receipt of training in each of 10 assessed areas on overweight/obesity prevention, assessment, and treatment. Most residents did not desire more training in the assessed areas; however, 54% wanted more training in motivational interviewing. About one-fourth believed that their own counseling on the prevention of overweight/obesity (26%) and treatment of obesity (22%) was very effective. Residents who rated their ability to use motivational interviewing as very good/excellent were more likely to rate their counseling on both the prevention and treatment of overweight/obesity as very effective (adjusted odds ratio [aOR] 4.33, 95% confidence interval [CI] 2.63-7.13; and aOR 4.69, 95% CI 2.72-8.07, respectively). Residents who received training in all 10 assessed areas were also more likely to rate their counseling on both prevention and treatment as very effective (aOR 2.58, 95% CI 1.61-4.14; aOR 2.41, 95% CI 1.46-3.97, respectively). Comprehensive training on overweight/obesity and inclusion of training in motivational interviewing may help residents feel better prepared to care for children with overweight/obesity. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights

  12. Studies on asymptomatic malaria, prevention and treatment seeking ...

    African Journals Online (AJOL)

    Studies on asymptomatic malaria, prevention and treatment seeking behaviours in Abeokuta, south-west Nigeria. ... Self-diagnosis for the disease was more common (60.8%) among the participants, compared to other measures; seeking laboratory test (26.5%) and clinical diagnosis (9.1%). A good proportion of the ...

  13. Psychosocial influencers and mediators of treatment adherence in haemodialysis patients.

    Science.gov (United States)

    Oh, Hyun Soo; Park, Ji Suk; Seo, Wha Sook

    2013-09-01

    This article is a report of the development and testing of the hypothetical model that illustrates relationships between treatment adherence and its psychosocial influencing factors and to elucidate the direct and indirect (mediating) effects of factors on treatment adherence. Poor adherence has been consistently reported in haemodialysis patients. Much research has showed various influencing factors of adherence, but these studies have failed to identify consistent influencing factors. This study was performed using a non-experimental, cross-sectional design. The study subjects were 150 end-stage renal failure patients on haemodialysis at a university hospital located in Incheon, South Korea. Data were collected over 10 months (June 2010-April 2011). The hypothetical model provided a good fit with data. Haemodialysis-related knowledge, perceived barrier to adherence, self-efficacy on adherence, and healthcare provider support had significant effects on adherence. Self-efficacy was found to mediate barrier-adherence and family support-adherence relationships. Self-efficacy in combination with barrier, family support, and healthcare provider support was found to mediate the depression-adherence relationship. Strategies aimed at the development of successful adherence interventions should focus on reducing perceived barriers and enhancing self-efficacy and knowledge. It can be suggested that efforts to improve the healthcare provider-patient relationship would enhance adherence. In depressive patients, strategies that promote self-efficacy and the support of family or healthcare providers could diminish the negative impact of depression on adherence. © 2013 Blackwell Publishing Ltd.

  14. Effectiveness of Mindfulness-Based Relapse Prevention in opioid Dependence Treatment &Mental Health

    Directory of Open Access Journals (Sweden)

    2008-11-01

    Findings: therapy compliance, retention in treatment, decrease in somatic symptoms, anxiety, social dysfunction and increase in health was significantly in both combination of psychological intervention method than the Naltroxan group. Mindfulness-based on relapse prevention was more effective than CBT relapse prevention in decreasing of, social dysfunction, relapse prevention, increase of therapy compliance, and health. Results: Mindfulness based relapse prevention was superior to CBT and Naltroxan and considerably increased effectiveness of opioid relapse prevention therapy.

  15. Mediators and Moderators of Outcome in the Behavioral Treatment of Childhood Social Phobia

    Science.gov (United States)

    Alfano, Candica A.; Pina, Armando A.; Villalta, Ian K.; Beidel, Deborah C.; Ammerman, Robert T.; Crosby, Lori E.

    2009-01-01

    Data from a study involving 88 youths who participated in one of two randomized controlled treatment trials of Social Effectiveness Therapy for Children reveals that loneliness scores and social effectiveness predicted changes in social anxiety and overall functioning after the treatment. Child-reported loneliness mediated changes in social…

  16. Error prevention in radiotherapy treatments using a record and verify system

    International Nuclear Information System (INIS)

    Navarrete Campos, S.; Hernandez Vitoria, A.; Canellas Anoz, M.; Millan Cebrian, E.; Garcia Romero, A.

    2001-01-01

    Computerized record-and-verify systems (RVS) are being used increasingly to improve the precision of radiotherapy treatments. With the introduction of new treatment devices, such as multileaf or asymmetric collimators and virtual wedges, the responsibility to ensure correct treatment has increased. The purpose of this paper is to present the method that we are following to prevent some potential radiotherapy errors and to point out some errors that can be easily detected using a RVS, through a check of the daily recorded treatment information. We conclude that a RVS prevents the occurrence of many errors, when the settings of the treatment machine do not match the intended parameters within some maximal authorized deviation, and allows to detect easily other potential errors related with a incorrect selection of the treatment patient data. A quality assurance program, including a check of all beam data and a weekly control of the manual and electronic chart, has helped reduce errors. (author)

  17. Evidence of effectiveness of preventive dental care in reducing dental treatment use and related expenditures.

    Science.gov (United States)

    Pourat, Nadereh; Choi, Moonkyung Kate; Chen, Xiao

    2018-02-06

    Preventive dental health services are intended to reduce the likelihood of development of tooth decay and the need for more intensive treatment overtime. The evidence on the effectiveness of preventive dental care in reducing treatment services and expenditures is lagging for adults, particularly those with lower incomes and chronic conditions. We assessed the impact of preventive dental services on dental treatment service use and expenditures overall and by category of service. We calculated the annual numbers of preventive (periodic diagnostic and prophylactic procedures) and treatment (restorative, surgery, prosthodontic, endodontic, and periodontic) services per beneficiary using Medicaid enrollment and claims data for beneficiaries with three categories of conditions (diabetes, heart disease, and respiratory disease) from 10 largest California counties. We used Cragg hurdle exponential regression models controlling for past service use, demographics, length of enrollment, and county. We found that using preventive services in 2005-2007 was associated with higher likelihood and number of treatment dental services used, but associated with lower treatment expenditures in 2008. The reduction in expenditures was noted only in restorative, prosthodontics, and periodontic services. The findings provide much needed evidence of the contribution of preventive dental care in maintaining oral health of low-income adults with chronic conditions and potential for savings to the Medicaid program. Providing lower cost preventive dental care to the individuals with chronic conditions would achieve better oral health and lower treatment expenditures. © 2018 American Association of Public Health Dentistry.

  18. Deep vein thrombosis: diagnosis, treatment, and prevention

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, W.P.; Youngswick, F.D.

    Deep vein thrombosis (DVT) is a dangerous complication that may present after elective foot surgery. Because of the frequency with which DVT occurs in the elderly patient, as well as in the podiatric surgical population, the podiatrist should be acquainted with this entity. A review of the diagnosis, treatment, prevention, and the role of podiatry in the management of DVT is discussed in this paper.

  19. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Nielsen, Morten Frost; Nielsen, T L; Wraae, K

    2010-01-01

    OBJECTIVE: Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants...... of the CB1 receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution. DESIGN AND METHODS: The single nucleotide polymorphisms (SNPs) rs806381, rs......10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20-29 years. RESULTS: The rs806381 polymorphism was significantly associated...

  20. Predictors, moderators, and mediators (correlates) of treatment outcome in major depressive disorder.

    Science.gov (United States)

    Papakostas, George I; Fava, Maurizio

    2008-01-01

    Major Depressive Disorder (MDD) is a prevalent illness that is frequently associated with significant disability, morbidity and mortality Despite the development and availability of numerous treatment options for MDD, studies have shown that antidepressant monotherapy yields only modest rates of response and remission. Clearly, there is an urgent need to develop more effective treatment strategies for patients with MDD. One possible approach towards the development of novel pharmacotherapeutic strategies for MDD involves identifying subpopulations of depressed patients who are more likely to experience the benefits of a given (existing) treatment versus placebo, or versus a second treatment. Attempts have been made to identify such "subpopulations", specifically by testing whether a given biological or clinical marker also serves as a moderator, mediator (correlate), or predictor of clinical improvement following the treatment of MDD with standard, first-line antidepressants. In the following article, we will attempt to summarize the literature focusing on several major areas ("leads") where preliminary evidence exists regarding clinical and biologic moderators, mediators, and predictors of symptom improvement in MDD. Such clinical leads will include the presence of hopelessness, anxious symptoms, or medical comorbidity. Biologic leads will include gene polymorphisms, brain metabolism, quantitative electroencephalography, loudness dependence of auditory evoked potentials, and functional brain asymmetry.

  1. Sunburn: Treatment and Prevention

    Science.gov (United States)

    ... Healthy Living Healthy Living Healthy Living Nutrition Fitness Sports Oral Health Emotional Wellness Growing Healthy Sleep Safety & Prevention Safety & Prevention Safety and Prevention Immunizations ...

  2. Childhood obesity treatment and prevention. Psychological perspectives of clinical approaches

    OpenAIRE

    Maria Catena Quattropani; Teresa Buccheri

    2013-01-01

    Objective: This work focuses on clinical psychologist’ presence within childhood obesity prevention programmes in several countries. Method: The Authors collected articles considering psychological, biological and social aspects linked to childhood obesity. Results: Studies reveal that childhood obesity prevention programmes are based on biological, medical and educational aspects; clinical psychologists up until now have been engaged almost exclusively in the treatment of obesity. Conclusion...

  3. Current problems of prevention diagnosis and treatment of radiation sickness

    International Nuclear Information System (INIS)

    Gus'kova, A.K.

    1986-01-01

    Causes of increasing interest to the problems of prevention, diagnosis and treatment of radiation sickness are presented. On the basis of recent publications some new aspects as quantitative criteria in radiobiology, organization problems of medical aid at radiation incidents estimation of efficiency of preventive medicine and radiation sickness therapy, theoretical development of radiotherapy of different organs et al., are characterized

  4. Preventing treatment errors in radiotherapy by identifying and evaluating near misses and actual incidents

    LENUS (Irish Health Repository)

    Holmberg, Ola

    2002-06-01

    When preparing radiation treatment, the prescribed dose and irradiation geometry must be translated into physical machine parameters. An error in the calculations or machine settings can negatively affect the intended treatment outcome. Analysing incidents originating in the treatment preparation chain makes it possible to find weak links and prevent treatment errors. The aim of this work is to study the effectiveness of a multilayered error prevention system by analysing both near misses and actual treatment errors.

  5. Guidelines on prevention and treatment of vitamin D deficiency

    Directory of Open Access Journals (Sweden)

    R. Nuti

    2011-11-01

    Full Text Available The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS has elaborated the following guidelines about the definition, prevention and treatment of inadequate vitamin D status. The highlights are presented here.

  6. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes.

    Science.gov (United States)

    Thompson, Zoe; Argueta, Donovan; Garland, Theodore; DiPatrizio, Nicholas

    2017-03-01

    The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by-wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA

  7. Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas.

    Science.gov (United States)

    Li, Chen; Jones, Peter M; Persaud, Shanta J

    2011-03-01

    The endocannabinoid system (ECS) is a signalling cascade consisting of CB1 and CB2 receptors, and enzymes for the synthesis and degradation of endogenous ligands for these receptors. Central CB1 receptors have been most widely studied since they play key roles in energy homeostasis and rimonabant, a CB1 receptor antagonist, was used clinically to treat obesity. Less is known about CB2 receptors, but their abundant expression by lymphocytes and macrophages has led to suggestions of their importance in immune and inflammatory reactions. More recently, it has become apparent that both CB1 and CB2 receptors are more widely expressed than originally thought, and the capacity of endocannabinoids to regulate energy balance also occurs through their interactions with cannabinoid receptors on a variety of peripheral tissues. In general, pathological overactivation of the ECS contributes to weight gain, reduced sensitivity to insulin and glucose intolerance, and blockade of CB1 receptors reduces body weight through increased secretion of anorectic signals and improved insulin sensitivity. However, the notion that the ECS per se is detrimental to energy homeostasis is an oversimplification, since activation of cannabinoid receptors expressed by islet cells can stimulate insulin secretion, which is obviously beneficial under conditions of impaired glucose tolerance or type 2 diabetes. We propose that under normal physiological conditions cannabinoid signalling in the endocrine pancreas is a bona fide mechanism of regulating insulin secretion to maintain blood glucose levels, but that energy balance becomes dysregulated with excessive food intake, leading to adipogenesis and fat accumulation through enhanced cannabinoid synthesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    Directory of Open Access Journals (Sweden)

    Patrizia eCampolongo

    2012-03-01

    Full Text Available Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p. on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal and Low Arousal conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the Low Arousal condition spent more time in the centre of the arena than vehicle-treated rats exposed to the High Arousal context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution.AM404 administration did not alter the locomotor activity of the animals exposed to both environmental conditions. Interestingly, AM404 administration increased the emotional reactivity of rats exposed to the High Arousal condition but did not influence emotionality of rats exposed to the Low Arousal condition. Moreover, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the High Arousal condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the Low Arousal condition.These findings suggest that drugs which enhance the endocannabinoid signalling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions.

  9. Genetic modification of cerebral arterial wall: implications for prevention and treatment of cerebral vasospasm.

    Science.gov (United States)

    Vijay, Anantha; Santhanam, R; Katusic, Zvonimir S

    2006-10-01

    Genetic modification of cerebral vessels represents a promising and novel approach for prevention and/or treatment of various cerebral vascular disorders, including cerebral vasospasm. In this review, we focus on the current understanding of the use of gene transfer to the cerebral arteries for prevention and/or treatment of cerebral vasospasm following subarachnoid hemorrhage (SAH). We also discuss the recent developments in vascular therapeutics, involving the autologous use of progenitor cells for repair of damaged vessels, as well as a cell-based gene delivery approach for the prevention and treatment of cerebral vasospasm.

  10. Complications of an implantable venous access port: Prevention and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Tae Seok; Song, Myung Gyu [Dept. of Radiology, Guro Hospital, Korea University College of Medicine, Seoul (Korea, Republic of); Cha, In Ho [Dept. Radiology, Chungang University Hospital, Chungang University College of Medicine, Seoul (Korea, Republic of)

    2016-11-15

    Placement of an implantable venous access port (IVAP) is a popular procedure for repeated and intermittent chemotherapy in patients with malignancy. In this article, we present various IVAP related complications. In addition, we review the technical tips to prevent and manage the complications. It is important that the operator should keep the mechanism of the complications in mind, perform a careful procedure for prevention, and manage the complication properly and immediately in case of its development for safety and satisfaction of the patients Complications of an implantable venous access port: Prevention and treatment.

  11. Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.

    Science.gov (United States)

    Gilbert, Peter B; Juraska, Michal; deCamp, Allan C; Karuna, Shelly; Edupuganti, Srilatha; Mgodi, Nyaradzo; Donnell, Deborah J; Bentley, Carter; Sista, Nirupama; Andrew, Philip; Isaacs, Abby; Huang, Yunda; Zhang, Lily; Capparelli, Edmund; Kochar, Nidhi; Wang, Jing; Eshleman, Susan H; Mayer, Kenneth H; Magaret, Craig A; Hural, John; Kublin, James G; Gray, Glenda; Montefiori, David C; Gomez, Margarita M; Burns, David N; McElrath, Julie; Ledgerwood, Julie; Graham, Barney S; Mascola, John R; Cohen, Myron; Corey, Lawrence

    2017-01-01

    Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark

  12. [Problem of motivation of the population to prevention and treatment dental diseases].

    Science.gov (United States)

    Kochlashvili, L Sh; Gogilashvili, K T; Gerzmava, O Kh

    2012-10-01

    Dental health is an integral part of a normal state of a human body and, first of all, depends on knowledge of the population of bases of individual hygiene of an oral cavity and ability to use them in practical life. Numerous researches indicate low level of knowledge of the population in questions of prevention of dental diseases and individual hygiene of an oral cavity that testifies to existence of problems in the organization of sanitary education. Existing practice of hygienic training and education, in a certain measure, lags behind modern requirements, and some questions demand specification and optimization. For efficiency of sanitary and preventive actions it is necessary to study character and motivation structure to prevention and treatment of dental diseases and to develop an effective method of its increase. Therefore actual search of new forms of psycho hygiene and psycho prevention with use of modern information technologies which should provide high level of dental health of the military personnel is represented. The purpose of the real research was establishment of the factors forming motivation to prevention and treatment of the main dental diseases, and development of a psycho physiological method of its increase. The carried-out research allows to expand and systematize ideas necessary for the practical doctor of the major factors forming motivation to prevention and treatment of the main dental diseases. Development of an objective technique of a complex assessment of level of motivation of patients to prevention and treatment of dental pathology will allow to prove the new perspective direction of the sanitary educational work, allowing to reduce fobiya level, effectively to increase motivation of the patient to receiving the timely dental help. It especially is important if to consider that numerous programs of hygienic training and the education, applied in our country, didn't lead to change of hygienic skills of the population in expected

  13. Psychological background of prevention and treatment in geriatrics

    Directory of Open Access Journals (Sweden)

    Nazarov M.l.

    2015-03-01

    Full Text Available Confidentiality as the component of an interpersonal "patient — medical practitioner" contact formation can be considered as a corner stone of geriatric practice. Major psychological pitfalls of geriatric practice have been reviewed. The main issue of the paper is psychological substantiation of treatment and prevention of elderly.

  14. Interpersonal impacts mediate the association between personality and treatment response in major depression.

    Science.gov (United States)

    Dermody, Sarah S; Quilty, Lena C; Bagby, R Michael

    2016-07-01

    Personality, as characterized by the Five-Factor Model, predicts response to psychotherapy for depression. To explain how personality impacts treatment response, the present study investigated patient and therapist interpersonal processes in treatment sessions as an explanatory pathway. A clinical trial was conducted in which 103 outpatients (mean age: 41.17 years, 65% female) with primary major depressive disorder completed 16-20 weeks of cognitive-behavioral or interpersonal therapy. Before treatment, patients completed the Revised NEO Personality Inventory to assess personality domains (neuroticism, extraversion, openness-to-experience, agreeableness, and conscientiousness). After 3 and 13 weeks, patient interpersonal behavior was rated by the therapist and vice versa to determine levels of patient and therapist communal and agentic behaviors. Depression levels were measured before and after treatment. Structural equation modeling supported that patients' interpersonal behavior during therapy mediated the associations between pretreatment personality and depression treatment outcome. Specifically, extraversion, conscientiousness, and neuroticism (inverse) predicted higher levels of patient communion throughout treatment, which was in turn associated with improved treatment outcomes. Furthermore, patient agreeableness was inversely associated with agency throughout treatment, which was linked to poorer treatment response. Therapist interpersonal behavior was not a significant mediator. Results suggest that patient interpersonal behavior during treatment may be one way that patient personality impacts clinical outcomes in depression. Results underscore the clinical utility of Five-Factor Model domains in treatment process and outcome. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  15. Dialectical behavior therapy skills use as a mediator and outcome of treatment for borderline personality disorder.

    Science.gov (United States)

    Neacsiu, Andrada D; Rizvi, Shireen L; Linehan, Marsha M

    2010-09-01

    A central component of Dialectical Behavior Therapy (DBT) is the teaching of specific behavioral skills with the aim of helping individuals with Borderline Personality Disorder (BPD) replace maladaptive behaviors with skillful behavior. Although existing evidence indirectly supports this proposed mechanism of action, no study to date has directly tested it. Therefore, we examined the skills use of 108 women with BPD participating in one of three randomized control trials throughout one year of treatment and four months of follow-up. Using a hierarchical linear modeling approach we found that although all participants reported using some DBT skills before treatment started, participants treated with DBT reported using three times more skills at the end of treatment than participants treated with a control treatment. Significant mediation effects also indicated that DBT skills use fully mediated the decrease in suicide attempts and depression and the increase in control of anger over time. DBT skills use also partially mediated the decrease of nonsuicidal self-injury over time. Anger suppression and expression were not mediated. This study is the first to clearly support the skills deficit model for BPD by indicating that increasing skills use is a mechanism of change for suicidal behavior, depression, and anger control. Published by Elsevier Ltd.

  16. How did it work? Who did it work for? Mediation in the context of a moderated prevention effect for children of divorce.

    Science.gov (United States)

    Tein, Jenn-Yun; Sandler, Irwin N; MacKinnon, David P; Wolchik, Sharlene A

    2004-08-01

    This study presents a reanalysis of data from an effective preventive intervention for children from divorced families to test mediation of program effects. The study involved 157 children, age 9-12 years, who were randomly assigned to a parenting program or a literature control condition. Program effects to reduce posttest internalizing problems were mediated through improvement in mother-child relationship quality. Program effects to reduce externalizing problems at posttest and 6 months were mediated through improvement in posttest parental methods of discipline and mother-child relationship quality. The study also describes a new methodology to test mediation of Program x Baseline Status interactions. Analyses demonstrate mediation effects primarily for children who began the program with poorer scores on discipline, mother-child relationship quality, and externalizing problems.

  17. Prevention and treatment of congenital toxoplasmosis

    DEFF Research Database (Denmark)

    Petersen, Eskild

    2007-01-01

    Infection with Toxoplasma gondii is transmitted to man by infected meat or meat products and by contact with soil or surface water. In theory, prevention by hygienic measures is possible, but this has never been proved to work in practice. Therefore, pre- and postnatal screening has been...... implemented in several countries aiming at early diagnosis. However, data on the effect of treatment are limited and no randomized, controlled trials have been performed. The risk of T. gondii infection in Europe is declining and studies using historical controls from earlier decades cannot be used...... for decision making. The screening of pregnant women or neonates makes the assumption that any children diagnosed can be offered an effective treatment. There is an urgent need to test new drugs and demonstrate, using randomized, controlled trials, that the currently used drugs are effective. Udgivelsesdato...

  18. Toxic Stress: Effects, Prevention and Treatment

    Directory of Open Access Journals (Sweden)

    Hillary A. Franke

    2014-11-01

    Full Text Available Children who experience early life toxic stress are at risk of long-term adverse health effects that may not manifest until adulthood. This article briefly summarizes the findings in recent studies on toxic stress and childhood adversity following the publication of the American Academy of Pediatrics (AAP Policy Report on the effects of toxic stress. A review of toxic stress and its effects is described, including factors of vulnerability, resilience, and the relaxation response. An integrative approach to the prevention and treatment of toxic stress necessitates individual, community and national focus.

  19. Diagnosis, treatment and prevention of HIV/AIDS | Lyamuya ...

    African Journals Online (AJOL)

    Diagnosis, treatment and prevention of HIV/AIDS. E Lyamuya. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL ...

  20. Prevention and treatment of relapse after stem cell transplantation by cellular therapies.

    Science.gov (United States)

    Falkenburg, Fred; Ruggiero, Eliana; Bonini, Chaira; Porter, David; Miller, Jeff; Malard, Floran; Mohty, Mohamad; Kröger, Nicolaus; Kolb, Hans Jochem

    2018-05-24

    Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized.

  1. Single-Participant Assessment of Treatment Mediators: Strategy Description and Examples from a Behavioral Activation Intervention for Depressed Adolescents

    Science.gov (United States)

    Gaynor, Scott T.; Harris, Amanda

    2008-01-01

    Determining the means by which effective psychotherapy works is critical. A generally recommended strategy for identifying the potential causal variables is to conduct group-level statistical tests of treatment mediators. Herein the case is made for also assessing mediators of treatment outcome at the level of the individual participant.…

  2. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    Directory of Open Access Journals (Sweden)

    Balapal S. Basavarajappa

    2015-10-01

    Full Text Available One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS, which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD. Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.

  3. Examination of the Relationship between Psychosocial Mediators and Intervention Effects in It’s Your Game: An Effective HIV/STI/Pregnancy Prevention Intervention for Middle School Students

    Directory of Open Access Journals (Sweden)

    Elizabeth Baumler

    2012-01-01

    Full Text Available A set of mediation analyses were carried out in this study using data from It’s Your Game. . .Keep It Real (IYG, a successful HIV/STI/pregnancy prevention program. The IYG study evaluated a skill and normbased. HIV/STI/pregnancy prevention program that was implemented from 2004 to 2007 among 907 urban low-income middle school youth in Houston, TX, USA. Analyses were carried out to investigate the degree to which a set of proposed psychosocial measures of behavioral knowledge, perceived self-efficacy, behavioral, and normative beliefs, and perceived risky situations, all targeted by the intervention, mediated the intervention’s effectiveness in reducing initiation of sex. The mediation process was assessed by examining the significance and size of the estimated effects from the mediating pathways. The findings from this study provide evidence that the majority of the psychosocial mediators targeted by the IYG intervention are indeed related to the desired behavior and provide evidence that the conceptual theory underlying the targeted psychosocial mediators in the intervention is appropriate. Two of the psychosocial mediators significantly mediated the intervention effect, knowledge of STI signs and symptoms and refusal self-efficacy. This study suggests that the underlying causal mechanisms of action of these interventions are complex and warrant further analyses.

  4. Therapies for Prevention and Treatment of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    J. Mendiola-Precoma

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is the most common cause of dementia associated with a progressive neurodegenerative disorder, with a prevalence of 44 million people throughout the world in 2015, and this figure is estimated to double by 2050. This disease is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuroinflammation, and hypometabolism; it is related to amyloid-β peptide accumulation and tau hyperphosphorylation as well as a decrease in acetylcholine levels and a reduction of cerebral blood flow. Obesity is a major risk factor for AD, because it induces adipokine dysregulation, which consists of the release of the proinflammatory adipokines and decreased anti-inflammatory adipokines, among other processes. The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA receptor antagonists and etiology-based treatments such as secretase inhibitors, amyloid binders, and tau therapies. Strategies for prevention of AD through nonpharmacological treatments are associated with lifestyle interventions such as exercise, mental challenges, and socialization as well as caloric restriction and a healthy diet. AD is an important health issue on which all people should be informed so that prevention strategies that minimize the risk of its development may be implemented.

  5. Reason analysis and preventive treatment countermeasure of impaired vision after LASIK

    Directory of Open Access Journals (Sweden)

    Zhang-Bing Mu

    2015-02-01

    Full Text Available AIM: To analyze the reasons of impaired vision after LASIK and explore its preventive treatment measures preliminarily. METHODS: In this retrospective study, 175 eyes of 134 patients whose vision was decreased after LASIK were included. The constituent ratio of every reason was counted and uncorrected visual acuity(UCVAbetween pre-treatment and post-treatment were compared by paired t-test respectively. RESULTS: The overall incidence of impaired vision after LASIK was 1.86%. The constituent ratio of regression was 51.43% and UCVA increased from 0.61±0.22 to 0.90±0.38(t=8.00, Pt=20.00, Pt=8.14, Pt=6.33, Pt=2.53, P0.05after treatment. The constituent ratio of fundus lesions and diffuse lamellar keratitis(DLKwas 2.86% and UCVA all increased by different degrees after treatment. CONCLUSION: The reasons of impaired vision after LASIK are many and varied. These cases could recover their vision by discovery and treatment in time, and the appropriate preventive measures were essential.

  6. Gastric cancer: epidemiology, prevention, classification, and treatment

    Directory of Open Access Journals (Sweden)

    Sitarz R

    2018-02-01

    Full Text Available Robert Sitarz,1–3 Małgorzata Skierucha,1,2 Jerzy Mielko,1 G Johan A Offerhaus,3 Ryszard Maciejewski,2 Wojciech P Polkowski1 1Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland; 2Department of Human Anatomy, Medical University of Lublin, Lublin, Poland; 3Department of Pathology, University Medical Centre, Utrecht, The Netherlands Abstract: Gastric cancer is the second most common cause of cancer-related deaths in the world, the epidemiology of which has changed within last decades. A trend of steady decline in gastric cancer incidence rates is the effect of the increased standards of hygiene, conscious nutrition, and Helicobacter pylori eradication, which together constitute primary prevention. Avoidance of gastric cancer remains a priority. However, patients with higher risk should be screened for early detection and chemoprevention. Surgical resection enhanced by standardized lymphadenectomy remains the gold standard in gastric cancer therapy. This review briefly summarizes the most important aspects of gastric cancers, which include epidemiology, risk factors, classification, diagnosis, prevention, and treatment. The paper is mostly addressed to physicians who are interested in updating the state of art concerning gastric carcinoma from easily accessible and credible source. Keywords: gastric cancer, epidemiology, classification, risk factors, treatment

  7. The television, school, and family smoking prevention and cessation project. VIII. Student outcomes and mediating variables.

    Science.gov (United States)

    Flay, B R; Miller, T Q; Hedeker, D; Siddiqui, O; Britton, C F; Brannon, B R; Johnson, C A; Hansen, W B; Sussman, S; Dent, C

    1995-01-01

    This paper presents the student outcomes of a large-scale, social-influences-based, school and media-based tobacco use prevention and cessation project in Southern California. The study provided an experimental comparison of classroom delivery with television delivery and the combination of the two in a 2 x 2 plus 1 design. Schools were randomly assigned to conditions. Control groups included "treatment as usual" and an "attention control" with the same outcome expectancies as the treatment conditions. Students were surveyed twice in grade 7 and once in each of grades 8 and 9. The interventions occurred during grade 7. We observed significant effects on mediating variables such as knowledge and prevalence estimates, and coping effort. The knowledge and prevalence estimates effects decayed partially but remained significant up to a 2-year follow-up. The coping effort effect did not persist at follow-ups. There were significant main effects of both classroom training and TV programming on knowledge and prevalence estimates and significant interactions of classroom and TV programming on knowledge (negative), disapproval of parental smoking, and coping effort. There were no consistent program effects on refusal/self-efficacy, smoking intentions, or behavior. Previous reports demonstrated successful development and pilot testing of program components and measures and high acceptance of the program by students and parents. The lack of behavioral effects may have been the result of imperfect program implementation or low base rates of intentions and behavior.

  8. Contentious Conversations: Using Mediation Techniques in Difficult Clinical Ethics Consultations.

    Science.gov (United States)

    Fiester, Autumn

    2015-01-01

    Mediators utilize a wide range of skills in the process of facilitating dialogue and resolving conflicts. Among the most useful techniques for clinical ethics consultants (CECs)-and surely the least discussed-are those employed in acrimonious, hostile conversations between stakeholders. In the context of clinical ethics disputes or other bedside conflicts, good mediation skills can reverse the negative interactions that have prevented the creation of workable treatment plans or ethical consensus. This essay lays out the central framework mediators use in distinguishing positions from interests and describes a set of strategies for managing contentious ethics consultations or working with "difficult" patients, families, or patient-careprovider interactions. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

  9. Helminthic therapy: using worms to treat immune-mediated disease.

    Science.gov (United States)

    Elliott, David E; Weinstock, Joel V

    2009-01-01

    There is an epidemic of immune-mediated disease in highly-developed industrialized countries. Such diseases, like inflammatory bowel disease, multiple sclerosis and asthma increase in prevalence as populations adopt modern hygienic practices. These practices prevent exposure to parasitic worms (helminths). Epidemiologic studies suggest that people who carry helminths have less immune-mediated disease. Mice colonized with helminths are protected from disease in models of colitis, encephalitis, Type 1 diabetes and asthma. Clinical trials show that exposure to helminths reduce disease activity in patients with ulcerative colitis or Crohn's disease. This chapter reviews some of the work showing that colonization with helminths alters immune responses, against dysregulated inflammation. These helminth-host immune interactions have potentially important implications for the treatment of immune-mediated diseases.

  10. Treatment of Oral Candidiasis Using Photodithazine®- Mediated Photodynamic Therapy In Vivo.

    Science.gov (United States)

    Carmello, Juliana Cabrini; Alves, Fernanda; G Basso, Fernanda; de Souza Costa, Carlos Alberto; Bagnato, Vanderlei Salvador; Mima, Ewerton Garcia de Oliveira; Pavarina, Ana Cláudia

    2016-01-01

    This study evaluated the effectiveness of antimicrobial photodynamic therapy (aPDT) in the treatment of oral candidiasis in a murine model using Photodithazine® (PDZ). This model of oral candidiasis was developed to allow the monitoring of the infection and the establishment of the aPDT treatment. Six-week-old female mice were immunosuppressed and inoculated with C. albicans to induce oral candidiasis. PDZ-mediated aPDT and nystatin treatment were carried out for 5 consecutive days with one application per day. The macroscopic evaluation of oral lesions was performed. After each treatment, the tongue was swabbed to recover C. albicans cells. Viable colonies were quantified and the number of CFU/ml determined. The animals were sacrificed 24 hours and 7 days after treatment and the tongues were surgically removed for histological analysis and analysis of inflammatory cytokines expression (IL-1, TNF-α and IL-6) by RT-qPCR. Data were analyzed by two-way ANOVA. PDZ-mediated aPDT was as effective as Nystatin (NYS group) in the inactivation of C. albicans, reducing 3 and 3.2 logs10 respectively, 24 h after treatment (poral lesions, while animals treated with NYS presented partial remission of oral lesions in both periods assessed. Histological evaluation revealed mild inflammatory infiltrate in the groups treated with aPDT and NYS in both periods assessed. The aPDT induced the TNF-α expression when compared with the control (P-L-) (poral candidiasis.

  11. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

    Science.gov (United States)

    Günthard, Huldrych F.; Saag, Michael S.; Benson, Constance A.; del Rio, Carlos; Eron, Joseph J.; Gallant, Joel E.; Hoy, Jennifer F.; Mugavero, Michael J.; Sax, Paul E.; Thompson, Melanie A.; Gandhi, Rajesh T.; Landovitz, Raphael J.; Smith, Davey M.; Jacobsen, Donna M.; Volberding, Paul A.

    2016-01-01

    IMPORTANCE New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. OBJECTIVE To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. EVIDENCE REVIEW A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. FINDINGS Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory

  12. Compliance with preventive care following dental treatment of children under general anaesthesia.

    Science.gov (United States)

    Peerbhay, F B M

    2009-11-01

    This study evaluated the self-reported preventive dental care compliance of parents/families whose children received dental treatment under general anaesthesia. Complete records of 68 pediatric patients who attended the University of Stellenbosch's Paediatric Dentistry Department for dental treatment were included in the survey. Parents of 41 (60%) patients were interviewed telephonically to evaluate parental dental health knowledge and preventive practices. The majority (85%) of parents had a good idea about the aetiology of dental caries. An assessment of the children's dental health behaviour reveals that parents were mostly responsible for brushing the childs' teeth (44%).The majority of parents (51%) reported that following dental treatment of the child under general anaesthesia, there was no change in their child's frequency of sugar consumption. Sixty-three percent of children treated under GA had returned for the one-week follow-up. However, only 22% of children returned for the three-month follow up appointment. Parents were informed about the importance of these follow-up appointments. Parental belief that proper dental health behaviour helps maintain the teeth, did not influence parents preventive compliance, despite them having received preventive instruction. Parents were mostly responsible for brushing their child's teeth following dental treatment of their children under general anaesthesia. This research found however that, in the majority of cases there was no change in the children's frequency of sugar intake.

  13. Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation.

    Science.gov (United States)

    Köse, Sevil; Aerts-Kaya, Fatima; Köprü, Çağla Zübeyde; Nemutlu, Emirhan; Kuşkonmaz, Barış; Karaosmanoğlu, Beren; Taşkıran, Ekim Zihni; Altun, Belgin; Uçkan Çetinkaya, Duygu; Korkusuz, Petek

    2018-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrβ). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34 + HSCs express CB1, CB2, and Adrβ subtypes. CD34 + HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  14. Preventive treatment of combined radiation injuries

    International Nuclear Information System (INIS)

    Boudagov, R.; Uljanova, L.; Makarov, G.

    1996-01-01

    The risk of sepsis development increases when thermal burns and other trauma occur in combination with exposure to radiation. Only surgical correction of the life-threatening state recommends within 48 hours after irradiation. All other arrangements have to carry out when hemopoiesis recovery will complete. However exposed patients with combined injuries (CI) die during the first two or three weeks mainly due to sepsis. Therefore prophylaxis and preventive therapy of infectious complications are need early. Actual difficulties in choice of valid treatment procedure for acute radiation syndrome (ARS) exhibit additional aggravation under CI. The available facts prove decreasing early therapy efficiency for rather high dose exposure and wound trauma occurrence. The own results showed that bacterial polysaccharide pyrogenal, glycopin (synthetic analogue of muramil-dipeptide), thymus preparations (thymozin, thymotropin, thymogen), tuftsin, heterologic human and bovine immunoglobulins did not modify the low values of 30-day survival under CI (irradiation + thermal burn). Single injection of prodigiozan, zymozan and some other yeast polysaccharides in 1 hr after CI resulted at moderate increasing of survival. The main purpose of this study, which bases upon our understanding of CI pathogenesis, was search more effective means for preventive treatment of combined radiation injuries. Two groups of remedies were under study. The first group included so called 'biological response modifiers' (BRM). These agents may increase host defences to infection, macrophage's activity and hemopoietic growth factor's secretion. The second group included antibiotics that should be directed against the potential gram-negative as well as gram-positive pathogens and simultaneously be useful for selective decontamination of gastrointestinal tract. (author)

  15. Social Justice and HIV Vaccine Research in the Age of Pre-Exposure Prophylaxis and Treatment as Prevention

    Science.gov (United States)

    Bailey, Theodore C.; Sugarman, Jeremy

    2014-01-01

    The advent of pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) as means of HIV prevention raises issues of justice concerning how most fairly and equitably to apportion resources in support of the burgeoning variety of established HIV treatment and prevention measures and further HIV research, including HIV vaccine research. We apply contemporary approaches to social justice to assess the ethical justification for allocating resources in support of HIV vaccine research given competing priorities to support broad implementation of HIV treatment and prevention measures, including TasP and PrEP. We argue that there is prima facie reason to believe that a safe and effective preventive HIV vaccine would offer a distinct set of ethically significant benefits not provided by current HIV treatment or prevention methods. It is thereby possible to justify continued support for HIV vaccine research despite tension with priorities for treatment, prevention, and other research. We then consider a counter-argument to such a justification based on the uncertainty of successfully developing a safe and effective preventive HIV vaccine. Finally, we discuss how HIV vaccine research might now be ethically designed and conducted given the new preventive options of TasP and PrEP, focusing on the ethically appropriate standard of prevention for HIV vaccine trials. PMID:24033297

  16. Sleep apnoea: Finnish National guidelines for prevention and treatment 2002-2012.

    Science.gov (United States)

    Laitinen, L A; Anttalainen, U; Pietinalho, A; Hämäläinen, P; Koskela, K

    2003-04-01

    (1) After negotiations with the Finnish Ministry of Social Affairs and Health, a national programme to promote prevention, treatment and rehabilitation of sleep apnoea for the years 2002-2012 has been prepared by the Finnish Lung Health Association on the basis of extensive collaboration. The programme needs to be revised as necessary, because of the rapid development in medical knowledge, and in appliance therapy in particular. (2) Sleep apnoea deteriorates slowly. Its typical features are snoring, interruptions of breathing during sleep and daytime tiredness. Sleep apnoea affects roughly 3% of middle-aged men and 2% of women. In Finland, there are approx. 150,000 sleep apnea patients, of which 15,000 patients have a severe disease, 50,000 patients are moderate and 85,000 have a mild form of the disease. Children are also affected by sleep apnea. A typical sleep apnea patient is a middle-aged man or a postmenopausal woman. (3) The obstruction of upper airways is essential in the occurrence of sleep apnoea. The obstruction can be caused by structural and/or functional factors. As for structural factors, there are various methods of intervention, such as to secure children's nasal respiration, to remove redundant soft tissue, as well as to correct malocclusions. It is possible to have an effect on the functional factors by treating well diseases predisposing to sleep apnoea, by reducing smoking, the consumption of alcohol and the use of medicines impairing the central nervous system. The most important single risk factor for sleep apnoea is obesity. (4) Untreated sleep apnoea leads to an increase morbidity and mortality through heart circulatory diseases and through accidents by tiredness. Untreated or undertreated sleep apnoea deteriorates a person's quality of life and working capacity. (5) The goals of the Programme for the prevention and treatment of sleep apnoea are as follows: (1) to decrease the incidence of sleep apnoea, (2) to ensure that as many patients

  17. Beyond total treatment effects in randomised controlled trials: Baseline measurement of intermediate outcomes needed to reduce confounding in mediation investigations.

    Science.gov (United States)

    Landau, Sabine; Emsley, Richard; Dunn, Graham

    2018-06-01

    Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise. Investigators increasingly carry out explanatory analyses to decompose total treatment effects into components that are mediated by an intermediate continuous outcome and a non-mediated part. Traditional mediation analysis might be performed based on (A) post-treatment values of the intermediate and clinical outcomes alone, (B) respective change scores or (C) conditioning on baseline measures of both intermediate and clinical outcomes. Using causal diagrams and Monte Carlo simulation, we investigated the performance of the three competing mediation approaches. We considered a data generating model that included three possible confounding processes involving baseline variables: The first two processes modelled baseline measures of the clinical variable or the intermediate variable as common causes of post-treatment measures of these two variables. The third process allowed the two baseline variables themselves to be correlated due to past common causes. We compared the analysis models implied by the competing mediation approaches with this data generating model to hypothesise likely biases in estimators, and tested these in a simulation study. We applied the methods to a randomised trial of pragmatic rehabilitation in patients with chronic fatigue syndrome, which examined the role of limiting activities as a mediator. Estimates of causal mediation effects derived by approach (A) will be biased if one of

  18. Contingency management for college student smokers: The role of drinking as a moderator and mediator of smoking abstinence during treatment.

    Science.gov (United States)

    Cassidy, Rachel N; Jackson, Kristina M; Rohsenow, Damaris J; Tidey, Jennifer W; Tevyaw, Tracy O' L; Barnett, Nancy P; Monti, Peter M; Miller, Mollie E; Colby, Suzanne M

    2018-05-01

    Contingency management (CM) is effective for promoting smoking abstinence; however, moderators and mediators of CM treatment efficacy in young adult populations are under-explored. We leveraged fine-grained data from a large randomized controlled trial: 1) to determine whether early attainment of sustained abstinence mediated the effect of treatment on abstinence; 2) to test whether heavy drinking moderated the effect of treatment on abstinence; and 3) to test a serial mediation model of the effects of drinking during early treatment on sustained smoking abstinence. College student smokers (N=110) were randomized to receive either CM treatment or noncontingent reinforcement (NR) over a 21-day treatment period. All participants received $5 for providing twice-daily breath carbon monoxide (CO) samples. In CM, additional money was provided for samples that indicated smoking reduction (Initial Phase; first 7days), and for samples ≤5ppm (Abstinence Phase; following 14days). CM treatment led to greater sustained abstinence relative to NR. Longer sustained abstinence in the Initial Phase partially mediated the effect of treatment on sustained abstinence in the Abstinence Phase. Heavier pretreatment drinkers had shorter periods of sustained abstinence in the Abstinence Phase; this effect was greater in CM. A serial mediation model determined that increased drinking during the Initial Phase led to decreased sustained abstinence, which then led to decreased sustained abstinence in the Abstinence Phase. These data provide a greater understanding of how heavy drinking and early sustained abstinence may affect success during treatment in young adults undergoing contingency management treatment for smoking. Copyright © 2018. Published by Elsevier Ltd.

  19. Response expectancies, treatment credibility, and hypnotic suggestibility: mediator and moderator effects in hypnotic and cognitive-behavioral pain interventions.

    Science.gov (United States)

    Milling, Leonard S; Shores, Jessica S; Coursen, Elizabeth L; Menario, Deanna J; Farris, Catherine D

    2007-04-01

    Several studies have shown that response expectancies are an important mechanism of popular psychological interventions for pain. However, there has been no research on whether response expectancies and treatment credibility independently mediate hypnotic and cognitive-behavioral pain interventions and whether the pattern of mediation is affected by experience with the interventions. Also, past research has indicated that hypnotic pain interventions may be moderated by hypnotic suggestibility. However, these studies have typically failed to measure the full range of suggestibility and have assessed pain reduction and suggestibility in the same experimental context, possibly inflating the association between these variables. To clarify the mediator role of response expectancies and treatment credibility, and the moderator role of hypnotic suggestibility in the hypnotic and cognitive-behavioral reduction of pain. Approximately 300 participants were assessed for suggestibility. Then, as part of an apparently unrelated experiment, 124 of these individuals received analogue cognitive-behavioral, hypnotic, or placebo control pain interventions. Response expectancies and credibility independently mediated treatment. The extent of mediation increased as participants gained more experience with the interventions. Suggestibility moderated treatment and was associated with relief only from the hypnotic intervention. Response expectancies and treatment credibility are unique mechanisms of hypnotic and cognitive-behavioral pain interventions. Hypnotic suggestibility predicts relief from hypnotic pain interventions and this association is not simply an artifact of measuring suggestibility and pain reduction in the same experimental context. The relationship between suggestibility and hypnotic pain reduction appears to be linear in nature.

  20. Effects of mood inductions by meal ambiance and moderate alcohol consumption on endocannabinoids and N-acylethanolamines in humans: a randomized crossover trial.

    Directory of Open Access Journals (Sweden)

    Ilse C Schrieks

    Full Text Available The endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG, anandamide (AEA, and some N-acylethanolamine (NAE congeners in humans.Healthy women (n = 28 participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol or alcohol-free sparkling white wine (340 mL; <2 g alcohol as part of a standard evening meal in a room with either a pleasant or an unpleasant ambiance.Plasma concentrations of palmitoylethanolamide (PEA and stearoylethanolamide (SEA increased after 30 min in the unpleasant ambiance, while they decreased in the pleasant ambiance. Changes in ECs and their NAE congeners correlated with mood states, such as happiness and fatigue, but in the pleasant ambiance without alcohol only. ECs and their NAE congeners were correlated with serum free fatty acids and cortisol.This is the first human study to demonstrate that plasma NAEs are responsive to an unpleasant meal ambiance. Furthermore, associations between mood states and ECs and their NAE congeners were observed.Clinicaltrials.gov NCT01426022.

  1. Use of ethanol extracts of Terminalia chebula to prevent periodontal disease induced by dental plaque bacteria.

    Science.gov (United States)

    Lee, Jongsung; Nho, Youn Hwa; Yun, Seok Kyun; Hwang, Young Sun

    2017-02-16

    The fruit of the Terminalia chebula tree has been widely used for the treatment of various disorders. Its anti-diabetic, anti-mutagenic, anti-oxidant, anti-bacterial, anti-fungal, and anti-viral effects have been studied. Dental plaque bacteria (DPB) are intimately associated with gingivitis and periodontitis. In the quest for materials that will prove useful in the treatment and prevention of periodontal disease, we investigated the preventive effects of an ethanol extract of Terminalia chebula (EETC) on DPB-induced inflammation and bone resorption. The anti-bacterial effect of EETC was analyzed using the disc diffusion method. The anti-inflammatory effect of EETC was determined by molecular biological analysis of the DPB-mediated culture cells. Prevention of osteoclastic bone resorption by EETC was explored using osteoclast formation and pit formation assays. EETC suppressed the growth of oral bacteria and reduced the induction of inflammatory cytokines and proteases, abolishing the expression of PGE2 and COX-2 and inhibiting matrix damage. By stimulating the DPB-derived lipopolysaccharides, EETC inhibited both osteoclast formation in osteoclast precursors and RANKL expression in osteoblasts, thereby contributing to the prevention of bone resorption. EETC may be a beneficial supplement to help prevent DPB-mediated periodontal disease.

  2. Prevention and treatment of respiratory consequences induced by sulfur mustard in Iranian casualties

    Directory of Open Access Journals (Sweden)

    Seyed M Razavi

    2013-01-01

    Full Text Available Background: About 100,000 Iranian have been exposed to chemical weapons during Iraq-Iran conflict (1980-88. After being spent of more than two decades, still about 30,000 of them are under follow-up treatment. The main aim of this study was to review various preventive and therapeutic methods for injured patients with sulfur mustard in different phases. Methods: For gathering information, we have used the electronic databases including Scopus, Medline, ISI, IranMedex, Irandoc sites. According to this search strategy, 104 published articles associated to respiratory problems and among them 50 articles related to prevention and treatment of respiratory problems were found and reviewed. Results: There is not any curative treatment for sulfur mustard induced lung injuries, but some valuable experienced measures for prevention and palliative treatments are available. Some useful measures in acute phase include: Symptomatic management, oxygen supplementation, tracheostomy in laryngospasm, use of moist air, respiratory physical therapy, mucolytic agents and bronchodilators. In the chronic phases, these measures include: Periodic clinical examinations, administration of inhaled corticosteroids alone or with long-acting beta 2 agonists, use of antioxidants, magnesium ions, long term oxygen supplement, therapeutic bronchoscopy, laser therapy, and use of respiratory tract stents. Conclusions: Most treatments are symptomatic but using preventive points immediately after exposure could improve following outcomes.

  3. Mediator phosphorylation prevents stress response transcription during non-stress conditions.

    Science.gov (United States)

    Miller, Christian; Matic, Ivan; Maier, Kerstin C; Schwalb, Björn; Roether, Susanne; Strässer, Katja; Tresch, Achim; Mann, Matthias; Cramer, Patrick

    2012-12-28

    The multiprotein complex Mediator is a coactivator of RNA polymerase (Pol) II transcription that is required for the regulated expression of protein-coding genes. Mediator serves as an end point of signaling pathways and regulates Pol II transcription, but the mechanisms it uses are not well understood. Here, we used mass spectrometry and dynamic transcriptome analysis to investigate a functional role of Mediator phosphorylation in gene expression. Affinity purification and mass spectrometry revealed that Mediator from the yeast Saccharomyces cerevisiae is phosphorylated at multiple sites of 17 of its 25 subunits. Mediator phosphorylation levels change upon an external stimulus set by exposure of cells to high salt concentrations. Phosphorylated sites in the Mediator tail subunit Med15 are required for suppression of stress-induced changes in gene expression under non-stress conditions. Thus dynamic and differential Mediator phosphorylation contributes to gene regulation in eukaryotic cells.

  4. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  5. Eculizumab for the Treatment of Severe Antibody-Mediated Rejection: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Duy Tran

    2016-01-01

    Full Text Available In renal transplantation, treatment options for antibody-mediated rejection are limited. Here, we report a case of severe AMR treated with eculizumab. A 50-year-old woman known for end stage kidney disease secondary to IgA nephropathy received a kidney transplant from a 50-year-old deceased donor. At 5 months after transplantation, she presented with acute graft dysfunction and biopsy showed a severe antibody-mediated rejection associated with thrombotic microangiopathy. Despite an aggressive conventional immunosuppressive regimen, signs of rejection persisted and the patient was treated with 3 doses of eculizumab. Following the therapy, markers of TMA improved and graft function stabilized. However, ongoing signs of rejection remained in the repeated biopsy. In kidney transplantation, eculizumab is an expensive treatment and its role in the treatment of antibody-mediated rejection remains to be determined.

  6. Easy and effective technique of preventing incisor flaring during Forsus treatment

    Directory of Open Access Journals (Sweden)

    Siddharth Shashidhar Revankar

    2014-01-01

    Full Text Available Lower incisor flaring is often encountered during Forsus treatment. To prevent this, consolidating the entire mandibular arch by ligature wire and cinching back the mandibular archwire has been recommended. However, lower incisor flaring might still occur due to ligature breakage from friction of the push rods and also cinching back the mandibular archwire might not be possible in few cases due to anatomic limitations. The following article describes an innovative technique to prevent any chances of lower incisor flaring during Forsus treatment in cases where cinching the archwire is not possible due to anatomic limitations. This method is simple, inexpensive, less time consuming and comfortable for the patient.

  7. Prenatal treatment prevents learning deficit in Down syndrome model.

    Science.gov (United States)

    Incerti, Maddalena; Horowitz, Kari; Roberson, Robin; Abebe, Daniel; Toso, Laura; Caballero, Madeline; Spong, Catherine Y

    2012-01-01

    Down syndrome is the most common genetic cause of mental retardation. Active fragments of neurotrophic factors release by astrocyte under the stimulation of vasoactive intestinal peptide, NAPVSIPQ (NAP) and SALLRSIPA (SAL) respectively, have shown therapeutic potential for developmental delay and learning deficits. Previous work demonstrated that NAP+SAL prevent developmental delay and glial deficit in Ts65Dn that is a well-characterized mouse model for Down syndrome. The objective of this study is to evaluate if prenatal treatment with these peptides prevents the learning deficit in the Ts65Dn mice. Pregnant Ts65Dn female and control pregnant females were randomly treated (intraperitoneal injection) on pregnancy days 8 through 12 with saline (placebo) or peptides (NAP 20 µg +SAL 20 µg) daily. Learning was assessed in the offspring (8-10 months) using the Morris Watermaze, which measures the latency to find the hidden platform (decrease in latency denotes learning). The investigators were blinded to the prenatal treatment and genotype. Pups were genotyped as trisomic (Down syndrome) or euploid (control) after completion of all tests. two-way ANOVA followed by Neuman-Keuls test for multiple comparisons, PDown syndrome-placebo; n = 11) did not demonstrate learning over the five day period. DS mice that were prenatally exposed to peptides (Down syndrome-peptides; n = 10) learned significantly better than Down syndrome-placebo (ptreatment with the neuroprotective peptides (NAP+SAL) prevented learning deficits in a Down syndrome model. These findings highlight a possibility for the prevention of sequelae in Down syndrome and suggest a potential pregnancy intervention that may improve outcome.

  8. Incorporating primary and secondary prevention approaches to address childhood obesity prevention and treatment in a low-income, ethnically diverse population

    Science.gov (United States)

    There is consensus that development and evaluation of a systems-oriented approach for child obesity prevention and treatment that includes both primary and secondary prevention efforts is needed. This article describes the study design and baseline data from the Texas Childhood Obesity Research Demo...

  9. Precautions for preventing criticality at plutonium fuel treatment facilities

    International Nuclear Information System (INIS)

    Deworm, J.P.; Fieuw, G.; Cank, H. de

    1976-01-01

    Four criticality accidents took place between 1958 and 1964 at fuel processing plants using wet methods. So far accident of this type has taken place at production units where fissionable material is used. The prevention of criticality is one of the major concerns of the officials in charge of the plutonium fuel research laboratories operated at the Mol Nuclear Energy Study Centre by the SCK/CEN-Belgonucleaire Association. The means of preventing such an accident are of three types: introducing different types of treatment in well-defined work units; thorough analysis of planned experiments or fabrication programmes to determine the sub-criticality factors; application of technical and administrative procedures which ensure that the facilities are always sub-critical during the treatment and storage of fissionable materials. The installation includes a detection and warning system and provision is made for the immediate evacuation of staff should a crticality incident occur. The effects of a critical excursion on the building have been assessed. (author)

  10. GENITAL CONDYLOMAS. PREVALENCE, ETIOLOGY, TREATMENT AND PREVENTION

    Directory of Open Access Journals (Sweden)

    L.K. Aslamazyan

    2008-01-01

    Full Text Available The article is dedicated to the papilloma virus infection. As it became known in October 2008, the nobel prize in the field of medicine and physiology this year is awarded to the German doctor of Harald Zur Hausen who has proved the role of the human papilloma virus as causative factor of the cervical carcinoma. This is epoch making discovery because of human papilloma virus is most frequent of sexually transmitted infections. The authors demonstrated the high HPV prevalence. One of the most frequent manifestations of this infection is in more details presented pointed condy loma, clinical course of the disease and differential diagnostics of its various forms. Considering treatment inefficiency, the authors convincingly demonstrate that the only opportunity available to keep a human from the illness development is a specific immune prevention.Key words: papillomavirus infection, pointed condylomas, precancers, prevention.

  11. Mediation of Changes in Anxiety and Depression During Treatment of Social Phobia

    Science.gov (United States)

    Moscovitch, David A.; Stefan G. Hofmann, Michael K.; Suvak, Michael K.; In-Albon, Tina

    2005-01-01

    To investigate the interactive process of changes in social anxiety and depression during treatment, the authors assessed weekly symptoms in 66 adult outpatients with social phobia (social anxiety disorder) who participated in cognitive- behavioral group therapy. Multilevel mediational analyses revealed that improvements in social anxiety mediated…

  12. Ten ways to improve the use of statistical mediation analysis in the practice of child and adolescent treatment research

    NARCIS (Netherlands)

    Maric, M.; Wiers, R.W.; Prins, P.J.M.

    2012-01-01

    Despite guidelines and repeated calls from the literature, statistical mediation analysis in youth treatment outcome research is rare. Even more concerning is that many studies that have reported mediation analyses do not fulfill basic requirements for mediation analysis, providing inconclusive data

  13. Resveratrol Prevents High Fluence Red Light-Emitting Diode Reactive Oxygen Species-Mediated Photoinhibition of Human Skin Fibroblast Migration.

    Directory of Open Access Journals (Sweden)

    Andrew Mamalis

    Full Text Available Skin fibrosis is a significant medical problem that leads to a functional, aesthetic, and psychosocial impact on quality-of-life. Light-emitting diode-generated 633-nm red light (LED-RL is part of the visible light spectrum that is not known to cause DNA damage and is considered a safe, non-invasive, inexpensive, and portable potential alternative to ultraviolet phototherapy that may change the treatment paradigm of fibrotic skin disease.The goal of our study was to investigate the how reactive oxygen species (ROS free radicals generated by high fluence LED-RL inhibit the migration of skin fibroblasts, the main cell type involved in skin fibrosis. Fibroblast migration speed is increased in skin fibrosis, and we studied cellular migration speed of cultured human skin fibroblasts as a surrogate measure of high fluence LED-RL effect on fibroblast function. To ascertain the inhibitory role of LED-RL generated ROS on migration speed, we hypothesized that resveratrol, a potent antioxidant, could prevent the photoinhibitory effects of high fluence LED-RL on fibroblast migration speed.High fluence LED-RL generated ROS were measured by flow cytometry analysis using dihydrorhodamine (DHR. For purposes of comparison, we assessed the effects of ROS generated by hydrogen peroxide (H2O2 on fibroblast migration speed and the ability of resveratrol, a well known antioxidant, to prevent LED-RL and H2O2 generated ROS-associated changes in fibroblast migration speed. To determine whether resveratrol could prevent the high fluence LED-RL ROS-mediated photoinhibition of human skin fibroblast migration, treated cells were incubated with resveratrol at concentrations of 0.0001% and 0.001% for 24 hours, irradiated with high fluences LED-RL of 480, 640, and 800 J/cm2.High fluence LED-RL increases intracellular fibroblast ROS and decreases fibroblast migration speed. LED-RL at 480, 640 and 800 J/cm2 increased ROS levels to 132.8%, 151.0%, and 158.4% relative to matched

  14. Maltreatment in early childhood: a scoping review of prevention, detection and treatment

    Directory of Open Access Journals (Sweden)

    Luis Lefio Celedón

    2013-08-01

    Full Text Available Purpose. To identify and synthesize the best available evidence on the effectiveness of interventions for universal prevention, detection and treatment of early childhood maltreatment (0-4 years. Design. Scoping Review. Data sources. MEDLINE, LILACS, PsycINFO, Psyclist, SciELO, ISI Web of Knowledge, Science Direct, EBSCO, EMBASE, Cochrane Library, DARE, Google Scholar and UNICEF Base. Methods. A variety of keywords were used to identify quantitative experimental and observational studies on detection, prevention and treatment strategies in different situations of child maltreatment. Sexual abuse was excluded. The search spanned from 2002 to 2012, in English and Spanish. Results. Of 105 articles, 36 met the selection criteria. In prevention, the best evaluated strategies were parenting programs based on cognitive or cognitive-behavioral approach and interactive learning strategies. In detection, only two instruments were identified with optimum specificity and positive predictive value. In treatment, a variety of treatment strategies were identified with favorable effects on behavioral, functional and psycho affective indicators. The population relevance of these interventions is unclear, as the differential effectiveness of these therapeutic approaches. Conclusions. There are many child maltreatment prevention strategies at the individual and family level. The instruments used for detection are not reliable for use at the collective level. Insofar as therapy, not enough evidence was found both in quality and quantity to favor one intervention over another. It is recommended to understand the problem from the public health perspective and to generate multisectoral and interdisciplinary approaches.

  15. Mediation analysis in nursing research: a methodological review.

    Science.gov (United States)

    Liu, Jianghong; Ulrich, Connie

    2016-12-01

    Mediation statistical models help clarify the relationship between independent predictor variables and dependent outcomes of interest by assessing the impact of third variables. This type of statistical analysis is applicable for many clinical nursing research questions, yet its use within nursing remains low. Indeed, mediational analyses may help nurse researchers develop more effective and accurate prevention and treatment programs as well as help bridge the gap between scientific knowledge and clinical practice. In addition, this statistical approach allows nurse researchers to ask - and answer - more meaningful and nuanced questions that extend beyond merely determining whether an outcome occurs. Therefore, the goal of this paper is to provide a brief tutorial on the use of mediational analyses in clinical nursing research by briefly introducing the technique and, through selected empirical examples from the nursing literature, demonstrating its applicability in advancing nursing science.

  16. Expectancies, working alliance, and outcome in transdiagnostic and single diagnosis treatment for anxiety disorders: An investigation of mediation.

    Science.gov (United States)

    Sauer-Zavala, Shannon; Boswell, James F; Bentley, Kate H; Thompson-Hollands, Johanna; Farchione, Todd J; Barlow, David H

    2018-04-01

    Patients' outcome expectancies and the working alliance are two psychotherapy process variables that researchers have found to be associated with treatment outcome, irrespective of treatment approach and problem area. Despite this, little is known about the mechanisms accounting for this association, and whether contextual factors (e.g., psychotherapy type) impact the strength of these relationships. The primary aim of this study was to examine whether patient-rated working alliance quality mediates the relationship between outcome expectancies and pre- to post-treatment change in anxiety symptoms using data from a recent randomized clinical trial comparing a transdiagnostic treatment (the Unified Protocol [UP]; Barlow et al., 2011a; Barlow, Sauer-Zavala, et al., in press) to single diagnosis protocols (SDPs) for patients with a principal heterogeneous anxiety disorder ( n = 179). The second aim was to explore whether cognitive-behavioral treatment condition (UP versus SDP) moderated this indirect relationship. Results from mediation and moderated mediation models indicated that, when collapsing across the two treatment conditions, the relationship between expectancies and outcome was partially mediated by the working alliance ( B = .037, SE = .05, 95% CI [.005, .096]). Interestingly, within-condition analyses showed that this conditional indirect effect was only present for SDP patients, whereas in the UP condition, working alliance did not account for the association between expectancies and outcome. These findings suggest that outcome expectancies and working alliance quality may interact to influence treatment outcomes, and that the nature and strength of the relationships among these constructs may differ as a function of the specific cognitive-behavioral treatment approach utilized.

  17. Testing the Causal Direction of Mediation Effects in Randomized Intervention Studies.

    Science.gov (United States)

    Wiedermann, Wolfgang; Li, Xintong; von Eye, Alexander

    2018-05-21

    In a recent update of the standards for evidence in research on prevention interventions, the Society of Prevention Research emphasizes the importance of evaluating and testing the causal mechanism through which an intervention is expected to have an effect on an outcome. Mediation analysis is commonly applied to study such causal processes. However, these analytic tools are limited in their potential to fully understand the role of theorized mediators. For example, in a design where the treatment x is randomized and the mediator (m) and the outcome (y) are measured cross-sectionally, the causal direction of the hypothesized mediator-outcome relation is not uniquely identified. That is, both mediation models, x → m → y or x → y → m, may be plausible candidates to describe the underlying intervention theory. As a third explanation, unobserved confounders can still be responsible for the mediator-outcome association. The present study introduces principles of direction dependence which can be used to empirically evaluate these competing explanatory theories. We show that, under certain conditions, third higher moments of variables (i.e., skewness and co-skewness) can be used to uniquely identify the direction of a mediator-outcome relation. Significance procedures compatible with direction dependence are introduced and results of a simulation study are reported that demonstrate the performance of the tests. An empirical example is given for illustrative purposes and a software implementation of the proposed method is provided in SPSS.

  18. Mediated moderation in combined cognitive behavioral therapy versus component treatments for generalized anxiety disorder.

    Science.gov (United States)

    Newman, Michelle G; Fisher, Aaron J

    2013-06-01

    This study examined (a) duration of generalized anxiety disorder (GAD) as a moderator of cognitive behavioral therapy (CBT) versus its components (cognitive therapy and self-control desensitization) and (b) increases in dynamic flexibility of anxious symptoms during the course of psychotherapy as a mediator of this moderation. Degree of dynamic flexibility in daily symptoms was quantified as the inverse of spectral power due to daily to intradaily oscillations in four-times-daily diary data (Fisher, Newman, & Molenaar, 2011). This was a secondary analysis of the data of Borkovec, Newman, Pincus, and Lytle (2002). Seventy-six participants with a principle diagnosis of GAD were assigned randomly to combined CBT (n = 24), cognitive therapy (n = 25), or self-control desensitization (n = 27). Duration of GAD moderated outcome such that those with longer duration showed greater reliable change from component treatments than they showed from CBT, whereas those with shorter duration fared better in response to CBT. Decreasing predictability in daily and intradaily oscillations of anxiety symptoms during therapy reflected less rigidity and more flexible responding. Increases in flexibility over the course of therapy fully mediated the moderating effect of GAD duration on condition, indicating a mediated moderation process. Individuals with longer duration of GAD may respond better to more focused treatments, whereas those with shorter duration of GAD may respond better to a treatment that offers more coping strategies. Importantly, the mechanism by which this moderation occurs appears to be the establishment of flexible responding during treatment.

  19. Prevention strategies for herpes zoster and post-herpetic neuralgia

    Science.gov (United States)

    Levin, Myron J.; Gershon, Anne A.; Dworkin, Robert H.; Brisson, Marc; Stanberry, Lawrence

    2017-01-01

    SUMMARY Impairment of varicella zoster virus (VZV)-specific cell-mediated immunity, including impairment due to immunosenescence, is associated with an increased risk of developing herpes zoster (HZ), whereas levels of anti-VZV antibodies do not correlate with HZ risk. This crucial role of VZV-specific cell-mediated immunity suggests that boosting these responses by vaccination will be an effective strategy for reducing the burden of HZ. Other strategies focus on preventing the major complication of HZ – post-herpetic neuralgia. These strategies include pre-emptive treatment with drugs such as tricyclic antidepressants, anticonvulsants and analgesics. PMID:20510262

  20. Mapping the evidence for the prevention and treatment of eating disorders in young people

    Science.gov (United States)

    2014-01-01

    Abstract Eating disorders often develop during adolescence and young adulthood, and are associated with significant psychological and physical burden. Identifying evidence-based interventions is critical and there is need to take stock of the extant literature, to inform clinical practice regarding well-researched interventions and to direct future research agendas by identifying gaps in the evidence base. Aim To investigate and quantify the nature and distribution of existing high-quality research on the prevention and treatment of eating disorders in young people using evidence mapping methodology. Method A systematic search for prevention and treatment intervention studies in adolescents and young adults (12–25 years) was conducted using EMBASE, PSYCINFO and MEDLINE. Studies were screened and mapped according to disorder, intervention modality, stage of eating disorder and study design. Included studies were restricted to controlled trials and systematic reviews published since 1980. Results The eating disorders evidence map included 197 trials and 22 systematic reviews. Prevention research was dominated by trials of psychoeducation (PE). Bulimia nervosa (BN) received the most attention in the treatment literature, with cognitive behavioural therapy (CBT) and antidepressants the most common interventions. For anorexia nervosa (AN), family based therapy (FBT) was the most studied. Lacking were trials exploring treatments for binge eating disorder (BED) and eating disorder not otherwise specified (EDNOS). Relapse prevention strategies were notably absent across the eating disorders. Conclusions Despite substantial literature devoted to the prevention and treatment of eating disorders in young people, the evidence base is not well established and significant gaps remain. For those identified as being at-risk, there is need for prevention research exploring strategies other than passive PE. Treatment interventions targeting BED and EDNOS are required, as are

  1. Infection prevention and control in deployed military medical treatment facilities.

    Science.gov (United States)

    Hospenthal, Duane R; Green, Andrew D; Crouch, Helen K; English, Judith F; Pool, Jane; Yun, Heather C; Murray, Clinton K

    2011-08-01

    Infections have complicated the care of combat casualties throughout history and were at one time considered part of the natural history of combat trauma. Personnel who survived to reach medical care were expected to develop and possibly succumb to infections during their care in military hospitals. Initial care of war wounds continues to focus on rapid surgical care with debridement and irrigation, aimed at preventing local infection and sepsis with bacteria from the environment (e.g., clostridial gangrene) or the casualty's own flora. Over the past 150 years, with the revelation that pathogens can be spread from patient to patient and from healthcare providers to patients (including via unwashed hands of healthcare workers, the hospital environment and fomites), a focus on infection prevention and control aimed at decreasing transmission of pathogens and prevention of these infections has developed. Infections associated with combat-related injuries in the recent operations in Iraq and Afghanistan have predominantly been secondary to multidrug-resistant pathogens, likely acquired within the military healthcare system. These healthcare-associated infections seem to originate throughout the system, from deployed medical treatment facilities through the chain of care outside of the combat zone. Emphasis on infection prevention and control, including hand hygiene, isolation, cohorting, and antibiotic control measures, in deployed medical treatment facilities is essential to reducing these healthcare-associated infections. This review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma.

  2. Implementing intermittent preventive treatment for malaria in pregnancy

    DEFF Research Database (Denmark)

    Mubyazi, Godfrey Martin; Magnussen, Pascal; Goodman, Catherine

    2011-01-01

    Introduction Implementing Intermittent Preventive Treatment for malaria in Pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) through antenatal care (ANC) clinics is recommended for malaria endemic countries. The vast biomedical literature on malaria prevention focuses more on the epidemiological...... of the recommended interventions. Objective To review literature on policy advances, achievements, constraints and challenges to malaria IPTp implementation, emphasising its operational feasibility in the context of health-care financing, provision and uptake, resource constraints and psychosocial factors in Africa...... discriminatory socio-cultural values on and attitudes towards SP, malaria, and quality of ANC; supply and cost of SP at health facilities; understaffing and demoralised staff; ambiguity and impracticability of user-fee exemption policy guidelines on essential ANC services; implementing IPTp, bednets, HIV...

  3. Methods employed in the prevention and treatment of malaria ...

    African Journals Online (AJOL)

    onasoga olayinka

    communities, health system, and workforce.8 The financial loss due to malaria annually is estimated ... in the form of treatment costs, prevention, loss of productivity and earning due to days lost from illness etc which whittle away Nigeria's prospects for development.9 .... combine the herbal medicine with orthodox drugs.

  4. Adherence to technology-mediated insomnia treatment: a meta-analysis, interviews, and focus groups

    NARCIS (Netherlands)

    Horsch, C.; Lancee, J.; Beun, R.J.; Neerincx, M.A.; Brinkman, W.-P.

    2015-01-01

    Background: Several technologies have been proposed to support the reduction of insomnia complaints. A user-centered assessment of these technologies could provide insight into underlying factors related to treatment adherence. Objective: Gaining insight into adherence to technology-mediated

  5. Mediation and Moderation of Psychological Pain Treatments: Response Expectancies and Hypnotic Suggestibility

    Science.gov (United States)

    Milling, Leonard S.; Reardon, John M.; Carosella, Gina M.

    2006-01-01

    The mediator role of response expectancies and the moderator role of hypnotic suggestibility were evaluated in the analogue treatment of pain. Approximately 1,000 participants were assessed for hypnotic suggestibility. Later, as part of a seemingly unrelated experiment, 188 of these individuals were randomly assigned to distraction,…

  6. The mediation as an apt tool for the prevention of crime as result of gender violence

    OpenAIRE

    Yaíma Águila Gutiérrez; Marileydis Pino Rosa

    2017-01-01

    Violence based in gender is an actual, social, historical and cultural matter. It affects to million persons around the world in the personal, familiar and social ambit. Violence based in gender could damage relationships and also could become in a crime. Mediation is an apt tool to use before the intervention of law for solving gender violence´s conflicts which could need the intervention of criminal law. Those reasons show that is necessary the prevention of gender violence so is important ...

  7. Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer.

    Science.gov (United States)

    Jeyabalan, Jeyaprakash; Aqil, Farrukh; Munagala, Radha; Annamalai, Lakshmanan; Vadhanam, Manicka V; Gupta, Ramesh C

    2014-05-07

    Berries are gaining increasing importance lately for their chemopreventive and therapeutic potential against several cancers. In earlier studies, a blueberry-supplemented diet has shown protection against 17β-estradiol (E2)-mediated mammary tumorigenesis. This study tested both preventive and therapeutic activities of diet supplemented with whole blueberry powder (50:50 blend of Tifblue and Rubel). Animals received 5% blueberry diet, either 2 weeks prior to or 12 weeks after E2 treatment in preventive and therapeutic groups, respectively. Both interventions delayed the tumor latency for palpable mammary tumors by 28 and 37 days, respectively. Tumor volume and multiplicity were also reduced significantly in both modes. The effect on mammary tumorigenesis was largely due to down-regulation of CYP 1A1 and ER-α gene expression and also favorable modulation of microRNA (miR-18a and miR-34c) levels. These data suggest that the blueberry blend tested is effective in inhibiting E2-mediated mammary tumorigenesis in both preventive and therapeutic modes.

  8. HIV Treatment and Prevention: A Simple Model to Determine Optimal Investment.

    Science.gov (United States)

    Juusola, Jessie L; Brandeau, Margaret L

    2016-04-01

    To create a simple model to help public health decision makers determine how to best invest limited resources in HIV treatment scale-up and prevention. A linear model was developed for determining the optimal mix of investment in HIV treatment and prevention, given a fixed budget. The model incorporates estimates of secondary health benefits accruing from HIV treatment and prevention and allows for diseconomies of scale in program costs and subadditive benefits from concurrent program implementation. Data sources were published literature. The target population was individuals infected with HIV or at risk of acquiring it. Illustrative examples of interventions include preexposure prophylaxis (PrEP), community-based education (CBE), and antiretroviral therapy (ART) for men who have sex with men (MSM) in the US. Outcome measures were incremental cost, quality-adjusted life-years gained, and HIV infections averted. Base case analysis indicated that it is optimal to invest in ART before PrEP and to invest in CBE before scaling up ART. Diseconomies of scale reduced the optimal investment level. Subadditivity of benefits did not affect the optimal allocation for relatively low implementation levels. The sensitivity analysis indicated that investment in ART before PrEP was optimal in all scenarios tested. Investment in ART before CBE became optimal when CBE reduced risky behavior by 4% or less. Limitations of the study are that dynamic effects are approximated with a static model. Our model provides a simple yet accurate means of determining optimal investment in HIV prevention and treatment. For MSM in the US, HIV control funds should be prioritized on inexpensive, effective programs like CBE, then on ART scale-up, with only minimal investment in PrEP. © The Author(s) 2015.

  9. Gaps in clinical prevention and treatment for alcohol use disorders: costs, consequences, and strategies.

    Science.gov (United States)

    Willenbring, Mark L

    2013-01-01

    Heavy drinking causes significant morbidity, premature mortality, and other social and economic burdens on society, prompting numerous prevention and treatment efforts to avoid or ameliorate the prevalence of heavy drinking and its consequences. However, the impact on public health of current selective (i.e., clinical) prevention and treatment strategies is unclear. Screening and brief counseling for at-risk drinkers in ambulatory primary care has the strongest evidence for efficacy, and some evidence indicates this approach is cost-effective and reduces excess morbidity and dysfunction. Widespread implementation of screening and brief counseling of nondependent heavy drinkers outside of the medical context has the potential to have a large public health impact. For people with functional dependence, no appropriate treatment and prevention approaches currently exist, although such strategies might be able to prevent or reduce the morbidity and other harmful consequences associated with the condition before its eventual natural resolution. For people with alcohol use disorders, particularly severe and recurrent dependence, treatment studies have shown improvement in the short term. However, there is no compelling evidence that treatment of alcohol use disorders has resulted in reductions in overall disease burden. More research is needed on ways to address functional alcohol dependence as well as severe and recurrent alcohol dependence.

  10. Caregiver acceptability and preferences for early childhood caries preventive treatments for Hispanic children.

    Science.gov (United States)

    Adams, Sally H; Hyde, Susan; Gansky, Stuart A

    2009-01-01

    The objective of this study was to determine caregiver treatment acceptability and preferences for five preventive dental treatments for early childhood caries in young Hispanic children. We interviewed 211 parents/caregivers of Hispanic children attending Head Start programs regarding their acceptability of, and preferences for, five standard preventive dental treatments for young children. Treatments assessed were toothbrushing with fluoride toothpaste, fluoride varnish, and xylitol in food for children, and xylitol gum and chlorhexidine rinse for mothers. The interview assessment included presentation of illustrated cards with verbal description of treatment, photograph/video clip, and treatment samples. Parents rated the acceptability of each treatment (1-5 scale) and treatment preferences within each of 10 possible pairs. Individual treatment preferences were summed to create overall preference scores (range 0-4). All treatments were rated as highly acceptable, however, there were differences (range 4.6-4.9; Friedman chi-square = 23.4, P treatment preferences revealed greater variability (means ranged 1.4-2.6; Friedman chi-square = 128.2, P treatments were highly acceptable, however, when choosing among treatments overall, fluoride varnish and toothbrushing were favored over other treatments.

  11. Effects of a combined parent-student alcohol prevention program on intermediate factors and adolescents' drinking behavior: A sequential mediation model.

    Science.gov (United States)

    Koning, Ina M; Maric, Marija; MacKinnon, David; Vollebergh, Wilma A M

    2015-08-01

    Previous work revealed that the combined parent-student alcohol prevention program (PAS) effectively postponed alcohol initiation through its hypothesized intermediate factors: increase in strict parental rule setting and adolescents' self-control (Koning, van den Eijnden, Verdurmen, Engels, & Vollebergh, 2011). This study examines whether the parental strictness precedes an increase in adolescents' self-control by testing a sequential mediation model. A cluster randomized trial including 3,245 Dutch early adolescents (M age = 12.68, SD = 0.50) and their parents randomized over 4 conditions: (1) parent intervention, (2) student intervention, (3) combined intervention, and (4) control group. Outcome measure was amount of weekly drinking measured at age 12 to 15; baseline assessment (T0) and 3 follow-up assessments (T1-T3). Main effects of the combined and parent intervention on weekly drinking at T3 were found. The effect of the combined intervention on weekly drinking (T3) was mediated via an increase in strict rule setting (T1) and adolescents' subsequent self-control (T2). In addition, the indirect effect of the combined intervention via rule setting (T1) was significant. No reciprocal sequential mediation (self-control at T1 prior to rules at T2) was found. The current study is 1 of the few studies reporting sequential mediation effects of youth intervention outcomes. It underscores the need of involving parents in youth alcohol prevention programs, and the need to target both parents and adolescents, so that change in parents' behavior enables change in their offspring. (c) 2015 APA, all rights reserved).

  12. Prevention and treatment of nutritional rickets.

    Science.gov (United States)

    Shaw, N J

    2016-11-01

    Nutritional rickets continues to be a significant health problem for children worldwide with recent evidence of increasing incidence in many developed countries. It is due to vitamin D deficiency and/or inadequate dietary calcium intake with variation in the relative contributions of each of these dependant on environmental factors such a dietary intake and sunlight exposure. Key to the prevention of rickets is ensuring that pregnant women and their infants receive vitamin D supplementation with good evidence from randomised controlled trials that infants who receive 400iu daily can achieve levels of 25 hydroxyvitamin D of >50nmol/l. However, public health implementation of daily supplementation is more challenging with a need to revisit food fortification strategies to ensure optimal vitamin D status of the population. Treatment of nutritional rickets has traditionally been with vitamin D2 or D3, often given as a daily oral dose for several weeks until biochemical and radiological evidence of healing. However, other treatment regimes with single or intermittent high doses have also proved to be effective. It is now recognised that oral calcium either as dietary intake or supplements should be routinely used in conjunction with vitamin D for treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility

    Directory of Open Access Journals (Sweden)

    Alexandre Fisette

    2016-10-01

    Full Text Available α/β-Hydrolase domain 6 (ABHD6 is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG. Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMHKO have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMHKO mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet. Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility.

  14. Preventive and therapeutic effects of blueberry (Vaccinium corymbosum) extract against DSS-induced ulcerative colitis by regulation of antioxidant and inflammatory mediators.

    Science.gov (United States)

    Pervin, Mehnaz; Hasnat, Md Abul; Lim, Ji-Hong; Lee, Yoon-Mi; Kim, Eun Ok; Um, Byung-Hun; Lim, Beong Ou

    2016-02-01

    Inflammatory bowel disease (IBD) is an inflammatory disorder caused by hyperactivation of effector immune cells that produce high levels of proinflammatory cytokines. The aims of our study were to determine whether orally administered blueberry extract (BE) could attenuate or prevent the development of experimental colitis in mice and to elucidate the mechanism of action. Female Balb/C mice (n=7) were randomized into groups differing in treatment conditions (prevention and treatment) and dose of BE (50 mg/kg body weight). Acute ulcerative colitis was induced by oral administration of 3% dextran sodium sulfate for 7 days in drinking water. Colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. BE significantly decreased disease activity index and improved the macroscopic and histological score of colons when compared to the colitis group (P<.05). BE markedly attenuated myeloperoxidase accumulation (colitis group 54.97±2.78 nmol/mg, treatment group 30.78±1.33 nmol/mg) and malondialdehyde in colon and prostaglandin E2 level in serum while increasing the levels of superoxide dismutase and catalase (colitis group 11.94±1.16 U/ml, BE treatment group 16.49±0.39 U/ml) compared with the colitis group (P<.05). mRNA levels of the cyclooxygenase (COX)-2, interferon-γ, interleukin (IL)-1β and inducible nitric oxide synthase cytokines were determined by reverse transcriptase polymerase chain reaction. Immunohistochemical analysis showed that BE attenuates the expression of COX-2 and IL-1β in colonic tissue. Moreover, BE reduced the nuclear translocation of nuclear transcription factor kappa B (NF-κB) by immunofluorescence analysis. Thus, the anti-inflammatory effect of BE at colorectal sites is a result of a number of mechanisms: antioxidation, down-regulation of the expression of inflammatory mediators and inhibition of the nuclear translocation of NF-κB. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Targeting burn prevention in Ukraine: evaluation of base knowledge in burn prevention and first aid treatment.

    Science.gov (United States)

    Gamelli, Liza; Mykychack, Iryna; Kushnir, Antin; Driscoll, Daniel N; Fuzaylov, Gennadiy

    2015-01-01

    Burn prevention has been identified by the World Health Organization (WHO) as a topic in need of further investigation and education throughout the world, with an increased need in low-income countries. It has been noted that implementing educational programs for prevention in high income countries has aided in lowering the rate of burn injuries. The purpose of this study is to evaluate the current education level of knowledge of prevention and first aid treatment of scald burns. A prevention campaign will target these educational needs as a part of an outreach program to improve burn care in Ukraine. The research team evaluated the current health structure in Ukraine and how it could benefit from the increased knowledge of burn prevention and first aid. A test was designed to assess the baseline level of knowledge with regard to first aid and scald prevention in parents, pregnant woman, and healthcare and daycare providers. A total of 14,456 tests were sent to pediatric clinics, obstetrician clinics, and daycare facilities to test respondents. A total of 6,120 completed tests were returned. Doctors presented with the highest level of knowledge averaging 77.0% on prevention and 67.5% on first aid while daycare workers presented the largest gap in knowledge at 65.0% in prevention and 54.3% in first aid. Interest in further educational materials was reported by 92% of respondents. The results of this study clearly show a lack of knowledge in first aid and prevention of scald burn injury in all the populations tested.

  16. Safety climate and workplace violence prevention in state-run residential addiction treatment centers.

    Science.gov (United States)

    Lipscomb, Jane A; London, M; Chen, Y M; Flannery, K; Watt, M; Geiger-Brown, J; Johnson, J V; McPhaul, K

    2012-01-01

    To examine the association between violence prevention safety climate measures and self reported violence toward staff in state-run residential addiction treatment centers. In mid-2006, 409 staff from an Eastern United States state agency that oversees a system of thirteen residential addiction treatment centers (ATCs) completed a self-administered survey as part of a comprehensive risk assessment. The survey was undertaken to identify and measure facility-level risk factors for violence, including staff perceptions of the quality of existing US Occupational Safety and Health Administration (OSHA) program elements, and ultimately to guide violence prevention programming. Key informant interviews and staff focus groups provided researchers with qualitative data with which to understand safety climate and violence prevention efforts within these work settings. The frequency with which staff reported experiencing violent behavior ranged from 37% for "clients raised their voices in a threatening way to you" to 1% for "clients pushed, hit, kicked, or struck you". Findings from the staff survey included the following significant predictors of violence: "client actively resisting program" (OR=2.34, 95% CI=1.35, 4.05), "working with clients for whom the history of violence is unknown" (OR=1.91, 95% CI=1.18, 3.09) and "management commitment to violence prevention" reported as "never/hardly ever" and "seldom or sometimes" (OR=4.30 and OR=2.31 respectively), while controlling for other covariates. We utilized a combination of qualitative and quantitative research methods to begin to describe the risk and potential for violence prevention in this setting. The prevalence of staff physical violence within the agency's treatment facilities was lower than would be predicted. Possible explanations include the voluntary nature of treatment programs; strong policies and consequences for resident behavior and ongoing quality improvement efforts. Quantitative data identified low

  17. Pharmacologic strategies in the prevention and treatment of corneal transplant rejection.

    Science.gov (United States)

    Tabbara, Khalid F

    2008-06-01

    Corneal transplantation remains one of the most successful organ transplantation procedures in humans. The unique structure of the cornea, with its absence of blood vessels and corneal lymphatic, allows the survival of corneal allograft. Recent advances in sutures, storage media, microsurgical instrumentation, and new pharmacological strategies have greatly improved the success of corneal transplantation and the prevention of corneal allograft rejection. Our strategies in the management and prevention of corneal graft rejection can modify and improve the survival of corneal allografts. Preoperative evaluation, understanding the risk factors, and management of ocular surface disorders may greatly improve the survival of the corneal transplant. Early recognition of corneal allograft rejection and aggressive treatment may improve the survival of the corneal graft. Furthermore, patients who undergo corneal transplantation should be maintained under close ophthalmic surveillance and patients should be informed to report immediately whenever symptoms of corneal graft rejection occur. The mainstay of therapy is topical corticosteroids. In severe cases, periocular, intravenous, and oral corticosteroids therapy can be rendered. New therapeutic modalities such as cyclosporine, tacrolimus, daclizumab, mycophenolate mofetil, leflunomide, rapamycin, and others may prove to be of help in the prevention and treatment of corneal graft rejection. Early recognition of corneal graft rejection and prompt treatment are mandatory for the successful survival of the corneal allograft.

  18. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  19. Prevention and treatment of the orofacial complications of radiotherapy

    International Nuclear Information System (INIS)

    Rothwell, B.R.

    1987-01-01

    Radiotherapy of malignant head and neck tumors often causes extensive, permanent changes in salivary glands, peridental alveolar bone, and mucosal structures. Dental neglect and inappropriate dental management can cause complications. The potential orofacial side effects of radiotherapy are reviewed, as are preventive strategies for the dental treatment of patients scheduled to undergo radiotherapy

  20. Trophic factors in the treatment and prevention of alimentary tract mucositis

    DEFF Research Database (Denmark)

    Rathe, Mathias; Shen, Rene L; Sangild, Per T

    2018-01-01

    PURPOSE OF REVIEW: Mucositis is a common adverse effect of cytotoxic anticancer treatment with serious implications for the quality of life, morbidity and mortality of cancers patients. Although, evidence supporting the use of certain treatments exists there is no gold standard for preventing...... clinical trials and uniform reporting of mucositis, are important elements to help establish new standard interventions that can be included into the continuously updated clinical recommendations for treatment of mucositis....