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Sample records for brain cannabinoid type-1

  1. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    International Nuclear Information System (INIS)

    Kronfeld, Andrea; Müller-Forell, Wibke; Buchholz, Hans-Georg; Maus, Stephan; Reuss, Stefan; Schreckenberger, Mathias; Miederer, Isabelle; Lutz, Beat

    2015-01-01

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [ 18 F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL templates

  2. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    Energy Technology Data Exchange (ETDEWEB)

    Kronfeld, Andrea; Müller-Forell, Wibke [Institute of Neuroradiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Buchholz, Hans-Georg; Maus, Stephan; Reuss, Stefan; Schreckenberger, Mathias; Miederer, Isabelle, E-mail: isabelle.miederer@unimedizin-mainz.de [Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Lutz, Beat [Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, Mainz 55128 (Germany)

    2015-12-15

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [{sup 18}F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL

  3. Preclinical evaluation and quantification of [(18)F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    OpenAIRE

    Casteels, Cindy; Koole, Michel; Celen, Sofie; Bormans, Guy; Van Laere, Koen

    2012-01-01

    PURPOSE: [(18)F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [(18)F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. METHODS: Dynamic small-animal PET scans with [(18)F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blo...

  4. Cannabinoids on the Brain

    Directory of Open Access Journals (Sweden)

    Andrew J. Irving

    2002-01-01

    Full Text Available Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

  5. Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    International Nuclear Information System (INIS)

    Casteels, Cindy; Koole, Michel; Laere, Koen van; Celen, Sofie; Bormans, Guy

    2012-01-01

    [ 18 F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [ 18 F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [ 18 F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (V T ) of [ 18 F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification. The percentage of intact [ 18 F]MK-9470 in arterial plasma samples was 80 ± 23 % at 10 min, 38 ± 30 % at 40 min and 13 ± 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. V T values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (≤10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [ 18 F]MK-9470 V T , but was correlated. A correlation between [ 18 F]MK-9470 V T and SUV in the brain was also found (R 2 = 0.26-0.33; p ≤ 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [ 18 F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input. (orig.)

  6. Computer modeling of Cannabinoid receptor type 1

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    Sapundzhi Fatima

    2018-01-01

    Full Text Available Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE. They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

  7. Preclinical evaluation and quantification of [{sup 18}F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Casteels, Cindy [K.U. Leuven, University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); Koole, Michel; Laere, Koen van [K.U. Leuven, University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); Celen, Sofie; Bormans, Guy [K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); K.U. Leuven, Laboratory for Radiopharmacy, Leuven (Belgium)

    2012-09-15

    [{sup 18}F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [{sup 18}F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [{sup 18}F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (V{sub T}) of [{sup 18}F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification. The percentage of intact [{sup 18}F]MK-9470 in arterial plasma samples was 80 {+-} 23 % at 10 min, 38 {+-} 30 % at 40 min and 13 {+-} 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. V{sub T} values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability ({<=}10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [{sup 18}F]MK-9470 V{sub T}, but was correlated. A correlation between [{sup 18}F]MK-9470 V{sub T} and SUV in the brain was also found (R {sup 2} = 0.26-0.33; p {<=} 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [{sup 18}F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input. (orig.)

  8. Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

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    Alessandro Silvani

    Full Text Available Cannabinoid type 1 (CB1 receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD. We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD and HFD. CB1 cannabinoid receptor knock-out (KO and wild-type (WT mice were fed SD or HFD for 4 months (n = 9-10 per group. Mice were instrumented with electroencephalographic (EEG and electromyographic electrodes. Recordings were performed during baseline (48 hours, sleep deprivation (gentle handling, 6 hours, sleep recovery (18 hours, and after cage switch (insomnia model paradigm, 6 hours. We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS and rapid-eye-movement sleep (REMS than WT during the dark (active period but not during the light (rest period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

  9. Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

    International Nuclear Information System (INIS)

    Casteels, Cindy; Martinez, Emili; Camon, Lluisa; Vera, Nuria de; Planas, Anna M.; Bormans, Guy; Baekelandt, Veerle; Laere, Koen van

    2010-01-01

    Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington's disease (HD). Using [ 18 F]MK-9470 and small animal PET, we investigated cerebral changes in type 1 cannabinoid (CB 1 ) receptor binding in the quinolinic acid (QA) rat model of HD in relation to glucose metabolism, dopamine D 2 receptor availability and amphetamine-induced turning behaviour. Twenty-one Wistar rats (11 QA and 10 shams) were investigated. Small animal PET acquisitions were conducted on a Focus 220 with approximately 18 MBq of [ 18 F]MK-9470, [ 18 F]FDG and [ 11 C]raclopride. Relative glucose metabolism and parametric CB 1 receptor and D 2 binding images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping (SPM2). In the QA model, [ 18 F]MK-9470 uptake, glucose metabolism and D 2 receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p -5 ), while an increase for these markers was observed on the contralateral side (>5%, all p -4 ). [ 18 F]MK-9470 binding was also increased in the cerebellum (p = 2.10 -5 ), where it was inversely correlated to the number of ipsiversive turnings (p = 7.10 -6 ), suggesting that CB 1 receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p = 1.10 -6 ). These data point to in vivo changes in endocannabinoid transmission, specifically for CB 1 receptors in the QA model, with involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D 2 and CB 1 neurotransmission in the contralateral hemisphere. (orig.)

  10. The future of type 1 cannabinoid receptor allosteric ligands.

    Science.gov (United States)

    Alaverdashvili, Mariam; Laprairie, Robert B

    2018-02-01

    Allosteric modulation of the type 1 cannabinoid receptor (CB1R) holds great therapeutic potential. This is because allosteric modulators do not possess intrinsic efficacy, but instead augment (positive allosteric modulation) or diminish (negative allosteric modulation) the receptor's response to endogenous ligand. Consequently, CB1R allosteric modulators have an effect ceiling which allows for the tempering of CB1R signaling without the desensitization, tolerance, dependence, and psychoactivity associated with orthosteric compounds. Pain, movement disorders, epilepsy, obesity are all potential therapeutic targets for CB1R allosteric modulation. Several challenges exist for the development of CB1R allosteric modulators, such as receptor subtype specificity, translation to in vivo systems, and mixed allosteric/agonist/inverse agonist activity. Despite these challenges, elucidation of crystal structures of CB1R and compound design based on structure-activity relationships will advance the field. In this review, we will cover recent progress for CB1R allosteric modulators and discuss the future promise of this research.

  11. Cannabinoid receptor type-1: breaking the dogmas [version 1; referees: 3 approved

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    Arnau Busquets Garcia

    2016-05-01

    Full Text Available The endocannabinoid system (ECS is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids, and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1. In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells and intracellular compartments (e.g., mitochondria. Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons. Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

  12. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers

    OpenAIRE

    Hirvonen, J; Goodwin, RS; Li, C-T; Terry, GE; Zoghbi, SS; Morse, C; Pike, VW; Volkow, ND; Huestis, MA; Innis, RB

    2011-01-01

    Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke ca...

  13. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.

    Science.gov (United States)

    Hirvonen, J; Goodwin, R S; Li, C-T; Terry, G E; Zoghbi, S S; Morse, C; Pike, V W; Volkow, N D; Huestis, M A; Innis, R B

    2012-06-01

    Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

  14. Neurofibromatosis type 1: brain stem tumours

    International Nuclear Information System (INIS)

    Bilaniuk, L.T.; Molloy, P.T.; Zimmerman, R.A.; Phillips, P.C.; Vaughan, S.N.; Liu, G.T.; Sutton, L.N.; Needle, M.

    1997-01-01

    We describe the clinical and imaging findings of brain stem tumours in patients with neurofibromatosis type 1 (NF1). The NF1 patients imaged between January 1984 and January 1996 were reviewed and 25 patients were identified with a brain stem tumour. Clinical, radiographical and pathological results were obtained by review of records and images. Brain stem tumour identification occurred much later than the clinical diagnosis of NF1. Medullary enlargement was most frequent (68 %), followed by pontine (52 %) and midbrain enlargement (44 %). Patients were further subdivided into those with diffuse (12 patients) and those with focal (13 patients) tumours. Treatment for hydrocephalus was required in 67 % of the first group and only 15 % of the second group. Surgery was performed in four patients and revealed fibrillary astrocytomas, one of which progressed to an anaplastic astrocytoma. In 40 % of patients both brain stem and optic pathway tumours were present. The biological behaviour of brain stem tumours in NF1 is unknown. Diffuse tumours in the patients with NF1 appear to have a much more favourable prognosis than patients with similar tumours without neurofibromatosis type 1. (orig.). With 7 figs., 3 tabs

  15. Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

    Energy Technology Data Exchange (ETDEWEB)

    Thanos, P.K.; Wang, G.; Thanos, P.K.; Gopez, V.; Delis, F.; Michaelides, M.; Grand, D.K.; Wang, G.-J.; Kunos, G.; Volkow, N.D.

    2011-01-01

    The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [{sup 3}H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.

  16. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p...

  17. Studies of the brain cannabinoid system using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S.J.; Volkow, N.D.

    1995-10-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.

  18. Studies of the brain cannabinoid system using positron emission tomography

    International Nuclear Information System (INIS)

    Gatley, S.J.; Volkow, N.D.

    1995-01-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available

  19. Marijuana and cannabinoid regulation of brain reward circuits

    OpenAIRE

    Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

    2004-01-01

    The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Δ9-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation o...

  20. Marijuana and cannabinoid regulation of brain reward circuits.

    Science.gov (United States)

    Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

    2004-09-01

    The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

  1. Cannabinoid Type-1 Receptor Gene Polymorphisms Are Associated with Central Obesity in a Southern Brazilian Population

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    Janaína P. Jaeger

    2008-01-01

    Full Text Available The CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in energy balance control, stimulating appetite and increasing body weight in wasting syndromes. Different studies have investigated the relationship between polymorphisms of the cannabinoid receptor 1 (CNR1 gene and obesity with conflicting results. In the present study, we investigated the 1359G/A (rs1049353, 3813A/G (rs12720071 and 4895A/G (rs806368 polymorphisms in the CNR1 gene in a Brazilian population of European descent. To verify the association between these variants and obesity-related traits in this population, 756 individuals were genotyped by PCR-RFLP methods. The 4895G allele was associated with waist to hip ratio (WHR (P = 0.014; P = 0.042 after Bonferroni correction. An additive effect with the GAA haplotype was associated with WHR (P = 0.028, although this statistical significance disappeared after Bonferroni correction (P = 0.084. No significant association was observed between the genotypes of the 1359G/A and 3813A/G polymorphisms and any of the quantitative variables investigated. Our findings suggest that CNR1 gene polymorphism is associated with central obesity in this Brazilian population of European ancestry.

  2. Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease.

    Science.gov (United States)

    Laprairie, Robert B; Bagher, Amina M; Kelly, Melanie E M; Denovan-Wright, Eileen M

    2016-03-01

    Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh(Q7/Q7)) or mutant huntingtin protein (STHdh(Q111/Q111)). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gαi/o, Gαs, Gαq, Gβγ, and β-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The Emax of Gαi/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gαi/o/Gβγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-arrestin-biased--such as THC found at high levels in modern varieties of marijuana--may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Type-1 cannabinoid receptors reduce membrane fluidity of capacitated boar sperm by impairing their activation by bicarbonate.

    Directory of Open Access Journals (Sweden)

    Barbara Barboni

    Full Text Available BACKGROUND: Mammalian spermatozoa acquire their full fertilizing ability (so called capacitation within the female genital tract, where they are progressively exposed to inverse gradients of inhibiting and stimulating molecules. METHODOLOGY/PRINCIPAL FINDINGS: In the present research, the effect on this process of anandamide, an endocannabinoid that can either activate or inhibit cannabinoid receptors depending on its concentration, and bicarbonate, an oviductal activatory molecule, was assessed, in order to study the role exerted by the type 1 cannabinoid receptor (CB1R in the process of lipid membrane remodeling crucial to complete capacitation. To this aim, boar sperm were incubated in vitro under capacitating conditions (stimulated by bicarbonate in the presence or in the absence of methanandamide (Met-AEA, a non-hydrolysable analogue of anandamide. The CB1R involvement was studied by using the specific inhibitor (SR141716 or mimicking its activation by adding a permeable cAMP analogue (8Br-cAMP. By an immunocytochemistry approach it was shown that the Met-AEA inhibits the bicarbonate-dependent translocation of CB1R from the post-equatorial to equatorial region of sperm head. In addition it was found that Met-AEA is able to prevent the bicarbonate-induced increase in membrane disorder and the cholesterol extraction, both preliminary to capacitation, acting through a CB1R-cAMP mediated pathway, as indicated by MC540 and filipin staining, EPR spectroscopy and biochemical analysis on whole membranes (CB1R activity and on membrane enriched fraction (C/P content and anisotropy. CONCLUSIONS/SIGNIFICANCE: Altogether, these data demonstrate that the endocannabinoid system strongly inhibits the process of sperm capacitation, acting as membrane stabilizing agent, thus increasing the basic knowledge on capacitation-related signaling and potentially opening new perspectives in diagnostics and therapeutics of male infertility.

  4. Cannabinoid Receptor Type 1 Expression in the Developing Avian Retina: Morphological and Functional Correlation With the Dopaminergic System

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    Luzia da Silva Sampaio

    2018-03-01

    Full Text Available The avian retina has been used as a model to study signaling by different neuro- and gliotransmitters. It is unclear how dopaminergic and cannabinoid systems are related in the retina. Here we studied the expression of type 1 and 2 cannabinoid receptors (CB1 and CB2, as well as monoacylglycerol lipase (MAGL, the enzyme that degrades 2-arachidonoylglycerol (2-AG, during retina development. Our data show that CB1 receptor is highly expressed from embryonic day 5 (E5 until post hatched day 7 (PE7, decreasing its levels throughout development. CB1 is densely found in the ganglion cell layer (GCL and inner plexiform layer (IPL. CB2 receptor was also found from E5 until PE7 with a decrease in its contents from E9 afterwards. CB2 was mainly present in the lamination of the IPL at PE7. MAGL is expressed in all retinal layers, mainly in the IPL and OPL from E9 to PE7 retina. CB1 and CB2 were found both in neurons and glia cells, but MAGL was only expressed in Müller glia. Older retinas (PE7 show CB1 positive cells mainly in the INL and co-expression of CB1 and tyrosine hydroxylase (TH are shown in a few cells when both systems are mature. CB1 co-localized with TH and was heavily associated to D1 receptor labeling in primary cell cultures. Finally, cyclic AMP (cAMP was activated by the selective D1 agonist SKF38393, and inhibited when cultures were treated with WIN55, 212–2 (WIN in a CB1 dependent manner. The results suggest a correlation between the endocannabinoid and dopaminergic systems (DSs during the avian retina development. Activation of CB1 limits cAMP accumulation via D1 receptor activation and may influence embryological parameters during avian retina differentiation.

  5. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of

  6. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8.

    Science.gov (United States)

    De Petrocellis, Luciano; Vellani, Vittorio; Schiano-Moriello, Aniello; Marini, Pietro; Magherini, Pier Cosimo; Orlando, Pierangelo; Di Marzo, Vincenzo

    2008-06-01

    The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Delta(9)-tetrahydrocannabinol (THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), respectively. Furthermore, the endocannabinoid anandamide is known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca2+ in either HEK-293 cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the compounds tested induced TRPA1-mediated Ca2+ elevation in HEK-293 cells with efficacy comparable with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC(50) = 60 nM) and the least potent being CBG and CBD acid (EC(50) = 3.4-12.0 microM). CBC also activated MO-sensitive DRG neurons, although with lower potency (EC(50) = 34.3 microM). Furthermore, although none of the compounds tested activated TRPM8-mediated Ca2+ elevation in HEK-293 cells, they all, with the exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG, THC, and THC acid were equipotent (IC(50) = 70-160 nM), whereas CBD acid was the least potent compound (IC(50) = 0.9-1.6 microM). CBG inhibited Ca2+ elevation also in icilin-sensitive DRG neurons with potency (IC(50) = 4.5 microM) similar to that of anandamide (IC(50) = 10 microM). Our findings suggest that phytocannabinoids and cannabis extracts exert some of their pharmacological actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.

  7. Activation of type-1 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II/III pyramidal neurons of the rat prelimbic cortex

    NARCIS (Netherlands)

    den Boon, F.S.; Werkman, T.R.; Schaafsma-Zhao, Q.; Houthuijs, K.; Vitalis, T.; Kruse, C.G.; Wadman, W.J.; Chameau, P.

    2015-01-01

    Activation of the endocannabinoid (eCB) system by exogenous cannabinoids (drug abuse) can alter the physiology of the brain circuits involved in higher-order cognitive functions such as the medial prefrontal cortex (mPFC). A proper balance between excitation and inhibition (E/I balance) is critical

  8. Spatial distribution of cannabinoid receptor type 1 (CB1 in normal canine central and peripheral nervous system.

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    Jessica Freundt-Revilla

    Full Text Available The endocannabinoid system is a regulatory pathway consisting of two main types of cannabinoid receptors (CB1 and CB2 and their endogenous ligands, the endocannabinoids. The CB1 receptor is highly expressed in the central and peripheral nervous systems (PNS in mammalians and is involved in neuromodulatory functions. Since endocannabinoids were shown to be elevated in cerebrospinal fluid of epileptic dogs, knowledge about the species specific CB receptor expression in the nervous system is required. Therefore, we assessed the spatial distribution of CB1 receptors in the normal canine CNS and PNS. Immunohistochemistry of several regions of the brain, spinal cord and peripheral nerves from a healthy four-week-old puppy, three six-month-old dogs, and one ten-year-old dog revealed strong dot-like immunoreactivity in the neuropil of the cerebral cortex, Cornu Ammonis (CA and dentate gyrus of the hippocampus, midbrain, cerebellum, medulla oblongata and grey matter of the spinal cord. Dense CB1 expression was found in fibres of the globus pallidus and substantia nigra surrounding immunonegative neurons. Astrocytes were constantly positive in all examined regions. CB1 labelled neurons and satellite cells of the dorsal root ganglia, and myelinating Schwann cells in the PNS. These results demonstrate for the first time the spatial distribution of CB1 receptors in the healthy canine CNS and PNS. These results can be used as a basis for further studies aiming to elucidate the physiological consequences of this particular anatomical and cellular distribution.

  9. Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

    Science.gov (United States)

    Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

    2015-08-01

    The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

  10. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-δ

    International Nuclear Information System (INIS)

    Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor

  11. Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model

    International Nuclear Information System (INIS)

    Vandeputte, Caroline; Casteels, Cindy; Koole, Michel; Gerits, Anneleen; Struys, Tom; Veghel, Daisy van; Evens, Nele; Bormans, Guy; Dresselaers, Tom; Himmelreich, Uwe; Lambrichts, Ivo; Laere, Koen van

    2012-01-01

    Recent ex vivo and pharmacological evidence suggests involvement of the endocannabinoid system in the pathophysiology of stroke, but conflicting roles for type 1 and 2 cannabinoid receptors (CB 1 and CB 2 ) have been suggested. The purpose of this study was to evaluate CB 1 and CB 2 receptor binding over time in vivo in a rat photothrombotic stroke model using PET. CB 1 and CB 2 microPET imaging was performed at regular time-points up to 2 weeks after stroke using [ 18 F]MK-9470 and [ 11 C]NE40. Stroke size was measured using MRI at 9.4 T. Ex vivo validation was performed via immunostaining for CB 1 and CB 2 . Immunofluorescent double stainings were also performed with markers for astrocytes (GFAP) and macrophages/microglia (CD68). [ 18 F]MK-9470 PET showed a strong increase in CB 1 binding 24 h and 72 h after stroke in the cortex surrounding the lesion, extending to the insular cortex 24 h after surgery. These alterations were consistently confirmed by CB 1 immunohistochemical staining. [ 11 C]NE40 did not show any significant differences between stroke and sham-operated animals, although staining for CB 2 revealed minor immunoreactivity at 1 and 2 weeks after stroke in this model. Both CB 1 + and CB 2 + cells showed minor immunoreactivity for CD68. Time-dependent and regionally strongly increased CB 1 , but not CB 2 , binding are early consequences of photothrombotic stroke. Pharmacological interventions should primarily aim at CB 1 signalling as the role of CB 2 seems minor in the acute and subacute phases of stroke. (orig.)

  12. Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model

    Energy Technology Data Exchange (ETDEWEB)

    Vandeputte, Caroline; Casteels, Cindy; Koole, Michel; Gerits, Anneleen [KU Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); Struys, Tom [Hasselt University, Laboratory of Histology, Biomedical Research Institute, Hasselt (Belgium); KU Leuven, Biomedical NMR Unit, Leuven (Belgium); Veghel, Daisy van; Evens, Nele; Bormans, Guy [KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); KU Leuven, Laboratory of Radiopharmacy, Leuven (Belgium); Dresselaers, Tom; Himmelreich, Uwe [KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); KU Leuven, Biomedical NMR Unit, Leuven (Belgium); Lambrichts, Ivo [Hasselt University, Laboratory of Histology, Biomedical Research Institute, Hasselt (Belgium); Laere, Koen van [KU Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); UZ Leuven, Division of Nuclear Medicine, Leuven (Belgium)

    2012-11-15

    Recent ex vivo and pharmacological evidence suggests involvement of the endocannabinoid system in the pathophysiology of stroke, but conflicting roles for type 1 and 2 cannabinoid receptors (CB{sub 1} and CB{sub 2}) have been suggested. The purpose of this study was to evaluate CB{sub 1} and CB{sub 2} receptor binding over time in vivo in a rat photothrombotic stroke model using PET. CB{sub 1} and CB{sub 2} microPET imaging was performed at regular time-points up to 2 weeks after stroke using [{sup 18}F]MK-9470 and [{sup 11}C]NE40. Stroke size was measured using MRI at 9.4 T. Ex vivo validation was performed via immunostaining for CB{sub 1} and CB{sub 2}. Immunofluorescent double stainings were also performed with markers for astrocytes (GFAP) and macrophages/microglia (CD68). [{sup 18}F]MK-9470 PET showed a strong increase in CB{sub 1} binding 24 h and 72 h after stroke in the cortex surrounding the lesion, extending to the insular cortex 24 h after surgery. These alterations were consistently confirmed by CB{sub 1} immunohistochemical staining. [{sup 11}C]NE40 did not show any significant differences between stroke and sham-operated animals, although staining for CB{sub 2} revealed minor immunoreactivity at 1 and 2 weeks after stroke in this model. Both CB{sub 1} {sup +} and CB{sub 2} {sup +} cells showed minor immunoreactivity for CD68. Time-dependent and regionally strongly increased CB{sub 1}, but not CB{sub 2}, binding are early consequences of photothrombotic stroke. Pharmacological interventions should primarily aim at CB{sub 1} signalling as the role of CB{sub 2} seems minor in the acute and subacute phases of stroke. (orig.)

  13. Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [11C]OMAR ([11C]JHU75528: Improvements in Image Quantification Using Wild-Type and Knockout Mice

    Directory of Open Access Journals (Sweden)

    Raúl Herance

    2011-11-01

    Full Text Available In this study, we assessed the feasibility of using positron emission tomography (PET and the tracer [11C]OMAR ([11C]JHU75528, an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1 receptor system. Wild-type (WT andCB1 knockout (KO animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50% than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [11C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals.

  14. Molecular mechanisms underlying the effects of cannabinoids in the brain

    OpenAIRE

    Puighermanal Puigvert, Emma, 1983-

    2011-01-01

    El sistema endocannabinoid és un sistema neuromodulador endogen que regula diverses funcions fisiològiques, incloent el control del moviment, la memòria, l’ansietat i el dolor, entre altres. Els compostos cannabinoids es troben principalment a la planta Cannabis sativa i exerceixen els seus efectes actuant al sistema endocannabinoid. Els cannabinoids tenen potencial terapèutic, principalment per l’esclerosi múltiple, el dolor i l’èmesi, tot i que una limitació important pel seu ús recau en el...

  15. Brain gray matter structural network in myotonic dystrophy type 1.

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    Atsuhiko Sugiyama

    Full Text Available This study aimed to investigate abnormalities in structural covariance network constructed from gray matter volume in myotonic dystrophy type 1 (DM1 patients by using graph theoretical analysis for further clarification of the underlying mechanisms of central nervous system involvement. Twenty-eight DM1 patients (4 childhood onset, 10 juvenile onset, 14 adult onset, excluding three cases from 31 consecutive patients who underwent magnetic resonance imaging in a certain period, and 28 age- and sex- matched healthy control subjects were included in this study. The normalized gray matter images of both groups were subjected to voxel based morphometry (VBM and Graph Analysis Toolbox for graph theoretical analysis. VBM revealed extensive gray matter atrophy in DM1 patients, including cortical and subcortical structures. On graph theoretical analysis, there were no significant differences between DM1 and control groups in terms of the global measures of connectivity. Betweenness centrality was increased in several regions including the left fusiform gyrus, whereas it was decreased in the right striatum. The absence of significant differences between the groups in global network measurements on graph theoretical analysis is consistent with the fact that the general cognitive function is preserved in DM1 patients. In DM1 patients, increased connectivity in the left fusiform gyrus and decreased connectivity in the right striatum might be associated with impairment in face perception and theory of mind, and schizotypal-paranoid personality traits, respectively.

  16. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

    Science.gov (United States)

    Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D.; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R.

    2013-01-01

    In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737

  17. BIASED AGONISM OF THREE DIFFERENT CANNABINOID RECEPTOR AGONISTS IN MOUSE BRAIN CORTEX

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    Rebeca Diez-Alarcia

    2016-11-01

    Full Text Available Cannabinoid receptors are able to couple to different families of G-proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, THC, WIN55212-2 and ACEA in mouse brain cortex.Stimulation of the [35S]GTPS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13, in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 µM was determined by Scintillation Proximity Assay (SPA technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.

  18. Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from functional and metabolic neuroimaging studies.

    Science.gov (United States)

    Rooijackers, Hanne M M; Wiegers, Evita C; Tack, Cees J; van der Graaf, Marinette; de Galan, Bastiaan E

    2016-02-01

    Hypoglycemia is the most frequent complication of insulin therapy in patients with type 1 diabetes. Since the brain is reliant on circulating glucose as its main source of energy, hypoglycemia poses a threat for normal brain function. Paradoxically, although hypoglycemia commonly induces immediate decline in cognitive function, long-lasting changes in brain structure and cognitive function are uncommon in patients with type 1 diabetes. In fact, recurrent hypoglycemia initiates a process of habituation that suppresses hormonal responses to and impairs awareness of subsequent hypoglycemia, which has been attributed to adaptations in the brain. These observations sparked great scientific interest into the brain's handling of glucose during (recurrent) hypoglycemia. Various neuroimaging techniques have been employed to study brain (glucose) metabolism, including PET, fMRI, MRS and ASL. This review discusses what is currently known about cerebral metabolism during hypoglycemia, and how findings obtained by functional and metabolic neuroimaging techniques contributed to this knowledge.

  19. Leptin Receptor Deficiency is Associated With Upregulation of Cannabinoid 1 Receptors in Limbic Brain Regions

    Science.gov (United States)

    THANOS, PANAYOTIS K.; RAMALHETE, ROBERTO C.; MICHAELIDES, MICHAEL; PIYIS, YIANNI K.; WANG, GENE-JACK; VOLKOW, NORA D.

    2009-01-01

    Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB1R) in overeating and the effects of food deprivation on CB1R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB1R (CB1R binding levels) were assessed using [3H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB1R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB1R binding levels than Le in most brain regions and food restriction was associated with higher CB1R levels in all brain regions in Ob, but not in Le rats. CB1R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB1R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB1R and that leptin interferes with CB1R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. PMID:18563836

  20. Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study

    Science.gov (United States)

    Neumeister, Alexander; Normandin, Marc D.; Pietrzak, Robert H.; Piomelli, Daniele; Zheng, Ming-Qiang; Gujarro-Anton, Ana; Potenza, Marc N.; Bailey, Christopher R.; Lin, Shu-fei; Najafzadeh, Soheila; Ropchan, Jim; Henry, Shannan; Corsi-Travali, Stefani; Carson, Richard E.; Huang, Yiyun

    2013-01-01

    Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma controls [TC]) and those without such histories (healthy controls [HC]). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance (MR) imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR VT values (F(2,53)=7.96, p=.001; 19.5% and 14.5% higher, respectively) which were most pronounced in women (F(1,53)=5.52, p=.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively—OMAR VT, anandamide, and cortisol—correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder. PMID:23670490

  1. Cannabinoid type 1 receptor ligands WIN 55,212-2 and AM 251 alter anxiety-like behaviors of marmoset monkeys in an open-field test.

    Science.gov (United States)

    Cagni, Priscila; Barros, Marilia

    2013-03-01

    Cannabinoid type 1 receptors (CB1r) are an important modulatory site for emotional behavior. However, little is known on the effects of CB1r ligands on emotionality aspects of primates, even with their highly similar behavioral response and receptor density/distribution as humans. Thus, we analyzed the effects of the CB1r agonist WIN 55,212-2 (WIN; 1mg/kg) and the antagonist AM 251 (AM; 2mg/kg), systemically administered prior to a single brief (15 min) exposure to a novel open-field (OF) environment, on the behavior of individually tested adult black tufted-ear marmosets. Both WIN- and AM-treated subjects, compared to vehicle controls, had significantly lower rates of long (contact) calls and exploration, while higher levels of vigilance-related behaviors (scan/glance); these are indicators of anxiolysis in this setup. Changes in locomotion were not detected. However, in the vehicle and AM-groups, sojourn in the peripheral zone of the OF was significantly higher than in its central region. WIN-treated marmosets spent an equivalent amount of time in both zones. Therefore, activation or blockade CB1r function prior to a short and individual exposure to an unfamiliar environment exerted a significant and complex influence on different behavioral indicators of anxiety in these monkeys (i.e., a partially overlapping anxiolytic-like profile). AM 251, however, has no anxiolytic effect when the time spent in the center of the OF is considered. This is a major difference when compared to the WIN-treated group. Data were compared to the response profile reported in other pre-clinical (rodent) and clinical studies. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Diabetes and the brain: Cognitive performance in type 1 and type 2 diabetes mellitus

    NARCIS (Netherlands)

    Brands, A.M.A.

    2007-01-01

    Both type 1 and type 2 diabetes mellitus are associated with altered brain function, a complication referred to as diabetic encephalopathy. The issues surrounding the cognitive and emotional status in chronic, older diabetic patients remain complex. The literature shows contrasting findings and

  3. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  4. Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain

    International Nuclear Information System (INIS)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D.; Goffin, Karolien; Laere, Koen van; Lepeleire, Inge de; Bormans, Guy

    2010-01-01

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [ 18 F]MK-9470 in human brain. [ 18 F]MK-9470 data were analysed using reversible models and the distribution volume V T and V ND k 3 (V ND k 3 = K 1 k 2 ) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K i and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined. A reversible two-tissue compartment model using a global k 4 value was necessary to describe brain kinetics. Both V T and V ND k 3 were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K i . The linear relationship between K i and V ND k 3 demonstrated that K i or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K i and FUR was 18 F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [ 18 F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  5. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

    Science.gov (United States)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    2017-01-01

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB 1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB 1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB 1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of

  6. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Choi

    Full Text Available Endoglin (ENG is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1. HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment, SM22α-Cre (smooth muscle and endothelial cell and LysM-Cre (lysozyme M-positive macrophage. An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.

  7. Diffusion tensor MR imaging in neurofibromatosis type 1: expanding the knowledge of microstructural brain abnormalities

    International Nuclear Information System (INIS)

    Ferraz-Filho, Jose R.L.; Muniz, Marcos P.; Souza, Antonio S.; Rocha, Antonio J. da; Goloni-Bertollo, Eny M.; Pavarino-Bertelli, Erika C.

    2012-01-01

    Neurofibromatosis type 1 (NF1) is a hereditary disease with a dominant autosomal pattern. In children and adolescents, it is frequently associated with the appearance of T2-weighted hyperintensities in the brain's white matter. MRI with diffusion tensor imaging (DTI) is used to detect white matter abnormalities by measuring fractional anisotropy (FA). This study employed DTI to evaluate the relationship between FA patterns and the findings of T2 sequences, with the aim of improving our understanding of anatomical changes and microstructural brain abnormalities in individuals with NF1. Forty-four individuals with NF1 and 20 control subjects were evaluated. The comparative analysis of FA between NF1 and control groups was based on four predetermined anatomical regions of the brain hemispheres (basal ganglia, cerebellum, pons, thalamus) and related the presence or absence of T2-weighted hyperintensities in the brain, which are called unidentified bright objects (UBOs). The FA values between the groups demonstrated statistically significant differences (P ≤ 0.05) for the cerebellum and thalamus in patients with NF1, independent of the occurrence of UBOs. Diffusion tensor MR imaging confirms the influence of UBOs in the decrease of FA values in this series of patients with NF1. Additionally, this technique allows the characterization of microstructural abnormalities even in some brain regions that appear normal in conventional MR sequences. (orig.)

  8. Atypical focal non-neoplastic brain changes in neurofibromatosis type 1: mass effect and contrast enhancement

    International Nuclear Information System (INIS)

    Raininko, R.; Thelin, L.; Eeg-Olofsson, O.

    2001-01-01

    Abstract Children and young adults with neurofibromatosis type 1 often have small high-signal foci on T2-weighted images of the brain. We describe follow-up of two patients in whom one of the foci had atypical features, commonly regarded as signs of a neoplasm. In the first, one lesion showed temporary contrast enhancement and decreasing mass effect. The second developed an expanding lesion that increased minimally in size over 4.5 year's follow-up. The borderline between neoplastic and non-neoplastic lesions seems to be indistinct. (orig.)

  9. Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study

    DEFF Research Database (Denmark)

    Frøkjær, J B; Brock, C; Søfteland, E

    2013-01-01

    .03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without...... peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated...... to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies...

  10. Kinetic analysis of the cannabinoid-1 receptor PET tracer [{sup 18}F]MK-9470 in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D. [Merck Research Laboratories, Imaging, West Point, PA (United States); Goffin, Karolien; Laere, Koen van [University Hospital and K.U. Leuven, Division of Nuclear Medicine, Leuven (Belgium); Lepeleire, Inge de [Merck Research Laboratories, Brussels (Belgium); Bormans, Guy [K.U. Leuven, Laboratory of Radiopharmacy, Leuven (Belgium)

    2010-05-15

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [{sup 18}F]MK-9470 in human brain. [{sup 18}F]MK-9470 data were analysed using reversible models and the distribution volume V{sub T} and V{sub ND} k{sub 3} (V{sub ND} k{sub 3} = K{sub 1} k{sub 2}) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K{sub i} and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined. A reversible two-tissue compartment model using a global k{sub 4} value was necessary to describe brain kinetics. Both V{sub T} and V{sub ND} k{sub 3} were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K{sub i}. The linear relationship between K{sub i} and V{sub ND} k{sub 3} demonstrated that K{sub i} or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K{sub i} and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics. [{sup 18}F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [{sup 18}F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  11. Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes.

    NARCIS (Netherlands)

    Brands, A.M.; Kessels, R.P.C.; Hoogma, R.P.L.M.; Henselmans, J.M.L.; Beek-Boter, J.W. van der; Kappelle, L.J.; Haan, E.H.F. de; Biessels, G.J.

    2006-01-01

    Modest cognitive impairment has been reported in young-adult patients with type 1 diabetes. In older patients with type 2 diabetes, cognitive impairments are more pronounced, which might be due to age but also to differential effects of type 1 diabetes and type 2 diabetes on the brain. This study

  12. Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1.

    Science.gov (United States)

    Serra, Laura; Silvestri, Gabriella; Petrucci, Antonio; Basile, Barbara; Masciullo, Marcella; Makovac, Elena; Torso, Mario; Spanò, Barbara; Mastropasqua, Chiara; Harrison, Neil A; Bianchi, Maria L E; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2014-05-01

    Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. Resting-state functional magnetic resonance imaging. Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. Our findings provide novel

  13. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Directory of Open Access Journals (Sweden)

    Wen Miao

    Full Text Available To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1 patients using multimodal MRI imaging.T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls.Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (p<0.001 uncorrected in the left precentral gyrus, left orbital frontal cortex, temporal pole and cingulate gyrus.CFEOM1 patients had structural and functional changes in grey matter, but the white matter was unaffected. These alterations in the brain may be due to the abnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  14. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Science.gov (United States)

    Miao, Wen; Man, Fengyuan; Wu, Shaoqin; Lv, Bin; Wang, Zhenchang; Xian, Junfang; Sabel, Bernhard A; He, Huiguang; Jiao, Yonghong

    2015-01-01

    To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1) patients using multimodal MRI imaging. T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls. Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (pleft precentral gyrus, left orbital frontal cortex, temporal pole and cingulate gyrus. CFEOM1 patients had structural and functional changes in grey matter, but the white matter was unaffected. These alterations in the brain may be due to the abnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  15. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study

    Science.gov (United States)

    Wu, Shaoqin; Lv, Bin; Wang, Zhenchang; Xian, Junfang; Sabel, Bernhard A.; He, Huiguang; Jiao, Yonghong

    2015-01-01

    Purpose To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1) patients using multimodal MRI imaging. Methods T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender- matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls. Results Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (pleft precentral gyrus, left orbital frontal cortex, temporal pole and cingulate gyrus. Conclusions CFEOM1 patients had structural and functional changes in grey matter, but the white matter was unaffected. These alterations in the brain may be due to the abnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1. PMID:26186732

  16. Type 1 Diabetes Modifies Brain Activation in Young Patients While Performing Visuospatial Working Memory Tasks

    Directory of Open Access Journals (Sweden)

    Geisa B. Gallardo-Moreno

    2015-01-01

    Full Text Available In recent years, increasing attention has been paid to the effects of Type 1 Diabetes (T1D on cognitive functions. T1D onset usually occurs during childhood, so it is possible that the brain could be affected during neurodevelopment. We selected young patients of normal intelligence with T1D onset during neurodevelopment, no complications from diabetes, and adequate glycemic control. The purpose of this study was to compare the neural BOLD activation pattern in a group of patients with T1D versus healthy control subjects while performing a visuospatial working memory task. Sixteen patients and 16 matched healthy control subjects participated. There was no significant statistical difference in behavioral performance between the groups, but, in accordance with our hypothesis, results showed distinct brain activation patterns. Control subjects presented the expected activations related to the task, whereas the patients had greater activation in the prefrontal inferior cortex, basal ganglia, posterior cerebellum, and substantia nigra. These different patterns could be due to compensation mechanisms that allow them to maintain a behavioral performance similar to that of control subjects.

  17. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1

    International Nuclear Information System (INIS)

    Lopes Ferraz Filho, Jose R.; Pontes Munis, Marcos; Soares Souza, Antonio; Sanches, Rafael A.; Goloni-Bertollo, Eni M.; Pavarino-Bertelli, Erika C.

    2008-01-01

    Lesions of the brain denominated as unidentified bright objects (UBOs), which are not included in the diagnostic criteria for neurofibromatosis type 1 (NF1) established by the National Institutes of Health (NIH), have been detected by MRI. The purpose of this study was to investigate the possibility of including the presence of UBOs as a diagnostic criterion for NF1 in children. The study included 88 children between the ages of 2 and 18 years. The case group consisted of 40 children diagnosed with sporadic or familial NF1 according to the criteria established by the NIH. A control group consisted of 48 individuals referred for routine MRI of the brain for other complaints not related to NF1. UBOs were identified in 70% of the NF1 patients and in none of the control group. The sensitivity of the presence of UBOs for the diagnosis of NF1 was 70% (CI 53-83%), with a false-negative rate of 30% (CI 27-47%), a specificity of 100% (CI 86-100%) and a false-positive rate of 0% (CI 0-14%). Faced with the difficulties in diagnosing NF1 in children and the high frequency and specificity of the presence UBOs identified by MRI in our series, we recommend the inclusion of the presence UBOs as a diagnostic criterion for NF1 in children. (orig.)

  18. Cognitive profile and disorders affecting higher brain functions in paediatric patients with neurofibromatosis type 1.

    Science.gov (United States)

    Vaucheret Paz, E; López Ballent, A; Puga, C; García Basalo, M J; Baliarda, F; Ekonen, C; Ilari, R; Agosta, G

    2017-04-18

    Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome often associated with specific cognitive deficits that are rarely monitored during follow-up of these patients. The purpose of our study is two-fold. First, we aimed to describe the cognitive profile of patients with NF1 and detect disorders in higher brain functions associated with the disease. Second, we identified the reasons for consultation associated with school performance in these patients. We conducted a descriptive cross-sectional study of 24 paediatric patients (ages 5 to 16) with NF1 who underwent neuropsychological assessment. The most frequent reasons for consultation were attention deficits (58.33%), learning disorders (25%), poor motor coordination (25%), and language impairment (0.8%). Although 96% of the patients displayed impairments in at least one of the assessed areas, only 83.34% of the parents had reported such impairments. Attention-deficit/hyperactivity disorder was present in 58.33% of the patients, whereas 33.33% had nonverbal learning disabilities, 20.83% had expressive language disorder, 8.33% had borderline intellectual functioning, 4.16% had mental retardation, and only 4.16% showed no cognitive impairment. Higher brain functions are frequently impaired in paediatric patients with NF1. Although many parents report such disorders, they can go undetected in some cases. Neuropsychological assessment is recommended for all paediatric patients with NF1 to detect cognitive impairment and provide early, effective rehabilitation treatment. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.

    Science.gov (United States)

    Morgan, Amanda J; Kingsley, Philip J; Mitchener, Michelle M; Altemus, Megan; Patrick, Toni A; Gaulden, Andrew D; Marnett, Lawrence J; Patel, Sachin

    2018-05-09

    Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.

  20. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.

    Science.gov (United States)

    Albayram, Onder; Alferink, Judith; Pitsch, Julika; Piyanova, Anastasia; Neitzert, Kim; Poppensieker, Karola; Mauer, Daniela; Michel, Kerstin; Legler, Anne; Becker, Albert; Monory, Krisztina; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras

    2011-07-05

    Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

  1. Severity of clinical presentation in youth with type 1 diabetes is associated with differences in brain structure.

    Science.gov (United States)

    Siller, Alejandro F; Lugar, Heather; Rutlin, Jerrel; Koller, Jonathan M; Semenkovich, Katherine; White, Neil H; Arbelaez, Ana Maria; Shimony, Joshua; Hershey, Tamara

    2017-12-01

    Differences in cognition and brain structure have been found in youth with type 1 diabetes compared with controls, even after relatively short disease duration. To determine whether severity of clinical presentation contributes to these differences, we obtained structural magnetic resonance imaging (MRI) scans in youth ages 7-17 who were either newly diagnosed with type 1 diabetes (presentation was measured by the presence of diabetic ketoacidosis (DKA) and degree of hyperglycemia exposure [hemoglobin A1c (HbA1c)] at diagnosis. MRI were obtained using T1-weighted, T2-weighted, and diffusion-weighted sequences. Within the group with type 1 diabetes, 12 subjects presented in DKA and 34 did not. After controlling for age, sex, and multiple comparisons, the type 1 diabetes group had lower volume in the left temporal-parietal-occipital cortex compared with controls. Within the type 1 diabetes group, DKA at presentation was associated with lower radial, axial, and mean diffusivity (MD) throughout major white matter tracts and higher HbA1c was associated with lower hippocampal, thalamic, and cerebellar white matter volumes, lower right posterior parietal cortical thickness, and greater right occipital cortical thickness. These data suggest that severity of clinical presentation is an important factor in predicting brain structural differences in youth with type 1 diabetes approximately 3 months after diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Brain metastasis of Wilms tumor with diffuse anaplasia and complex cytogenetic phenotype in a child with neurofibromatosis Type 1.

    Science.gov (United States)

    Shvartsbeyn, Marianna; Bassani, Luigi; Mikolaenko, Irina; Wisoff, Jeffrey H

    2011-10-01

    The authors report the first case of a Wilms tumor (WT) with diffuse anaplasia metastatic to the brain in a 13-year-old girl with a history of neurofibromatosis Type 1. At presentation, the metastatic tumor had radiological features that suggested a meningioma. Histologically it was characterized by striking anaplasia and features similar to the patient's previously resected WT with diffuse anaplasia.

  3. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

    Science.gov (United States)

    Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

    2016-04-01

    Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

  4. Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Aslihan Okan Ibiloglu

    2017-09-01

    Full Text Available Synthetic cannabinoids which is a subgroup of cannabinoids are commonly used for recreational drug use throughout the whole world. Although both marijuana and synthetic cannabinoids stimulate the same receptors, cannabinoid receptor 1 (CB1 and cannabinoid receptor 2 (CB2, studies have shown that synthetic cannabinoids are much more potent than marijuana. The longer use of synthetic cannabinoids can cause severe physical and psychological symptoms that might even result in death, similar to many known illicit drugs. Main treatment options mostly involve symptom management and supportive care. The aim of this article is to discuss clinical and pharmacological properties of the increasingly used synthetic cannabinoids. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(3.000: 317-328

  5. Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

    Science.gov (United States)

    Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

    2013-06-01

    Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. [The impact of dysglycemia on brain function in children with type 1 diabetes mellitus].

    Science.gov (United States)

    Pańkowska, Ewa

    2012-01-01

    Diabetes is a metabolic disease defined by increased blood glucose level above the references value. Insulin therapy is mandatory for all patients with type 1 diabetes melitus (T1DM). However, the insulin therapy is also the potential factor of hyperglycemia as well as hypoglycemia condition called dysglycemia. Moreover, T1DM leads to late organ changes such as retinopathy and nephropathy primarily due to diabetic angiopathy. Neuropathy is one of diabetic complications which can occur from the beginning of the disease. The pathogenesis of diabetic neuropathy, a structural and morphological abnormality, has been well described. In adults with T1DM diagnosed in childhood more frequent incidence of epilepsy, abnormal EEG and impaired cognitive functions were diagnosed. In children with type I diabetes further in depth studies are needed concerning the structural and functional damage of the central nervous system (cns). Research studies carried out in children have shown that the metabolic and morphological cns changes are the result of both hypo- and hyperglycemia.

  7. Maternal deprivation and adolescent cannabinoid exposure impact hippocampal astrocytes, CB1 receptors and brain-derived neurotrophic factor in a sexually dimorphic fashion.

    Science.gov (United States)

    López-Gallardo, M; López-Rodríguez, A B; Llorente-Berzal, Á; Rotllant, D; Mackie, K; Armario, A; Nadal, R; Viveros, M-P

    2012-03-01

    We have recently reported that early maternal deprivation (MD) for 24 h [postnatal day (PND) 9-10] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (CP) [0.4 mg/kg, PND 28-42] in Wistar rats induced, in adulthood, diverse sex-dependent long-term behavioral and physiological modifications. Here we show the results obtained from investigating the immunohistochemical analysis of CB1 cannabinoid receptors, glial fibrillary acidic protein (GFAP) positive (+) cells and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the same animals. MD induced, in males, a significant increase in the number of GFAP+ cells in CA1 and CA3 areas and in the polymorphic layer of the dentate gyrus (DG), an effect that was attenuated by CP in the two latter regions. Adolescent cannabinoid exposure induced, in control non-deprived males, a significant increase in the number of GFAP+ cells in the polymorphic layer of the DG. MD induced a decrease in CB1 expression in both sexes, and this effect was reversed in males by the cannabinoid treatment. In turn, the drug "per se" induced, in males, a general decrease in CB1 immunoreactivity, and the opposite effect was observed in females. Cannabinoid exposure tended to reduce BDNF expression in CA1 and CA3 of females, whereas MD counteracted this trend and induced an increase of BDNF in females. As a whole, the present results show sex-dependent long-term effects of both MD and juvenile cannabinoid exposure as well as functional interactions between the two treatments. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. MATERNAL DEPRIVATION AND ADOLESCENT CANNABINOID EXPOSURE IMPACT HIPPOCAMPAL ASTROCYTES, CB1 RECEPTORS AND BRAIN-DERIVED NEUROTROPHIC FACTOR IN A SEXUALLY DIMORPHIC FASHION

    Science.gov (United States)

    LÓPEZ-GALLARDO, M.; LÓPEZ-RODRÍGUEZ, A. B.; LLORENTE-BERZAL, Á.; ROTLLANT, D.; MACKIE, K.; ARMARIO, A.; NADAL, R.; VIVEROS, M.-P.

    2013-01-01

    We have recently reported that early maternal deprivation (MD) for 24 h [postnatal day (PND) 9–10] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (CP) [0.4 mg/kg, PND 28–42] in Wistar rats induced, in adulthood, diverse sex-dependent long-term behavioral and physiological modifications. Here we show the results obtained from investigating the immunohistochemical analysis of CB1 cannabinoid receptors, glial fibrillary acidic protein (GFAP) positive (+) cells and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the same animals. MD induced, in males, a significant increase in the number of GFAP+ cells in CA1 and CA3 areas and in the polymorphic layer of the dentate gyrus (DG), an effect that was attenuated by CP in the two latter regions. Adolescent cannabinoid exposure induced, in control non-deprived males, a significant increase in the number of GFAP+ cells in the polymorphic layer of the DG. MD induced a decrease in CB1 expression in both sexes, and this effect was reversed in males by the cannabinoid treatment. In turn, the drug “per se” induced, in males, a general decrease in CB1 immunoreactivity, and the opposite effect was observed in females. Cannabinoid exposure tended to reduce BDNF expression in CA1 and CA3 of females, whereas MD counteracted this trend and induced an increase of BDNF in females. As a whole, the present results show sex-dependent long-term effects of both MD and juvenile cannabinoid exposure as well as functional interactions between the two treatments. PMID:22001306

  9. Reduced artefacts and improved assessment of hyperintense brain lesions with BLADE MR imaging in patients with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Kalle, Thekla von; Fabig-Moritz, Claudia; Mueller-Abt, Peter; Zieger, Michael; Winkler, Peter [Department of Paediatric Radiology, Stuttgart (Germany); Blank, Bernd [Haematology and Immunology, Department of Paediatric Oncology, Stuttgart (Germany); Wohlfarth, Katrin [Siemens Healthcare Sector, Erlangen (Germany)

    2009-11-15

    Assessment of small brain lesions in children is often compromised by pulsation, flow or movement artefacts. MRI with a rotating blade-like k-space covering (BLADE, PROPELLER) can compensate for these artefacts. We compared T2-weighted FLAIR images that were acquired with different k-space trajectories (conventional Cartesian and BLADE) to evaluate the impact of BLADE technique on the delineation of small or low-contrast brain lesions. The subject group comprised 26 children with neurofibromatosis type 1 (NF 1), who had been routinely scanned at 1.5 T for optic pathway gliomas with both techniques and who had the typical hyperintense brain lesions seen in NF 1. Four experienced radiologists retrospectively compared unlabelled 4-mm axial images with respect to the presence of artefacts, visibility of lesions, quality of contour and contrast. Both techniques were comparable in depicting hyperintense lesions as small as 2 mm independent of contrast and edge definition. Pulsation and movement artefacts were significantly less common with BLADE k-space trajectory. In 7 of 26 patients (27%), lesions and artefacts were rated as indistinguishable in conventional FLAIR, but not in BLADE FLAIR images. BLADE imaging significantly improved the depiction of lesions in T2-W FLAIR images due to artefact reduction especially in the posterior fossa. (orig.)

  10. Reduced artefacts and improved assessment of hyperintense brain lesions with BLADE MR imaging in patients with neurofibromatosis type 1

    International Nuclear Information System (INIS)

    Kalle, Thekla von; Fabig-Moritz, Claudia; Mueller-Abt, Peter; Zieger, Michael; Winkler, Peter; Blank, Bernd; Wohlfarth, Katrin

    2009-01-01

    Assessment of small brain lesions in children is often compromised by pulsation, flow or movement artefacts. MRI with a rotating blade-like k-space covering (BLADE, PROPELLER) can compensate for these artefacts. We compared T2-weighted FLAIR images that were acquired with different k-space trajectories (conventional Cartesian and BLADE) to evaluate the impact of BLADE technique on the delineation of small or low-contrast brain lesions. The subject group comprised 26 children with neurofibromatosis type 1 (NF 1), who had been routinely scanned at 1.5 T for optic pathway gliomas with both techniques and who had the typical hyperintense brain lesions seen in NF 1. Four experienced radiologists retrospectively compared unlabelled 4-mm axial images with respect to the presence of artefacts, visibility of lesions, quality of contour and contrast. Both techniques were comparable in depicting hyperintense lesions as small as 2 mm independent of contrast and edge definition. Pulsation and movement artefacts were significantly less common with BLADE k-space trajectory. In 7 of 26 patients (27%), lesions and artefacts were rated as indistinguishable in conventional FLAIR, but not in BLADE FLAIR images. BLADE imaging significantly improved the depiction of lesions in T2-W FLAIR images due to artefact reduction especially in the posterior fossa. (orig.)

  11. Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.

    Science.gov (United States)

    Köfalvi, Attila; Lemos, Cristina; Martín-Moreno, Ana M; Pinheiro, Bárbara S; García-García, Luis; Pozo, Miguel A; Valério-Fernandes, Ângela; Beleza, Rui O; Agostinho, Paula; Rodrigues, Ricardo J; Pasquaré, Susana J; Cunha, Rodrigo A; de Ceballos, María L

    2016-11-01

    Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral (18)F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Brain metabolite changes on proton magnetic resonance spectroscopy in children with poorly controlled type 1 diabetes mellitus

    International Nuclear Information System (INIS)

    Sarac, K.; Alkan, A.; Baysal, T.; Akinci, A.; Aslan, M.; Oezcan, C.

    2005-01-01

    The metabolite changes in the brains of children with poorly controlled type 1 diabetes mellitus (DM) were investigated by proton magnetic resonance spectroscopy (MRS). A total of 30 subjects and 14 age-matched healthy volunteers underwent single-voxel MRS (TE: 136). The duration of disease, medication, presence of hypoglycaemia episodes and the level of haemoglobin A1C (HbA1C) in the patients were noted. Voxels were placed in the pons, left basal ganglion (LBG) and left posterior parietal white matter (PPWM). N-acetylaspartate (NAA)/creatinine (Cr) and choline (Cho)/Cr ratios were calculated. The average HbA1c level was 11.9±3.4 (8.2-19.4). The average number of keto-acidosis episodes was 1.9±2.2 (0-9) and the average number of daily insulin injections was 2.8±0.97 (2-4). MRS revealed lower NAA/Cr and Cho/Cr ratios in the pons and lower NAA/Cr ratio in the PPWM of patients with DM than in control subjects. No significant correlation was observed between the number of hypoglycaemia episodes and metabolite ratios. Metabolic abnormalities have been observed by MRS in the brain of poorly controlled type 1 DM children. These metabolic changes, in particular in the pons region, include a decrease in NAA, indicating neuronal loss or functional impairment, and likely explanations for a decrease in Cho may be dynamic changes in membrane lipids and/or decreased membrane turnover. (orig.)

  13. Brain metabolite changes on proton magnetic resonance spectroscopy in children with poorly controlled type 1 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Sarac, K.; Alkan, A.; Baysal, T. [Inonu University School of Medicine, Department of Radiology, Malatya (Turkey); Akinci, A.; Aslan, M. [Inonu University School of Medicine, Department of Paediatric Endocrinology, Malatya (Turkey); Oezcan, C. [Inonu University School of Medicine, Department of Neurology, Malatya (Turkey)

    2005-07-01

    The metabolite changes in the brains of children with poorly controlled type 1 diabetes mellitus (DM) were investigated by proton magnetic resonance spectroscopy (MRS). A total of 30 subjects and 14 age-matched healthy volunteers underwent single-voxel MRS (TE: 136). The duration of disease, medication, presence of hypoglycaemia episodes and the level of haemoglobin A1C (HbA1C) in the patients were noted. Voxels were placed in the pons, left basal ganglion (LBG) and left posterior parietal white matter (PPWM). N-acetylaspartate (NAA)/creatinine (Cr) and choline (Cho)/Cr ratios were calculated. The average HbA1c level was 11.9{+-}3.4 (8.2-19.4). The average number of keto-acidosis episodes was 1.9{+-}2.2 (0-9) and the average number of daily insulin injections was 2.8{+-}0.97 (2-4). MRS revealed lower NAA/Cr and Cho/Cr ratios in the pons and lower NAA/Cr ratio in the PPWM of patients with DM than in control subjects. No significant correlation was observed between the number of hypoglycaemia episodes and metabolite ratios. Metabolic abnormalities have been observed by MRS in the brain of poorly controlled type 1 DM children. These metabolic changes, in particular in the pons region, include a decrease in NAA, indicating neuronal loss or functional impairment, and likely explanations for a decrease in Cho may be dynamic changes in membrane lipids and/or decreased membrane turnover. (orig.)

  14. A Review of the Therapeutic Antitumor Potential of Cannabinoids.

    Science.gov (United States)

    Bogdanović, Višnja; Mrdjanović, Jasminka; Borišev, Ivana

    2017-11-01

    The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment. A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment. Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of "cannabinoid sensitizers." Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness. A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with

  15. Synthetic Cannabinoids.

    Science.gov (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  16. Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

    Directory of Open Access Journals (Sweden)

    Marco Koch

    2017-05-01

    Full Text Available Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB1 represents the most relevant target molecule of cannabinoids so far. One main function of central CB1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade of CB1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB1-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB1 activation but also contributing to control of feeding behavior will be introduced.

  17. Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future.

    Science.gov (United States)

    Panagis, George; Mackey, Brian; Vlachou, Styliani

    2014-01-01

    Over the last decades, the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain-reward circuits and the regulation of motivational processes. Importantly, behavioral studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine, and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioral experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure, and the reinstatement of drug-seeking behavior procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain-reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists, and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction-related disorders.

  18. Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: a step back into the future

    Directory of Open Access Journals (Sweden)

    George ePanagis

    2014-07-01

    Full Text Available Over the last decades the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain reward circuits and the regulation of motivational processes. Importantly, behavioural studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioural experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the reinstatement of drug-seeking behaviour procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1 receptor agonists, antagonists and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggests that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction related disorders.

  19. High-affinity cannabinoid binding site in brain: A possible marijuana receptor

    International Nuclear Information System (INIS)

    Nye, J.S.

    1988-01-01

    The mechanism by which delta 9 tetrahydrocannabinol (delta 9 THC), the major psychoactive component of marijuana or hashish, produces its potent psychological and physiological effects is unknown. To find receptor binding sites for THC, we designed a water-soluble analog for use as a radioligand. 5'-Trimethylammonium-delta 8 THC (TMA) is a positively charged analog of delta- 8 THC modified on the 5' carbon, a portion of the molecule not important for its psychoactivity. We have studied the binding of [ 3 H]-5'-trimethylammonium-delta- 8 THC ([ 3 H]TMA) to rat neuronal membranes. [ 3 H]TMA binds saturably and reversibly to brain membranes with high affinity to apparently one class of sites. Highest binding site density occurs in brain, but several peripheral organs also display specific binding. Detergent solubilizes the sites without affecting their pharmacologial properties. Molecular sieve chromatography reveals a bimodal peak of [ 3 H]TMA binding activity of approximately 60,000 daltons apparent molecular weight

  20. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function

    NARCIS (Netherlands)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CBI

  1. Type 1 narcolepsy

    DEFF Research Database (Denmark)

    Degn, Matilda; Kornum, Birgitte Rahbek

    2015-01-01

    Type 1 narcolepsy is a sleep disorder characterized by excessive daytime sleepiness with unintentional sleep attacks and cataplexy. The disorder is caused by a loss of hypocretinergic neurons in the brain. The specific loss of these neurons in narcolepsy is thought to result from an autoimmune...

  2. Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189.

    Science.gov (United States)

    Liu, Yu; McAfee, Samuel S; Guley, Natalie M; Del Mar, Nobel; Bu, Wei; Heldt, Scott A; Honig, Marcia G; Moore, Bob M; Reiner, Anton; Heck, Detlef H

    2017-01-01

    Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

  3. Cannabinoid Hyperemesis Relieved by Compulsive Bathing

    OpenAIRE

    Chang, Yoon Hee; Windish, Donna M.

    2009-01-01

    Cannabinoid hyperemesis is a clinical syndrome characterized by repeated vomiting and associated learned compulsive hot water bathing behavior due to long-term marijuana use. Research has indentified type 1 cannabinoid receptors in the intestinal nerve plexus that have an inhibitory effect on gastrointestinal motility. This inhibitory effect may lead to hyperemesis in marijuana users. The thermoregulatory role of endocannabinoids may be responsible for the patient's need to take hot showers. ...

  4. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  5. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

    International Nuclear Information System (INIS)

    Noda, Akihiro; Fushiki, Hiroshi; Murakami, Yoshihiro; Sasaki, Hiroshi; Miyoshi, Sosuke; Kakuta, Hirotoshi; Nishimura, Shintaro

    2012-01-01

    Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT 1 ) receptor (AT 1 R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [ 11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT 1 R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT 1 R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT 1 R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

  6. Detection of GAD65 autoantibodies of type-1 diabetes using anti-GAD65-abs reagent produced from bovine brain tissue

    Directory of Open Access Journals (Sweden)

    Djoko W. Soeatmadji

    2005-12-01

    Full Text Available Clinically, type 1 diabetes may presents as type 2 diabetes which sometimes not easily differentiated. Perhaps only autoimmune markers of β-cells destruction could differentiate those two clinical conditions. Due to extremely high cost ( $ 150/test, examination of anti-glutamic acid decarboxylase-65 auto-antibodies (anti-GAD65Abs may not be routinely performed in most, if not all, clinical laboratories in Indonesia. Hence, the production of anti-GAD65 Abs reagent in Indonesia may reduce the cost and improve the quality of diabetes care in Indonesia. We produce reagent to detect anti-GAD65-Abs using bovine brain tissue as source of GAD enzyme in 3 steps. Step 1, isolation, purification of GAD65 from bovine brain tissue and used it as a primary antigen to stimulate the generation of anti-GAD65 antibodies in Wistar rat. Step 2, the purified GAD65 antibodies were than used as a secondary antibody to induce the production of anti-anti-GAD65-antibodies in Wistar rat and rabbit. Step 3. Labeling  anti-anti GAD65-antibodies with alkaline phoshpatase and peroxidase, and detecting anti-GAD65Abs previously detected using commercial kit. The anti-anti-GAD65- antibodies reagent produced in our laboratories  successfully identify anti-GAD65-Abs of type 1 diabetic patients previously detected  with commercial reagent. (Med J Indones 2005; 14: 197-203Keywords: GAD, type-1 Diabetes

  7. Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

    International Nuclear Information System (INIS)

    Lan, Ruoxi; Makriyannis, Alexandros; Gatley, S.J.

    1996-01-01

    We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author)

  8. Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Ruoxi; Makriyannis, Alexandros [Connecticut Univ., Molecular and Cell Biology Dept., Storrs, CT (United States); Gatley, S.J. [Brookhaven National Lab., Medical Dept., Upton, NY (United States)

    1996-10-01

    We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author).

  9. The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

    Science.gov (United States)

    White, C Michael

    2017-03-01

    This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.

  10. Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

    Science.gov (United States)

    Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

    2009-12-15

    Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

  11. Deuterium labeled cannabinoids

    International Nuclear Information System (INIS)

    Driessen, R.A.

    1979-01-01

    Complex reactions involving ring opening, ring closure and rearrangements hamper complete understanding of the fragmentation processes in the mass spectrometric fragmentation patterns of cannabinoids. Specifically labelled compounds are very powerful tools for obtaining more insight into fragmentation mechanisms and ion structures and therefore the synthesis of specifically deuterated cannabinoids was undertaken. For this, it was necessary to investigate the preparation of cannabinoids, appropriately functionalized for specific introduction of deuterium atom labels. The results of mass spectrometry with these labelled cannabinoids are described. (Auth.)

  12. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.

    Science.gov (United States)

    Han, Jing; Kesner, Philip; Metna-Laurent, Mathilde; Duan, Tingting; Xu, Lin; Georges, Francois; Koehl, Muriel; Abrous, Djoher Nora; Mendizabal-Zubiaga, Juan; Grandes, Pedro; Liu, Qingsong; Bai, Guang; Wang, Wei; Xiong, Lize; Ren, Wei; Marsicano, Giovanni; Zhang, Xia

    2012-03-02

    Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Haloperidol, a Novel Treatment for Cannabinoid Hyperemesis Syndrome.

    Science.gov (United States)

    Witsil, Joanne C; Mycyk, Mark B

    Cannabinoid hyperemesis syndrome (CHS) is typically unresponsive to conventional pharmacologic antiemetics, and patients often require excessive laboratory and radiographic testing and hospital admission. We report 4 cases of CHS that failed standard emergency department therapy but improved significantly after treatment with haloperidol. Although the exact mechanism for CHS remains unclear, dysregulation at cannabinoid type 1 seems to play a role. Recent animal data demonstrate complex interactions between dopamine and cannabinoid type 1 signaling, a potential mechanism for haloperidol success in patients with CHS. Our success with haloperidol in these 4 patients warrants further investigation of haloperidol as an emergency department treatment for CHS.

  14. Cannabinoids and Pain

    Directory of Open Access Journals (Sweden)

    J Michael Walker

    2001-01-01

    Full Text Available Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late 1980s and have been found to mediate the effects of cannabinoids on the nervous system. Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities. These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity. The therapeutic potential of cannabinoids remains an important topic for future investigations, with previous work suggesting utility in clinical studies of cancer and surgical pain. New modes of delivery and/or new compounds lacking the psychotropic properties of the standard cannabinoid ligands offer promise for cannabinoid therapeutics for pain.

  15. Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [11C]MA2 and [18F]MA3

    Directory of Open Access Journals (Sweden)

    Muneer Ahamed

    2016-09-01

    Full Text Available Abstract The type 2 cannabinoid receptor (CB2 is a member of the endocannabinoid system and is known for its important role in (neuroinflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([11C]MA2 and a fluorine-18 ([18F]MA3 labeled analogue of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM. MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analogue 12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.

  16. Synthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3.

    Science.gov (United States)

    Ahamed, Muneer; van Veghel, Daisy; Ullmer, Christoph; Van Laere, Koen; Verbruggen, Alfons; Bormans, Guy M

    2016-01-01

    The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([ 11 C]MA2) and a fluorine-18 ([ 18 F]MA3) labeled analog of a highly potent N -arylamide oxadiazole CB2 agonist (EC 50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC 50 : 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for h CB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC 50 values when compared to the originally reported trifluoromethyl analog 12 . [ 11 C]MA2 and [ 18 F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [ 11 C]MA2 and [ 18 F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.

  17. Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: implication for PTSD and drug abuse.

    Science.gov (United States)

    Xing, Guoqiang; Carlton, Janis; Zhang, Lei; Jiang, Xiaolong; Fullerton, Carol; Li, He; Ursano, Robert

    2011-09-08

    Recent study demonstrated a close relationship between cerebellum atrophy and symptom severity of pediatric maltreatment-related posttraumatic stress disorder (PTSD). It has also been known that females are more vulnerable than males in developing anxiety disorders after exposure to traumatic stress. The mechanisms are unknown. Because cannabinoid receptors (CB₁ and CB₂) are neuroprotective and highly expressed in the cerebellum, we investigated cerebellar CB expression in stressed rats. Young male and female Sprague-Dawley rats were given 40 unpredictable electric tail-shocks for 2h daily on 3 consecutive days. CB₁ and CB₂ mRNA and protein levels in rat cerebellum and brain stem were determined using quantitative real-time PCR and Western blot, respectively. Two-way ANOVA revealed significant gender and stress effects on cerebellar CB₁ mRNA expression, with females and non-stressed rats exhibiting higher CB₁ mRNA levels than the males (3 fold, pstressed rats (30%, pstress increased the level of phosphorylated CB₁ receptors, the inactivated CB₁, in rat cerebellum (pstress interaction. Thus, repeated severe stress caused greater CB₁ mRNA suppression and CB₁ receptor phosphorylation in female cerebellum that could lead to increased susceptibility to stress-related anxiety disorders including PTSD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. Excess of Aminopeptidase A in the Brain Elevates Blood Pressure via the Angiotensin II Type 1 and Bradykinin B2 Receptors without Dipsogenic Effect

    Directory of Open Access Journals (Sweden)

    Takuto Nakamura

    2017-01-01

    Full Text Available Aminopeptidase A (APA cleaves angiotensin (Ang II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv APA in a conscious, unrestrained state after pretreatment with (i vehicle, (ii 80 μg of telmisartan, an Ang II type-1 (AT1 receptor blocker, (iii 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg. Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg. In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.

  19. Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Shuxian Jiang

    2007-07-01

    Full Text Available Characterization of intrinsic and extrinsic factors regulating the self-renewal/division and differentiation of stem cells is crucial in determining embryonic stem (ES cell fate. ES cells differentiate into multiple hematopoietic lineages during embryoid body (EB formation in vitro, which provides an experimental platform to define the molecular mechanisms controlling germ layer fate determination and tissue formation.The cannabinoid receptor type 1 (CB1 and cannabinoid receptor type 2 (CB2 are members of the G-protein coupled receptor (GPCR family, that are activated by endogenous ligands, the endocannabinoids. CB1 receptor expression is abundant in brain while CB2 receptors are mostly expressed in hematopoietic cells. However, the expression and the precise roles of CB1 and CB2 and their cognate ligands in ES cells are not known. We observed significant induction of CB1 and CB2 cannabinoid receptors during the hematopoietic differentiation of murine ES (mES-derived embryoid bodies. Furthermore, mES cells as well as ES-derived embryoid bodies at days 7 and 14, expressed endocannabinoids, the ligands for both CB1 and CB2. The CB1 and CB2 antagonists (AM251 and AM630, respectively induced mES cell death, strongly suggesting that endocannabinoids are involved in the survival of mES cells. Treatment of mES cells with the exogenous cannabinoid ligand Delta(9-THC resulted in the increased hematopoietic differentiation of mES cells, while addition of AM251 or AM630 blocked embryoid body formation derived from the mES cells. In addition, cannabinoid agonists induced the chemotaxis of ES-derived embryoid bodies, which was specifically inhibited by the CB1 and CB2 antagonists.This work has not been addressed previously and yields new information on the function of cannabinoid receptors, CB1 and CB2, as components of a novel pathway regulating murine ES cell differentiation. This study provides insights into cannabinoid system involvement in ES cell

  20. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  1. Type 1 diabetes

    Science.gov (United States)

    Insulin-dependent diabetes; Juvenile onset diabetes; Diabetes - type 1; High blood sugar - type 1 diabetes ... Type 1 diabetes can occur at any age. It is most often diagnosed in children, adolescents, or young adults. Insulin is ...

  2. Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier.

    Science.gov (United States)

    Curis, Céline; Percher, Florent; Jeannin, Patricia; Montange, Thomas; Chevalier, Sébastien A; Seilhean, Danielle; Cartier, Luis; Couraud, Pierre-Olivier; Gout, Olivier; Gessain, Antoine; Ceccaldi, Pierre-Emmanuel; Afonso, Philippe V

    2016-08-15

    Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4(+) T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis. Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear

  3. Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

    Science.gov (United States)

    López-Moreno, J A; López-Jiménez, A; Gorriti, M A; de Fonseca, F Rodríguez

    2010-04-01

    Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.

  4. Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

    Directory of Open Access Journals (Sweden)

    Nicola H. Morgan

    2008-01-01

    Full Text Available Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM, increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

  5. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  6. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death

    International Nuclear Information System (INIS)

    Tomiyama, Ken-ichi; Funada, Masahiko

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB 1 receptor antagonist AM251, but not with the selective CB 2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB 1 receptor, but not by the CB 2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB 1 receptor, but not by the CB 2 receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB 1 receptors

  7. Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Eric J. Downer

    2011-01-01

    Full Text Available The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS, and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids, have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs, a major family of pattern recognition receptors (PRRs that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.

  8. Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

    Science.gov (United States)

    Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

    2010-12-01

    The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced

  9. Diabetes, Type 1

    OpenAIRE

    Riazi, Afsane; Bradley, Clare

    2007-01-01

    This chapter provides an overview of the role of psychological stress in Type 1 diabetes. Studies relating to stress and Type 1 diabetes onset and control, as well as the evidence relating to stress management training in people with Type 1 diabetes are discussed.

  10. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology

    Directory of Open Access Journals (Sweden)

    Justine eRenard

    2014-11-01

    Full Text Available Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology and neurochemistry (e.g., dopamine, GABA, and glutamate. These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC, the principal psychoactive component in marijuana, acts as an agonist of the cannabinoid type 1 receptor (CB1R. Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g. THC, CP-55,940, and WIN55,212-2 during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.

  11. Effects of the cannabinoid CB1 receptor agonist CP55,940 and antagonist SR141716A on d-amphetamine-induced behaviours in Cebus monkeys

    DEFF Research Database (Denmark)

    Madsen, Morten V; Peacock, Linda; Werge, Thomas

    2006-01-01

    Several clinical studies have shown that alterations in the cannabinoid system in the brain may be associated with schizophrenia. Although evidence points towards an antipsychotic potential for cannabinoid antagonists, experimental studies have shown inconsistent behavioural effects of cannabinoi...

  12. Case Series of Synthetic Cannabinoid Intoxication from One Toxicology Center

    Directory of Open Access Journals (Sweden)

    Kenneth D. Katz

    2016-05-01

    Full Text Available Synthetic cannabinoid use has risen at alarming rates. This case series describes 11 patients exposed to the synthetic cannabinoid, MAB-CHMINACA who presented to an emergency department with life-threatening toxicity including obtundation, severe agitation, seizures and death. All patients required sedatives for agitation, nine required endotracheal intubation, three experienced seizures, and one developed hyperthermia. One developed anoxic brain injury, rhabdomyolysis and died. A significant number were pediatric patients. The mainstay of treatment was aggressive sedation and respiratory support. Synthetic cannabinoids pose a major public health risk. Emergency physicians must be aware of their clinical presentation, diagnosis and treatment.

  13. Diabetes mellitus type 1

    OpenAIRE

    Desta, Semere Tekeste

    2017-01-01

    Høgskulen på Vestlandet Avdeling for helsefag for sykepleiere Tittel: Diabetes type 1 Bakgrunn for val av tema: I 2000 var det ca. 130 000 personer i Norge med diabetes, av disse hadde ca. 20 000 diabetes type 1. I dag er det ca. 230 000 personer som har diabetes i Norge. Av disse ca. 28 000 type 1 diabetes. Tallet viser hvor alvorlig sykdommen er, fordi det har vært og fortsatt er, en økning av antall diabetikere i Norge. Type 1 diabetes kan komme i alle aldersgrupper, men vanligvis...

  14. Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

    Science.gov (United States)

    Khani, Abbas; Kermani, Mojtaba; Hesam, Soghra; Haghparast, Abbas; Argandoña, Enrike G; Rainer, Gregor

    2015-06-01

    Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions.

  15. Diabetes Type 1

    Science.gov (United States)

    Diabetes means your blood glucose, or blood sugar, levels are too high. With type 1 diabetes, your pancreas does not make insulin. Insulin is ... kidneys, nerves, and gums and teeth. Type 1 diabetes happens most often in children and young adults ...

  16. Type 1 Diabetes Facts

    Science.gov (United States)

    ... Affiliates JDRF Celebrity Ambassadors JDRF Logo Usage Contact Us Donate Events More Type 1 Diabetes Facts Type 1 diabetes (T1D) is an autoimmune ... about Insulin and T1D Learn More What Is Diabetes? Causes of T1D The Complexity of Diagnosing ... US CAREERS NEWSROOM FOR RESEARCHERS © JDRF 2018 • Privacy Policy • ...

  17. PHARMACOLOGY OF CANNABINOIDS

    Directory of Open Access Journals (Sweden)

    Ilonka Ferjan

    2015-06-01

    Full Text Available The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives. Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials. Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used. Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. g. severe central nervous system depression, are more pronounced in children than in adults. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority. Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale."

  18. How important are sex differences in cannabinoid action?

    Science.gov (United States)

    Fattore, Liana; Fratta, Walter

    2010-06-01

    In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experience and emotions in different ways, display diverse attitudes, language and social skills, and show sex-related differences in the brain anatomy and organization. Drug addiction is a widespread relapsing illness that affects both men and women. Sex-dependent differences have been frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. Beside sex differences observed in the cannabinoid-induced effects related to cannabis abuse and dependence, cannabinoids have been shown to exert sex-dependent effects also in other physiological and behavioural aspects, such as food intake and energy balance (more evident in males), or anxiety and depression (more evident in females). Research has just begun to identify factors which could provide a neurobiological basis for gender-based differences in cannabinoid effects, among which, gonadal hormones seem to play a crucial role. Yet, cannabinoid pharmacodynamic and pharmacokinetic may also be important, as sex differences in cannabinoid effects might be due, at least in part, to differences in muscle mass and fat tissue distribution between males and females. Here, we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid effects, and put forward some suggestions for future studies to fill the gap in our knowledge of gender-specific bias in cannabinoid pharmacology.

  19. Type 1 diabetes

    DEFF Research Database (Denmark)

    Green, Anders; Kyvik, Kirsten Ohm

    2001-01-01

    Prediction of Type 1 diabetes at individual level is relevant for any possible intervention before clinical disease develops. Currently available markers of Type 1 diabetes include genetic specificities and immune markers, in addition to a positive family history. This chapter reviews the measures...... and methods of importance in predicting Type 1 diabetes. Based on numerical examples it is demonstrated that available markers have a low level of performance, even when combined. Even so, combined marker information may allow for the identification of the large majority of the general population who...... is at very low disease risk. The impact at population level of predicting Type 1 diabetes varies between societies because the performance of markers depends on levels of disease risk and distribution of markers within a population. The incorporation of the influence of non-genetic etiological factors may...

  20. Type 1 diabetes

    OpenAIRE

    Atkinson, Mark A; Eisenbarth, George S; Michels, Aaron W

    2013-01-01

    Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identifi...

  1. Diabetes mellitus type 1

    OpenAIRE

    Tøraasen, Lisa Vangen; Al-Sultan, Zainab

    2014-01-01

    Bacheloroppgave i sykepleie, 2014 Hvert år blir rundt 600 nordmenn diagnostisert med sykdommen diabetes type 1, og Norge er et av landene i verden med størst andel av barnediabetes. I dag er det 15 000- 20 000 personer i Norge som har diabetes type 1, og antall barn som får diabetes har fordoblet seg de siste 30 årene (Diabetesforbundet, 2014). Problemstillingen vår gikk ut på hvordan sykepleiere kan veilede og undervise ungdom med nyoppdaget diabetes type på sykehus. Ut i fra litteraturst...

  2. Diabetes mellitus type 1

    OpenAIRE

    Tøraasen, Lisa Vangen; Al-Sultan, Zainab

    2014-01-01

    Hvert år blir rundt 600 nordmenn diagnostisert med sykdommen diabetes type 1, og Norge er et av landene i verden med størst andel av barnediabetes. I dag er det 15 000- 20 000 personer i Norge som har diabetes type 1, og antall barn som får diabetes har fordoblet seg de siste 30 årene (Diabetesforbundet, 2014). Problemstillingen vår gikk ut på hvordan sykepleiere kan veilede og undervise ungdom med nyoppdaget diabetes type på sykehus. Ut i fra litteraturstudiet har vi arbeidet oss frem for å ...

  3. Cannabinoids: Medical implications.

    Science.gov (United States)

    Schrot, Richard J; Hubbard, John R

    2016-01-01

    Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

  4. What Are Synthetic Cannabinoids?

    Science.gov (United States)

    ... years, synthetic cannabinoid mixtures have been easy to buy in drug paraphernalia shops, novelty stores, gas stations, and over ... abuse, authorities have made it illegal to sell, buy, or possess some of ... use is that standard drug tests cannot easily detect many of the chemicals ...

  5. [Cannabinoids in pain medicine].

    Science.gov (United States)

    Karst, M

    2018-06-07

    The endocannabinoid system (ECS) controls a large number of vital functions. Suboptimal tone of the ECS in certain regions of the nervous system may be associated with disorders that are also associated with pain. Pain and inflammation processes can be modulated by the exogenous supply of cannabinoids. Low-to-moderate pain-relieving effects and in individual cases large pain-relieving effects were observed in randomized, controlled studies of various types of chronic pain. People with chronic neuropathic pain and stress symptoms seem to particularly benefit. The therapeutic range of cannabinoids is small; often small doses are sufficient for clinically significant effects. The "Cannabis-als-Medizin-Gesetz" (cannabis as medicine law) allows the prescription of cannabis preparations under certain conditions. Available data indicate good long-term efficacy and tolerability. However, there is little systematic long-term experience from clinical studies.

  6. Type 1 autoimmune pancreatitis.

    Science.gov (United States)

    Zen, Yoh; Bogdanos, Dimitrios P; Kawa, Shigeyuki

    2011-12-07

    Before the concept of autoimmune pancreatitis (AIP) was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP) has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney) and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of regulatory T-cells are assumed

  7. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  8. Type 1 Tyrosinaemia

    LENUS (Irish Health Repository)

    Mannion, MA

    2016-06-01

    Tyrosinaemia type 1 (TYR1, OMIM# 276700) is a rare autosomal recessive disease that results from an enzyme defect that leads to a deficiency in fumarylacetoacetase (FAH)1. We present 3 cases of TYR1 in the Irish population over a 9 year period, the only cases known to have been diagnosed in Ireland since 1989. The common presenting symptom was hypoglycaemia and the diagnosis was made by the identification of the pathognomonic biomarker succinylacetone on urine organic acid analysis. We discuss the clinical presentation, biochemical and genetic results including one novel mutation. We also highlight the importance of early initiation of Nitisinone (NTBC), which reduces the complications of TYR1 and the incidence of liver transplantation in this population2.

  9. Mouse adenovirus type 1 infection of macrophages

    NARCIS (Netherlands)

    Ashley, S.L.; Welton, A.R.; Harwood, K.M.; Rooijen, van N.; Spindler, K.R.

    2009-01-01

    Mouse adenovirus type 1 (MAV-1) causes acute and persistent infections in mice, with high levels of virus found in the brain, spinal cord and spleen in acute infections. MAV-1 infects endothelial cells throughout the mouse, and monocytes/macrophages have also been implicated as targets of the virus.

  10. Cannabis, cannabinoids, and health.

    Science.gov (United States)

    Lafaye, Genevieve; Karila, Laurent; Blecha, Lisa; Benyamina, Amine

    2017-09-01

    Cannabis (also known as marijuana) is the most frequently used illicit psychoactive substance in the world. Though it was long considered to be a "soft" drug, studies have proven the harmful psychiatric and addictive effects associated with its use. A number of elements are responsible for the increased complications of cannabis use, including the increase in the potency of cannabis and an evolution in the ratio between the two primary components, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (toward a higher proportion of Δ 9 -THC), Synthetic cannabinoid (SC) use has rapidly progressed over the last few years, primarily among frequent cannabis users, because SCs provide similar psychoactive effects to cannabis. However, their composition and pharmacological properties make them dangerous substances. Cannabis does have therapeutic properties for certain indications. These therapeutic applications pertain only to certain cannabinoids and their synthetic derivatives. The objective of this article is to summarize current developments concerning cannabis and the spread of SCs. Future studies must further explore the benefit-risk profile of medical cannabis use.

  11. Pregnenolone can protect the brain from cannabis intoxication.

    Science.gov (United States)

    Vallée, Monique; Vitiello, Sergio; Bellocchio, Luigi; Hébert-Chatelain, Etienne; Monlezun, Stéphanie; Martin-Garcia, Elena; Kasanetz, Fernando; Baillie, Gemma L; Panin, Francesca; Cathala, Adeline; Roullot-Lacarrière, Valérie; Fabre, Sandy; Hurst, Dow P; Lynch, Diane L; Shore, Derek M; Deroche-Gamonet, Véronique; Spampinato, Umberto; Revest, Jean-Michel; Maldonado, Rafael; Reggio, Patricia H; Ross, Ruth A; Marsicano, Giovanni; Piazza, Pier Vincenzo

    2014-01-03

    Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

  12. Beyond THC: the new generation of cannabinoid designer drugs

    Directory of Open Access Journals (Sweden)

    Liana eFattore

    2011-09-01

    Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

  13. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    Science.gov (United States)

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Cannabinoids for epilepsy.

    Science.gov (United States)

    Gloss, David; Vickrey, Barbara

    2014-03-05

    Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy. To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy. We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the references in the identified studies. Randomized controlled trials (RCTs) whether blinded or not. Two authors independently selected trials for inclusion and extracted the data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included responder rate at six months or more, objective quality of life data, and adverse events. We found four randomized trial reports that included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract and another was a letter to the editor. Anti-epileptic drugs were continued in all studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects. No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was

  15. Modulation of limbic noradrenergic circuits by cannabinoids

    OpenAIRE

    Carvalho, Ana Raquel Franky Gomes

    2010-01-01

    Tese de doutoramento Medicina The endocannabinoid system has been implicated in the regulation of several physiological functions. The widespread distribution of the endocannabinoid system in the central nervous system (CNS) accounts for many effects attributed to cannabinoids. Importantly, cannabinoids have been shown to modulate mood, cognition and memory. There is growing evidence suggesting that cannabinoids can interact with the noradrenergic system. Noradrenergic trans...

  16. Plant cannabinoids: a neglected pharmacological treasure trove.

    Science.gov (United States)

    Mechoulam, Raphael

    2005-12-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Delta(9)-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  17. The Analgesic Potential of Cannabinoids

    Science.gov (United States)

    Elikottil, Jaseena; Gupta, Pankaj; Gupta, Kalpna

    2013-01-01

    Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. Since opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain. PMID:20073408

  18. Type 1 Diabetes and Sleep

    OpenAIRE

    Farabi, Sarah S.

    2016-01-01

    IN BRIEF In people with type 1 diabetes, sleep may be disrupted as a result of both behavioral and physiological aspects of diabetes and its management. This sleep disruption may negatively affect disease progression and development of complications. This review highlights key research findings regarding sleep in people with type 1 diabetes.

  19. Cannabinoids for fibromyalgia.

    Science.gov (United States)

    Walitt, Brian; Klose, Petra; Fitzcharles, Mary-Ann; Phillips, Tudor; Häuser, Winfried

    2016-07-18

    This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the

  20. [Cannabinoid hyperemesis syndrome].

    Science.gov (United States)

    Stuijvenberg, Marleen P; Ramaekers, Guy M G I; Bijpost, Yan

    2011-01-01

    A 22-year-old man was referred to our clinic with a 7-year history of episodes of severe vomiting interspersed with symptom-free periods. We saw another patient, a 22-year-old woman, after she had been admitted for the second time with dehydration and hypokalaemia following severe vomiting. We saw a third patient, a 25-year-old woman with a personality disorder and cannabis addiction, after she had gone to the casualty department following several days of persistent excessive vomiting. All three patients seemed to be suffering from cannabinoid hyperemesis syndrome. This is a rarely described syndrome, characterised by the triad of chronic cannabis abuse, unexplained cyclical excessive vomiting and compulsive taking of hot baths for symptom relief. A subgroup of chronic frequent cannabis users suffer from this syndrome, which can appear for the first time several years after initial cannabis use. The exact mechanism of origin is unknown, though various theories exist. In the case of unexplained chronic symptoms of nausea and vomiting our advice is always to question the patient about substance misuse, and showering and bathing habits.

  1. Müller cells express the cannabinoid CB2 receptor in the vervet monkey retina

    DEFF Research Database (Denmark)

    Bouskila, Joseph; Javadi, Pasha; Casanova, Christian

    2013-01-01

    The presence of the cannabinoid receptor type 1 (CB1R) has been largely documented in the rodent and primate retinae in recent years. There is, however, some controversy concerning the presence of the CB2 receptor (CB2R) within the central nervous system. Only recently, CB2R has been found in the...

  2. Angiotensin II type 1 receptor blockade by telmisartan prevents stress-induced impairment of memory via HPA axis deactivation and up-regulation of brain-derived neurotrophic factor gene expression.

    Science.gov (United States)

    Wincewicz, D; Juchniewicz, A; Waszkiewicz, N; Braszko, J J

    2016-09-01

    Physical and psychological aspects of chronic stress continue to be a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. By the results of our previous work it has been demonstrated that telmisartan (TLM), an angiotensin type 1 receptor (AT1) blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ), alleviates stress-induced cognitive decline. Understanding of mechanistic background of this phenomenon is hampered by both dual binding sites of TLM and limited data on the consequences of central AT1 blockade and PPARγ activation. Therefore, a critical need exists for progress in the characterization of this target for pro-cognitive drug discovery. An unusual ability of novel ARBs to exert various PPARγ binding activities is commonly being viewed as predominant over angiotensin blockade in terms of neuroprotection. Here we aimed to verify this hypothesis using an animal model of chronic psychological stress (Wistar rats restrained 2.5h daily for 21days) with simultaneous oral administration of TLM (1mg/kg), GW9662 - PPARγ receptor antagonist (0.5mg/kg), or both in combination, followed by a battery of behavioral tests (open field, elevated plus maze, inhibitory avoidance - IA, object recognition - OR), quantitative determination of serum corticosterone (CORT) and evaluation of brain-derived neurotrophic factor (BDNF) gene expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Stressed animals displayed decreased recall of the IA behavior (pBDNF in the mPFC (paxis deactivation associated with changes in primarily cortical gene expression. This study confirms the dual activities of TLM that controls hypertension and cognition through AT1 blockade. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Cannabinoid modulation of drug reward and the implications of marijuana legalization.

    Science.gov (United States)

    Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F

    2015-12-02

    Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Cannabinoid modulation of executive functions

    NARCIS (Netherlands)

    Pattij, T.; Wiskerke, J.; Schoffelmeer, A.N.M.

    2008-01-01

    Executive functions are higher-order cognitive processes such as attention, behavioural flexibility, decision-making, inhibitory control, planning, time estimation and working memory that exert top-down control over behaviour. In addition to the role of cannabinoid signaling in other cognitive

  5. Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging

    Directory of Open Access Journals (Sweden)

    Ahmed Haider

    2016-07-01

    Full Text Available Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1 is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2 in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2 and 1.0 ± 0.2 µM (CB1 for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2 and 1.1 ± 0.1 µM (CB1. Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail

  6. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Charu Sharma

    2015-01-01

    Full Text Available The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2 which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

  7. Evaluation of the In Vivo and Ex Vivo Binding of Novel BC1 Cannabinoid Receptor Radiotracers

    Energy Technology Data Exchange (ETDEWEB)

    Miller, A.; Gatley, J.; Gifford, A.

    2002-01-01

    The primary active ingredient of marijuana, 9-tetrahydrocannabinol, exerts its psychoactive effects by binding to cannabinoid CB1 receptors. These receptors are found throughout the brain with high concentrations in the hippocampus and cerebellum. The current study was conducted to evaluate the binding of a newly developed putative cannabinoid antagonist, AM630, and a classical cannabinoid 8-tetrahydrocannabinol as potential PET and/or SPECT imaging agents for brain CB1 receptors. For both of these ligands in vivo and ex vivo studies in mice were conducted. AM630 showed good overall brain uptake (as measure by %IA/g) and a moderately rapid clearance from the brain with a half-clearance time of approximately 30 minutes. However, AM630 did not show selective binding to CB1 cannabinoid receptors. Ex vivo autoradiography supported the lack of selective binding seen in the in vivo study. Similar to AM630, 8-tetrahydrocanibol also failed to show selective binding to CB1 receptor rich brain areas. The 8-tetrahydrocanibol showed moderate overall brain uptake and relatively slow brain clearance as compared to AM630. Further studies were done with AM2233, a cannabinoid ligand with a similar structure as AM630. These studies were done to develop an ex vivo binding assay to quantify the displacement of [131I]AM2233 binding by other ligands in Swiss-Webster and CB1 receptor knockout mice. By developing this assay we hoped to determine the identity of an unknown binding site for AM2233 present in the hippocampus of CB1 knockout mice. Using an approach based on incubation of brain slices prepared from mice given intravenous [131I]AM2233 in either the presence or absence of AM2233 (unlabelled) it was possible to demonstrate a significant AM2233-displacable binding in the Swiss-Webster mice. Future studies will determine if this assay is appropriate for identifying the unknown binding site for AM2233 in the CB1 knockout mice.

  8. Living with Type 1 Diabetes

    Science.gov (United States)

    ... elements: blood glucose control and insulin management, exercise, nutrition and support. Medication A diagnosis of type 1 diabetes means ... crucial part of your daily routine. Learn more: Nutrition How foods ... meal plans Support Emotional support, while not often initially considered, plays ...

  9. Safety and Toxicology of Cannabinoids

    OpenAIRE

    Sachs, Jane; McGlade, Erin; Yurgelun-Todd, Deborah

    2015-01-01

    There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will...

  10. Cannabinoids cases in polish athletes

    Directory of Open Access Journals (Sweden)

    A Pokrywka

    2009-07-01

    Full Text Available The aim of this study was to investigate the number of cases and the profiles of Polish athletes who had occasionally been using marijuana or hashish throughout the period of 1998-2004, with respect to: sex, age, and discipline of sport as well as the period of testing (in- and out-of-competition. Results of the study were compared with some data reported by other WADA accredited anti-doping laboratories. Totally, 13 631 urine samples taken from Polish athletes of both sexes, aged 10-67 years, performing 46 disciplines of sport were tested. Cannabinoids were detected in 267 samples. Among Polish athletes the relative number of positive THC (tetrahydrocannabinol samples was one of the highest in Europe. The group of young Polish athletes (aged 16-24 years was the most THC-positive. THC-positive cases were noted more frequently in male athletes tested during out of competitions. The so-called contact sports (rugby, ice hockey, skating, boxing, badminton, body building and acrobatic sports were those sports, where the higher risk of cannabis use was observed. The legal interpretation of some positive cannabinoids results would be difficult because of some accidental and unintentional use of the narcotics by sportsmen. It was concluded that national anti-doping organizations (NADO’s, which are competent to judge whether the anti-doping rules were violated, should take into account the possibility of non-intentional doping use of cannabinoids via passive smoking of marijuana.

  11. 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.

  12. Barn og diabetes type 1

    OpenAIRE

    Ramstad, Marte Elise; Sagbakken, Sina Bekkelund

    2017-01-01

    Bacheloroppgave sykepleie, 2017 Bakgrunn: Vi har valgt denne problemstillingen fordi diabetes type 1 er svært utbredt hos barn i Norge. Videre har vi lite erfaringer med barn og ønsket å lære mer om denne pasientgruppen. Vi ønsket videre å se på hvordan vi kan undervise og veilede for å gi god og hensiktsmessig sykepleie til barn og deres familier. Hensikt: Finne ut hvordan sykepleier kan fremme egenomsorg hos barn med diabetes gjennom veiledning og undervisning. Dette er noe som sykepl...

  13. Cannabis and Cannabinoids for Chronic Pain.

    Science.gov (United States)

    Romero-Sandoval, E Alfonso; Kolano, Ashley L; Alvarado-Vázquez, P Abigail

    2017-10-05

    The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use. We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids. Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.

  14. What causes type 1 diabetes?

    DEFF Research Database (Denmark)

    Buschard, Karsten

    2011-01-01

    To study type 1 diabetes (T1D), excellent animal models exist, both spontaneously diabetic and virus-induced. Based on knowledge from these, this review focuses on the environmental factors leading to T1D, concentrated into four areas which are: (1) The thymus-dependent immune system: T1D is a T...... T cell reaction and less autoimmunity. Glycolipids presented by CD1 molecules are central in this stimulation. (4) Importance of the intestine and gliadin intake: Gluten-free diet dramatically inhibits T1D in animal models, and epidemiological data are supportive of such an effect in humans....... The mechanisms include less subclinical intestinal inflammation and permeability, and changed composition of bacterial flora, which can also be obtained by intake of probiotics. Gluten-free diet is difficult to implement, and short-term intake has no effect. Regarding the onset of the T1D disease process, slow...

  15. Safety and Toxicology of Cannabinoids.

    Science.gov (United States)

    Sachs, Jane; McGlade, Erin; Yurgelun-Todd, Deborah

    2015-10-01

    There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will then be compared with the current social and political climate to suggest future policy directions and general guidelines.

  16. Feeding induced by cannabinoids is mediated independently of the melanocortin system.

    Directory of Open Access Journals (Sweden)

    Puspha Sinnayah

    2008-05-01

    Full Text Available Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance.Here, we show that peripherally administered CB1-R antagonist (AM251 or agonist equally suppressed or stimulated feeding respectively in A(y , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals.Our results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.

  17. Involvement of the cannabinoid CB1 receptor in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats.

    Science.gov (United States)

    Dazzi, Laura; Talani, Giuseppe; Biggio, Francesca; Utzeri, Cinzia; Lallai, Valeria; Licheri, Valentina; Lutzu, Stefano; Mostallino, Maria Cristina; Secci, Pietro Paolo; Biggio, Giovanni; Sanna, Enrico

    2014-01-01

    Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC) and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1 cannabinoid receptor in this

  18. Involvement of the cannabinoid CB1 receptor in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats.

    Directory of Open Access Journals (Sweden)

    Laura Dazzi

    Full Text Available Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1

  19. Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring.

    Directory of Open Access Journals (Sweden)

    María Teresa Ramírez-López

    Full Text Available Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS. In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a the adult expression of endocannabinoid-related behaviors, b the metabolic profile of adult offspring and c the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.

  20. Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats.

    Directory of Open Access Journals (Sweden)

    Hila Abush

    Full Text Available The use of cannabis can impair cognitive function, especially short-term memory. A controversial question is whether long-term cannabis use during the late-adolescence period can cause irreversible deficits in higher brain function that persist after drug use stops. In order to examine the short- and long-term effects of chronic exposure to cannabinoids, rats were administered chronic i.p. treatment with the CB1/CB2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg for two weeks during the late adolescence period (post-natal days 45-60 and tested for behavioral and electrophysiological measures of cognitive performance 24 hrs, 10 and 30 days after the last drug injection. The impairing effects of chronic WIN on short-term memory in the water maze and the object recognition tasks as well as long-term potentiation (LTP in the ventral subiculum (vSub-nucleus accumbens (NAc pathway were temporary as they lasted only 24 h or 10 d after withdrawal. However, chronic WIN significantly impaired hippocampal dependent short-term memory measured in the object location task 24 hrs, 10, 30, and 75 days after the last drug injection. Our findings suggest that some forms of hippocampal-dependent short-term memory are sensitive to chronic cannabinoid administration but other cognitive impairments are temporary and probably result from a residue of cannabinoids in the brain or acute withdrawal effects from cannabinoids. Understanding the effects of cannabinoids on cognitive function may provide us with tools to overcome these impairments and for cannabinoids to be more favorably considered for clinical use.

  1. Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat.

    Science.gov (United States)

    Lange, M D; Daldrup, T; Remmers, F; Szkudlarek, H J; Lesting, J; Guggenhuber, S; Ruehle, S; Jüngling, K; Seidenbecher, T; Lutz, B; Pape, H C

    2017-10-01

    The brain circuits underlying behavioral fear have been extensively studied over the last decades. Although the vast majority of experimental studies assess fear as a transient state of apprehension in response to a discrete threat, such phasic states of fear can shift to a sustained anxious apprehension, particularly in face of diffuse cues with unpredictable environmental contingencies. Unpredictability, in turn, is considered an important variable contributing to anxiety disorders. The networks of the extended amygdala have been suggested keys to the control of phasic and sustained states of fear, although the underlying synaptic pathways and mechanisms remain poorly understood. Here, we show that the endocannabinoid system acting in synaptic circuits of the extended amygdala can explain the fear response profile during exposure to unpredictable threat. Using fear training with predictable or unpredictable cues in mice, combined with local and cell-type-specific deficiency and rescue of cannabinoid type 1 (CB1) receptors, we found that presynaptic CB1 receptors on distinct amygdala projections to bed nucleus of the stria terminalis (BNST) are both necessary and sufficient for the shift from phasic to sustained fear in response to an unpredictable threat. These results thereby identify the causal role of a defined protein in a distinct brain pathway for the temporal development of a sustained state of anxious apprehension during unpredictability of environmental influences, reminiscent of anxiety symptoms in humans.

  2. Cannabinoids facilitate the swallowing reflex elicited by the superior laryngeal nerve stimulation in rats.

    Science.gov (United States)

    Mostafeezur, Rahman Md; Zakir, Hossain Md; Takatsuji, Hanako; Yamada, Yoshiaki; Yamamura, Kensuke; Kitagawa, Junichi

    2012-01-01

    Cannabinoids have been reported to be involved in affecting various biological functions through binding with cannabinoid receptors type 1 (CB1) and 2 (CB2). The present study was designed to investigate whether swallowing, an essential component of feeding behavior, is modulated after the administration of cannabinoid. The swallowing reflex evoked by the repetitive electrical stimulation of the superior laryngeal nerve in rats was recorded before and after the administration of the cannabinoid receptor agonist, WIN 55-212-2 (WIN), with or without CB1 or CB2 antagonist. The onset latency of the first swallow and the time intervals between swallows were analyzed. The onset latency and the intervals between swallows were shorter after the intravenous administration of WIN, and the strength of effect of WIN was dose-dependent. Although the intravenous administration of CB1 antagonist prior to intravenous administration of WIN blocked the effect of WIN, the administration of CB2 antagonist did not block the effect of WIN. The microinjection of the CB1 receptor antagonist directly into the nucleus tractus solitarius (NTS) prior to intravenous administration of WIN also blocked the effect of WIN. Immunofluorescence histochemistry was conducted to assess the co-localization of CB1 receptor immunoreactivity to glutamic acid decarboxylase 67 (GAD67) or glutamate in the NTS. CB1 receptor was co-localized more with GAD67 than glutamate in the NTS. These findings suggest that cannabinoids facilitate the swallowing reflex via CB1 receptors. Cannabinoids may attenuate the tonic inhibitory effect of GABA (gamma-aminobuteric acid) neurons in the central pattern generator for swallowing.

  3. Cannabinoids facilitate the swallowing reflex elicited by the superior laryngeal nerve stimulation in rats.

    Directory of Open Access Journals (Sweden)

    Rahman Md Mostafeezur

    Full Text Available Cannabinoids have been reported to be involved in affecting various biological functions through binding with cannabinoid receptors type 1 (CB1 and 2 (CB2. The present study was designed to investigate whether swallowing, an essential component of feeding behavior, is modulated after the administration of cannabinoid. The swallowing reflex evoked by the repetitive electrical stimulation of the superior laryngeal nerve in rats was recorded before and after the administration of the cannabinoid receptor agonist, WIN 55-212-2 (WIN, with or without CB1 or CB2 antagonist. The onset latency of the first swallow and the time intervals between swallows were analyzed. The onset latency and the intervals between swallows were shorter after the intravenous administration of WIN, and the strength of effect of WIN was dose-dependent. Although the intravenous administration of CB1 antagonist prior to intravenous administration of WIN blocked the effect of WIN, the administration of CB2 antagonist did not block the effect of WIN. The microinjection of the CB1 receptor antagonist directly into the nucleus tractus solitarius (NTS prior to intravenous administration of WIN also blocked the effect of WIN. Immunofluorescence histochemistry was conducted to assess the co-localization of CB1 receptor immunoreactivity to glutamic acid decarboxylase 67 (GAD67 or glutamate in the NTS. CB1 receptor was co-localized more with GAD67 than glutamate in the NTS. These findings suggest that cannabinoids facilitate the swallowing reflex via CB1 receptors. Cannabinoids may attenuate the tonic inhibitory effect of GABA (gamma-aminobuteric acid neurons in the central pattern generator for swallowing.

  4. Seventh European Workshop on Cannabinoid Research and IACM Eighth Conference on Cannabinoids in Medicine

    OpenAIRE

    Cheer, Joseph F.; Maccarrone, Mauro; Piomelli, Daniele

    2016-01-01

    Abstract The joint 7th European Workshop on Cannabinoid Research and IACM 8th Conference on Cannabinoids in Medicine was held in the beach town of Sestri Levante, Italy, on September 17?19, 2015. In this beautiful setting, world-leading investigators in the field of (endo)cannabinoid research presented exciting new data spanning a broad array of preclinical and clinical topics?from cellular electrophysiology to drug discovery and from potential indications for the therapeutic use of cannabis ...

  5. G-protein coupling of cannabinoid receptors

    International Nuclear Information System (INIS)

    Glass, M.

    2001-01-01

    Full text: Since the cloning of the cannabinoid CB1 and CB2 receptors in the early 1990's extensive research has focused on understanding their signal transduction pathways. While it has been known for sometime that both receptors can couple to intracellular signalling via pertussis toxin sensitive G-proteins (Gi/Go), the specificity and kinetics of these interactions have only recently been elucidated. We have developed an in situ reconstitution approach to investigating receptor-G-protein interactions. This approach involves chaotropic extraction of receptor containing membranes in order to inactivate or remove endogenous G-proteins. Recombinant or isolated brain G-proteins can then be added back to the receptors, and their activation monitored through the binding of [ 35 S]-GTPγS. This technique has been utilised for an extensive study of cannabinoid receptor mediated activation of G-proteins. In these studies we have established that CB1 couples with high affinity to both Gi and Go type G-proteins. In contrast, CB2 couples strongly to Gi, but has a very low affinity for Go. This finding correlated well with the previous findings that while CB1 and CB2 both couple to the inhibition of adenylate cyclase, CB1 but not CB2 could also inhibit calcium channels. We then examined the ability of a range of cannabinoid agonists to activate the Gi and Go via CB1. Conventional receptor theory suggests that a receptor is either active or inactive with regard to a G-protein and that the active receptor activates all relevant G-proteins equally. However, in this study we found that agonists could produce different degrees of activation, depending on which G-protein was present. Further studies have compared the ability of the two endocannabinoids to drive the activation of Gi or Go. These studies show that agonists can induce multiple forms of activated receptor that differ in their ability to catalyse the activation of Gi or Go. The ability of an agonist to drive a receptor

  6. Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice

    Directory of Open Access Journals (Sweden)

    Diego C. Mascarenhas

    2017-10-01

    Full Text Available Divergent results in pain management account for the growing number of studies aiming at elucidating the pharmacology of the endocannabinoid/endovanilloid anandamide (AEA within several pain-related brain structures. For instance, the stimulation of both Transient Receptor Potential Vanilloid type 1 (TRPV1 and Cannabinoid type 1 (CB1 receptors led to paradoxical effects on nociception. Here, we attempted to propose a clear and reproducible methodology to achieve the antinociceptive effect of exogenous AEA within the dorsal periaqueductal gray (dPAG of mice exposed to the tail-flick test. Accordingly, male Swiss mice received intra-dPAG injection of AEA (CB1/TRPV1 agonist, capsaicin (TRPV1 agonist, WIN (CB1 agonist, AM251 (CB1 antagonist, and 6-iodonordihydrocapsaicin (6-IODO (TRPV1 selective antagonist and their nociceptive response was assessed with the tail-flick test. In order to assess AEA effects on nociception specifically at vanilloid or cannabinoid (CB substrates into the dPAG, mice underwent an intrinsically inactive dose of AM251 or 6-IODO followed by local AEA injections and were subjected to the same test. While intra-dPAG AEA did not change acute pain, local injections of capsaicin or WIN induced a marked TRPV1- and CB1-dependent antinociceptive effect, respectively. Regarding the role of AEA specifically at CB/vanilloid substrates, while the blockade of TRPV1 did not change the lack of effects of intra-dPAG AEA on nociception, local pre-treatment of AM251, a CB1 antagonist, led to a clear AEA-induced antinociception. It seems that the exogenous AEA-induced antinociception is unmasked when it selectively binds to vanilloid substrates, which might be useful to address acute pain in basic and perhaps clinical trials.

  7. Development of radiometric methods for the determination of enzyme activities of iodothyronine deiodinases. Effect of the antidepressant fluoxetine on type 1, 2 and 3 deiodinase activities in the rat brain

    International Nuclear Information System (INIS)

    Pavelka, Stanislav

    2010-01-01

    The objectives of the present study were to establish valid assay conditions for measurement of the types 1, 2, and 3 (Dl, D2, and D3, respectively) iodothyronine deiodinases (IDs) activities, and to use the radiometric enzyme assays especially to follow the effects of antidepressant drug fluoxetine (Prozac) on the metabolism of thyroid hormones (TH) in the rat. In particular, the effects of subchronic administration of fluoxetine alone and in combination with 3,5,3'-triiodothyronine (T 3 ) on T 3 production and degradation in the CNS and peripheral tissues were investigated. The newly developed radiometric enzyme assays for IDs, based on the use of preferred 125 I-labeled iodothyronines as substrates, TLC separation of radioactive products from the unconsumed substrates, film-less autoradiography of radiochromatograms using storage phosphor screens, and quantification of the separated compounds with the BAS-5000 laser scanner, proved to be very sensitive and rapid and, at the same time, reliable and robust. (author)

  8. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    International Nuclear Information System (INIS)

    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N.; Moran, Jeffery H.; Prather, Paul L.

    2013-01-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB 1 Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB 2 Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB 2 Rs (hCB 2 Rs). The affinity of cannabinoids for hCB 2 Rs was determined by competition binding studies employing CHO-hCB 2 membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB 2 cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB 2 Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB 2 Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ 9 -tetrahydrocannabinol (Δ 9 -THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB 2 R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB 2 Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB 2 Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB 1 and CB 2 Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2

  9. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2013-06-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

  10. Insulin requirements in type 1 diabetic pregnancy

    DEFF Research Database (Denmark)

    Callesen, Nicoline; Ringholm, Lene; Stage, Edna

    2012-01-01

    To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy.......To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy....

  11. Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti-Reward

    Science.gov (United States)

    Blum, Kenneth; Oscar-Berman, Marlene; Braverman, Eric R.; Febo, Marcelo; Li, Mona; Gold, Mark S.

    2015-01-01

    Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ9-tetrahydrocannabinol (THC) enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1) receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Long-term blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and non-substance (behavioral) addictions. PMID:26306328

  12. Sustainable production of cannabinoids with supercritical carbon dioxide technologies

    NARCIS (Netherlands)

    Perrotin-Brunel, H.

    2011-01-01

    This thesis concerns the production of natural compounds from plant material for pharmaceutical and food applications. It describes the production (extraction and isolation) of cannabinoids, the active components present in cannabis. Many cannabinoids have medicinal properties but not all

  13. Sustainable Production of Cannabinoids with Supercritical Carbon Dioxide Technologies

    NARCIS (Netherlands)

    Perrotin-Brunel, H.

    2011-01-01

    This thesis concerns the production of natural compounds from plant material for pharmaceutical and food applications. It describes the production (extraction and isolation) of cannabinoids, the active components present in cannabis. Many cannabinoids have medicinal properties but not all

  14. Therapeutic Mechanisms for Cannabinoid-Promoted Survival of Oligodendrocytes

    Science.gov (United States)

    2013-06-21

    Studies in vivo were performed to characterize the effect of a novel synthetic cannabinoid compound in preventing inflammation, demyelination and...studied as a possible treatment for MS and one class of compounds that is showing particular promise are the cannabinoids. Cannabis, or marijuana , as it...thus differing in their chemical structures (77). The third class of cannabinoids relates to the synthetic cannabinoids. These synthetic

  15. Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

    Science.gov (United States)

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  16. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Directory of Open Access Journals (Sweden)

    Masahiro Matsunaga

    Full Text Available Happiness has been viewed as a temporary emotional state (e.g., pleasure and a relatively stable state of being happy (subjective happiness level. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater

  17. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Science.gov (United States)

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  18. The therapeutic potential of cannabis and cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo; Müller-Vahl, Kirsten

    2012-07-01

    Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.

  19. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

    Directory of Open Access Journals (Sweden)

    Katia eBefort

    2015-02-01

    Full Text Available The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins and dynorphins. The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids, enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.

  20. Autoimmune Hypoglycemia in Type 1 Diabetes Mellitus.

    Science.gov (United States)

    Ambigapathy, Jayakumar; Sahoo, Jayaprakash; Kamalanathan, Sadishkumar

    2017-07-15

    Antibodies against exogenous insulin are common in type 1 diabetes mellitus patients. They can cause hypoglycemia, albeit uncommonly. A 14-year-old girl with type 1 diabetes mellitus presented with recurrent hypoglycemia. High insulin, low C-peptide and raised insulin antibody levels documented during hypoglycemia. Plasmapheresis led to remission of hypoglycemia. Antibodies to exogenous insulin should be considered as a cause of recurrent refractory hypoglycemia in type 1 diabetes mellitus patients.

  1. Type 1 Diabetes and Interferon Therapy

    OpenAIRE

    Nakamura, Kan; Kawasaki, Eiji; Imagawa, Akihisa; Awata, Takuya; Ikegami, Hiroshi; Uchigata, Yasuko; Kobayashi, Tetsuro; Shimada, Akira; Nakanishi, Koji; Makino, Hideichi; Maruyama, Taro; Hanafusa, Toshiaki

    2011-01-01

    OBJECTIVE Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey. RESEARCH DESIGN AND METHODS Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy. RESULTS Median ...

  2. Eating disorders in type 1 diabetes

    DEFF Research Database (Denmark)

    Nash, J.; Skinner, T. C.

    2005-01-01

    There is some debate in the literature as to whether there is an increased risk of developing eating disorders in individuals with type 1 diabetes. This review located 12 empirical studies of eating pathology in females with type 1 diabetes. Review of these papers indicates...... that there is no evidence for an increase in the rates of anorexia or bulimia, in females with type 1 diabetes. However, the data do suggest that eating disorders not otherwise specified (EDNOS) are more prevalent in individuals with type 1 diabetes. Key features of these articles are reviewed and discussed....

  3. Emergency Physicians' Knowledge of Cannabinoid Designer Drugs

    Directory of Open Access Journals (Sweden)

    Patrick M Lank

    2013-09-01

    Full Text Available Introduction: The use of synthetic drugs of abuse in the United States has grown in the last few years, with little information available on how much physicians know about these drugs and how they are treating patients using them. The objective of this study was to assess emergency physician (EP knowledge of synthetic cannabinoids (SC.Methods: A self-administered internet-based survey of resident and attending EPs at a large urban emergency department (ED was administered to assess familiarity with the terms Spice or K2 and basic knowledge of SC, and to describe some practice patterns when managing SC intoxication in the ED.Results: Of the 83 physicians invited to participate, 73 (88% completed surveys. The terms “Spice” and “K2” for SC were known to 25/73 (34% and 36/73 (49% of respondents. Knowledge of SC came most commonly (72% from non-medical sources, with lay publications and the internet providing most respondents with information. Among those with previous knowledge of synthetic cannabinoids, 25% were not aware that SC are synthetic drugs, and 17% did not know they are chemically most similar to marijuana. Among all participants, 80% felt unprepared caring for a patient in the ED who had used synthetic cannabinoids.Conclusion: Clinically active EPs are unfamiliar with synthetic cannabinoids. Even those who stated they had heard of synthetic cannabinoids answered poorly on basic knowledge questions. More education is needed among EPs of all ages and levels of training on synthetic cannabinoids. [West J Emerg Med. 2013;14(5:467–470.

  4. Cannabinoids modulate hippocampal memory and plasticity.

    Science.gov (United States)

    Abush, Hila; Akirav, Irit

    2010-10-01

    Considerable evidence demonstrates that cannabinoid agonists impair whereas cannabinoid antagonists improve memory and plasticity. However, recent studies suggest that the effects of cannabinoids on learning do not necessarily follow these simple patterns, particularly when emotional memory processes are involved. We investigated the involvement of the cannabinoid system in hippocampal learning and plasticity using the fear-related inhibitory avoidance (IA) and the non-fear-related spatial learning paradigms, and cellular models of learning and memory, i.e., long-term potentiation (LTP) and long-term depression (LTD). We found that microinjection into the CA1 of the CB1/CB2 receptor agonist WIN55,212-2 (5 μg/side) and an inhibitor of endocannabinoid reuptake and breakdown AM404 (200 ng/side) facilitated the extinction of IA, while the CB1 receptor antagonist AM251 (6 ng/side) impaired it. WIN55,212-2 and AM251 did not affect IA conditioning, while AM404 enhanced it, probably due to a drug-induced increase in pain sensitivity. However, in the water maze, systemic or local CA1 injections of AM251, WIN55,212-2, and AM404 all impaired spatial learning. We also found that i.p. administration of WIN55,212-2 (0.5 mg/kg), AM404 (10 mg/kg), and AM251 (2 mg/kg) impaired LTP in the Schaffer collateral-CA1 projection, whereas AM404 facilitated LTD. Our findings suggest diverse effects of the cannabinoid system on CA1 memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect of cannabinoid activation and deactivation, respectively. Moreover, they provide preclinical support for the suggestion that targeting the endocannabinoid system may aid in the treatment of disorders associated with impaired extinction-like processes, such as post-traumatic stress disorder. © 2009 Wiley-Liss, Inc.

  5. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana.

    Science.gov (United States)

    Lauritsen, Kirstin J; Rosenberg, Harold

    2016-07-01

    Although initially developed for medical purposes, synthetic cannabinoids have also been consumed for recreational purposes. To evaluate whether agreement with positive and negative outcome expectancies differed for synthetic cannabinoids versus botanical marijuana, and assess reported reasons for using synthetic cannabinoids. Using a web-based recruitment and data collection procedure, 186 adults who had used both synthetic cannabinoids and botanical marijuana and 181 adults who had used botanical marijuana but not synthetic cannabinoids, completed measures of outcome expectancies and other relevant questionnaires. A significant interaction revealed that participants who had used both synthetic cannabinoids and botanical marijuana indicated lower agreement with positive expectancies for synthetic cannabinoids, and higher agreement with positive expectancies for botanical marijuana, than did those participants who used only botanical marijuana. There was no interaction between type of drug and use history on agreement with negative expectancies, and participants agreed more strongly with negative outcome expectancies for synthetic cannabinoids than for botanical marijuana whether they had used one or both types of these drugs. The most frequently provided reasons for using synthetic cannabinoids included availability, perceived legality, cost, curiosity, and social interaction. Given growing public acceptance of recreational and medical marijuana, coupled with negative perceptions and increasing regulation of synthetic cannabinoid compounds, botanical marijuana is likely to remain more available and more popular than synthetic cannabinoids.

  6. Relapsing/remitting type 1 diabetes

    NARCIS (Netherlands)

    van Megen, Kayleigh M.; Spindler, Matthew P.; Keij, Fleur M.; Bosch, Ineke; Sprangers, Fleur; van Royen-Kerkhof, Annet; Nikolic, Tatjana; Roep, Bart O.

    2017-01-01

    Aims/hypothesis: Type 1 diabetes is believed to be an autoimmune disease associated with irreversible loss of insulin secretory function that follows a chronic progressive course. However, it has been speculated that relapsing/remitting disease progression may occur in type 1 diabetes. Methods: We

  7. Type 1 Diabetes: What Is It?

    Science.gov (United States)

    ... Videos for Educators Search English Español Type 1 Diabetes: What Is It? KidsHealth / For Parents / Type 1 ... español Diabetes tipo 1: ¿Qué es? What Is Diabetes? Diabetes is a disease that affects how the ...

  8. 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.

  9. Cannabinoid Receptor 1 Gene Polymorphisms and Marijuana Misuse Interactions On White Matter and Cognitive Deficits in Schizophrenia

    OpenAIRE

    Ho, Beng-Choon; Wassink, Thomas H.; Ziebell, Steven; Andreasen, Nancy C.

    2011-01-01

    Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag s...

  10. Interactions of Cannabinoids With Biochemical Substrates

    Directory of Open Access Journals (Sweden)

    Brian F Thomas

    2017-05-01

    Full Text Available Recent decades have seen much progress in the identification and characterization of cannabinoid receptors and the elucidation of the mechanisms by which derivatives of the Cannabis sativa plant bind to receptors and produce their physiological and psychological effects. The information generated in this process has enabled better understanding of the fundamental physiological and psychological processes controlled by the central and peripheral nervous systems and has fostered the development of natural and synthetic cannabinoids as therapeutic agents. A negative aspect of this decades-long effort is the proliferation of clandestinely synthesized analogs as recreational street drugs with dangerous effects. Currently, the interactions of cannabinoids with their biochemical substrates are extensively but inadequately understood, and the clinical application of derived and synthetic receptor ligands remains quite limited. The wide anatomical distribution and functional complexity of the cannabinoid system continue to indicate potential for both therapeutic and side effects, which offers challenges and opportunities for medicinal chemists involved in drug discovery and development.

  11. Maculopathy and spinocerebellar ataxia type 1

    DEFF Research Database (Denmark)

    Lebranchu, Pierre; Le Meur, Guylène; Magot, Armelle

    2013-01-01

    Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported...

  12. Genetics Home Reference: type 1 diabetes

    Science.gov (United States)

    ... Jan 4. Review. Citation on PubMed or Free article on PubMed Central van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011 Jan;91( ...

  13. Genetics Home Reference: distal arthrogryposis type 1

    Science.gov (United States)

    ... 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. ... distal arthrogryposis type 1 . However, researchers speculate that contractures may be related to problems with muscle contraction ...

  14. Methylenetetrahydrofolate reductase gene polymorphism in type 1 ...

    African Journals Online (AJOL)

    Mohammed A AboElAsrar

    2012-05-05

    May 5, 2012 ... in type 1 diabetes mellitus: Relationship to microvascular complications ... b Pediatric Molecular Genetics Department, Ankara University, Turkey. Received 15 .... Patients with diabetic nephropathy were classified into two.

  15. Liraglutide for treating type 1 diabetes

    DEFF Research Database (Denmark)

    Dejgaard, Thomas Fremming; Frandsen, Christian Seerup; Holst, Jens Juul

    2016-01-01

    INTRODUCTION: Many persons with type 1 diabetes do not achieve glycemic targets, why new treatments, complementary to insulin, are of interest. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist could be a potential pharmacological supplement to insulin. This review discusses...... the mechanism of actions, efficacy and safety of liraglutide as add-on to insulin in persons with type 1 diabetes. AREAS COVERED: Physiological and clinical data on liraglutide in type 1 diabetes were reviewed. We searched the Cochrane library, MEDLINE and EMBASE, with the final search performed February 16...... there was no clinically relevant effect on HbA1c. Adverse events were mostly transient gastrointestinal side effects, primarily nausea. Based on the available data, liraglutide cannot be recommended as add-on therapy to insulin in persons with type 1 diabetes with the aim to improve glycemic control. Ongoing trials...

  16. Immunogenetics of type 1 diabetes mellitus

    African Journals Online (AJOL)

    EL-HAKIM

    to other autoimmune diseases, the etiology of T1D remains obscure but ..... T1D, type 1 diabetes; AIT, autoimmune thyroiditis; CD, celiac disease; AD, Addison's disease. Table 5. .... (GAD65Ab) in prediabetic adults developing diabetes.

  17. Cannabinoid Receptors CB1 and CB2 Modulate the Electroretinographic Waves in Vervet Monkeys

    Directory of Open Access Journals (Sweden)

    Joseph Bouskila

    2016-01-01

    Full Text Available The expression patterns of the cannabinoid receptor type 1 (CB1R and the cannabinoid receptor type 2 (CB2R are well documented in rodents and primates. In vervet monkeys, CB1R is present in the retinal neurons (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells and CB2R is exclusively found in the retinal glia (Müller cells. However, the role of these cannabinoid receptors in normal primate retinal function remains elusive. Using full-field electroretinography in adult vervet monkeys, we recorded changes in neural activity following the blockade of CB1R and CB2R by the intravitreal administration of their antagonists (AM251 and AM630, resp. in photopic and scotopic conditions. Our results show that AM251 increases the photopic a-wave amplitude at high flash intensities, whereas AM630 increases the amplitude of both the photopic a- and b-waves. In scotopic conditions, both blockers increased the b-wave amplitude but did not change the a-wave amplitude. These findings suggest an important role of CB1R and CB2R in primate retinal function.

  18. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    Science.gov (United States)

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB 1 /CB 2 ) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB 1 /CB 2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  19. Neurophysiological evidence for the presence of cannabinoid CB1 receptors in the laterodorsal tegmental nucleus

    DEFF Research Database (Denmark)

    Soni, Neeraj; Satpathy, Shankha; Kohlmeier, Kristi Anne

    2014-01-01

    Marijuana, which acts within the endocannabinoid (eCB) system as an agonist of the cannabinoid type 1 receptor (CB1R), exhibits addictive properties and has powerful actions on the state of arousal of an organism. The laterodorsal tegmental nucleus (LDT), as a component of the reticular activating...... the firing frequency and synaptic activity of neurons in this nucleus. Therefore, endogenous eCB transmission could play a role in processes involving the LDT, such as cortical activation and motivated behaviours and, further, behavioural actions of marijuana are probably mediated, in part, via cellular...

  20. Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration

    Directory of Open Access Journals (Sweden)

    Juan Mendizabal-Zubiaga

    2016-10-01

    Full Text Available The cannabinoid type 1 (CB1 receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1, where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles. Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis and myocardium from wild-type and CB1-KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahidrocannabinol (Δ9-THC concentrations (100 nM or 200 nM was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1-KO mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12% and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1-KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1-WT and CB1-KO. CB1-KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant

  1. Should Type 1 diabetics fast in Ramadan.

    Science.gov (United States)

    Mohsin, Fauzia; Azad, Kishwar; Zabeen, Bedowra; Tayyeb, Samin; Baki, Abdul; Nahar, Nazmun

    2015-05-01

    Fasting during the holy month of Ramadan is obligatory for all healthy adult and adolescent Muslims from the age of 12 years. This involves abstaining from eating or drinking from early dawn (Suhur/Sehri) till sunset (Iftar).Fasting is not meant to create excessive hardships or impart any adverse effect to the Muslim individual. As such, Islam has exempted certain categories of people from fasting including young children, travelers, the sick, the elderly,and pregnant and lactating women. According to expert opinion, people with type 1 diabetes who fast during Ramadan are at very high risk of metabolic deterioration. However, some recent studies have demonstrated that individuals with type 1 diabetes who are otherwise healthy and stable, can fast during Ramadan provided they comply with the Ramadan focused management plan and are under close professional supervision. This article discusses how to assess, counsel, monitor and manage people with type 1 diabetes who wish to fast during Ramadan.

  2. Distal technologies and type 1 diabetes management.

    Science.gov (United States)

    Duke, Danny C; Barry, Samantha; Wagner, David V; Speight, Jane; Choudhary, Pratik; Harris, Michael A

    2018-02-01

    Type 1 diabetes requires intensive self-management to avoid acute and long-term health complications. In the past two decades, substantial advances in technology have enabled more effective and convenient self-management of type 1 diabetes. Although proximal technologies (eg, insulin pumps, continuous glucose monitors, closed-loop and artificial pancreas systems) have been the subject of frequent systematic and narrative reviews, distal technologies have received scant attention. Distal technologies refer to electronic systems designed to provide a service remotely and include heterogeneous systems such as telehealth, mobile health applications, game-based support, social platforms, and patient portals. In this Review, we summarise the empirical literature to provide current information about the effectiveness of available distal technologies to improve type 1 diabetes management. We also discuss privacy, ethics, and regulatory considerations, issues of global adoption, knowledge gaps in distal technology, and recommendations for future directions. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Neurofibromatosis type 1: clinical and radiological aspects

    International Nuclear Information System (INIS)

    Muniz, Marcos Pontes; Souza, Antonio Soares; Bertelli, Erika Cristina Pavarino; Bertollo, Eny Maria Goloni

    2006-01-01

    Neurofibromatosis type 1 is a genetic disease with an incidence of approximately 1 in 3,000 people, characterized mainly by systemic and progressive involvement, manifesting by physical deformity and compromising of neurological functions. The diagnosis of the neurofibromatosis type 1 must be performed the earliest possible through clinical exams and familiar history. The use of imaging diagnosis as radiography, computed tomography, and magnetic resonance imaging is valuable for diagnosis, treatment, follow-up of patients and control of lesions, preventing complications. In this study we describe the clinical and radiological aspects of the neurofibromatosis type 1, considering clinical features, genetics, bone alterations in chest, vertebral column, upper and lower limbs, and craniofacial abnormalities. (author)

  4. 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.

  5. Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect

    Directory of Open Access Journals (Sweden)

    Ivonne Marie Figueroa-Rivera

    2015-01-01

    Full Text Available Despite well-established antiemetic properties of marijuana, there has been increasing evidence of a paradoxical effect in the gastrointestinal tract and central nervous system, given rise to a new and underrecognized clinical entity called the Cannabinoid Hyperemesis Syndrome. Reported cases in the medical literature have established a series of patients exhibiting a classical triad of symptoms: cyclic vomiting, chronic marijuana use, and compulsive bathing. We present a case of a 29-year-old man whose clinical presentation strongly correlates with cannabinoid hyperemesis syndrome. Despite a diagnosis of exclusion, this syndrome should be considered plausible in the setting of a patient with recurrent intractable vomiting and a strong history of cannabis use as presented in this case.

  6. Are cannabinoids effective in multiple sclerosis?

    Directory of Open Access Journals (Sweden)

    Rodrigo Meza

    2017-03-01

    Full Text Available Resumen En el último tiempo, se han descrito diversos beneficios con el uso de cannabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la esclerosis múltiple, pero la real utilidad clínica es tema de debate. Para responder a esta pregunta utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos. Identificamos 25 revisiones sistemáticas que en conjunto incluyen 35 estudios que responden la pregunta de interés, entre ellos 26 estudios aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de cannabinoides en esclerosis múltiple no reduce la espasticidad ni el dolor, y probablemente se asocia a efectos adversos frecuentes.

  7. Canine adenovirus type 1 in a fennec fox (Vulpes zerda).

    Science.gov (United States)

    Choi, Jeong-Won; Lee, Hyun-Kyoung; Kim, Seong-Hee; Kim, Yeon-Hee; Lee, Kyoung-Ki; Lee, Myoung-Heon; Oem, Jae-Ku

    2014-12-01

    A 10-mo-old female fennec fox (Vulpes zerda) with drooling suddenly died and was examined postmortem. Histologic examination of different tissue samples was performed. Vacuolar degeneration and diffuse fatty change were observed in the liver. Several diagnostic methods were used to screen for canine parvovirus, canine distemper virus, canine influenza virus, canine coronavirus, canine parainfluenza virus, and canine adenovirus (CAdV). Only CAdV type 1 (CAdV-1) was detected in several organs (liver, lung, brain, kidney, spleen, and heart), and other viruses were not found. CAdV-1 was confirmed by virus isolation and nucleotide sequencing.

  8. Quantification of Cannabinoid Content in Cannabis

    Science.gov (United States)

    Tian, Y.; Zhang, F.; Jia, K.; Wen, M.; Yuan, Ch.

    2015-09-01

    Cannabis is an economically important plant that is used in many fields, in addition to being the most commonly consumed illicit drug worldwide. Monitoring the spatial distribution of cannabis cultivation and judging whether it is drug- or fiber-type cannabis is critical for governments and international communities to understand the scale of the illegal drug trade. The aim of this study was to investigate whether the cannabinoids content in cannabis could be spectrally quantified using a spectrometer and to identify the optimal wavebands for quantifying the cannabinoid content. Spectral reflectance data of dried cannabis leaf samples and the cannabis canopy were measured in the laboratory and in the field, respectively. Correlation analysis and the stepwise multivariate regression method were used to select the optimal wavebands for cannabinoid content quantification based on the laboratory-measured spectral data. The results indicated that the delta-9-tetrahydrocannabinol (THC) content in cannabis leaves could be quantified using laboratory-measured spectral reflectance data and that the 695 nm band is the optimal band for THC content quantification. This study provides prerequisite information for designing spectral equipment to enable immediate quantification of THC content in cannabis and to discriminate drug- from fiber-type cannabis based on THC content quantification in the field.

  9. Treatment of Tourette Syndrome with Cannabinoids

    Directory of Open Access Journals (Sweden)

    Kirsten R. Müller-Vahl

    2013-01-01

    Full Text Available Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.

  10. The Feasibility of Detecting Neuropsychologic and Neuroanatomic Effects of Type 1 Diabetes in Young Children

    Science.gov (United States)

    Aye, Tandy; Reiss, Allan L.; Kesler, Shelli; Hoang, Sherry; Drobny, Jessica; Park, Yaena; Schleifer, Kristin; Baumgartner, Heidi; Wilson, Darrell M.; Buckingham, Bruce A.

    2011-01-01

    OBJECTIVE To determine if frequent exposures to hypoglycemia and hyperglycemia during early childhood lead to neurocognitive deficits and changes in brain anatomy. RESEARCH DESIGN AND METHODS In this feasibility, cross-sectional study, young children, aged 3 to 10 years, with type 1 diabetes and age- and sex-matched healthy control (HC) subjects completed neuropsychologic (NP) testing and magnetic resonance imaging (MRI) scans of the brain. RESULTS NP testing and MRI scanning was successfully completed in 98% of the type 1 diabetic and 93% of the HC children. A significant negative relationship between HbA1c and Wechsler Intelligence Scale for Children (WISC) verbal comprehension was observed. WISC index scores were significantly reduced in type 1 diabetic subjects who had experienced seizures. White matter volume did not show the expected increase with age in children with type 1 diabetes compared with HC children (diagnosis by age interaction, P = 0.005). A similar trend was detected for hippocampal volume. Children with type 1 diabetes who had experienced seizures showed significantly reduced gray matter and white matter volumes relative to children with type 1 diabetes who had not experienced seizures. CONCLUSIONS It is feasible to perform MRI and NP testing in young children with type 1 diabetes. Further, early signs of neuroanatomic variation may be present in this population. Larger cross-sectional and longitudinal studies of neurocognitive function and neuroanatomy are needed to define the effect of type 1 diabetes on the developing brain. PMID:21562318

  11. Learning Disabilities in Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-12-01

    Full Text Available The frequency of specific leaning disabilities (SLD in neurofibromatosis type 1 (NF1 was determined in a cohort of 81 patients (43 males, 38 females; mean age 11 years 6 months; age range 8-16 followed at Children's Hospital, Westmead, NSW, Australia.

  12. Outcomes in type 1 diabetic pregnancies

    DEFF Research Database (Denmark)

    Jensen, Dorte Møller; Damm, Peter; Moelsted-Pedersen, Lars

    2004-01-01

    OBJECTIVE: The aim of this study was to compare pregnancy outcomes in type 1 diabetic pregnancies with the background population. RESEARCH DESIGN AND METHODS: This nationwide prospective multicenter study took place in eight Danish centers treating pregnant women with type 1 diabetes during 1993...... mortality rate was 3.1% in type 1 diabetic pregnancies compared with 0.75% in the background population (RR 4.1 [95% CI 2.9-5.6]), and the stillbirth rate was 2.1% compared with 0.45 (4.7 [3.2-7.0]). The congenital malformation rate was 5.0% in the study population and 2.8% (1.7 [1.3-2.2]) in the background......, daily self-monitoring was associated with a reduction in serious adverse outcomes. The caesarean section rate was 55.9 and 12.6%, respectively, and the risk of preterm delivery was 41.7 and 6.0%, respectively. CONCLUSIONS: Type 1 diabetic pregnancies are still complicated by considerably higher rates...

  13. Premarriage counseling in Type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Gagan Priya

    2018-01-01

    Full Text Available Type 1 diabetes is a challenging illness and needs lifelong diabetes self-care. At the same time, there is a significant stigma associated with it, especially with relation to marriage. There are concerns related to premarriage disclosure, marital relationship, ability to procreate, risk during pregnancy in women, and the risk of disease in children. In this document, we discuss the issue of disease-related stigma which may become a significant challenge for a prospective spouse and the impact of type 1 diabetes on marital relationships and procreation. We also highlight the need for premarriage counseling to ensure long-term success in achieving both individual and interpersonal well-being.

  14. Reporting Severe Hypoglycemia in Type 1 Diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2017-01-01

    PURPOSE OF REVIEW: To describe potential factors influencing reporting of severe hypoglycemia in adult patients with type 1 diabetes and to analyze their effect on reported rates of severe hypoglycemia. RECENT FINDINGS: Reported rates of severe hypoglycemia defined as need for third party...... by partners report higher rates of severe hypoglycemia. There is a large variation between studies reporting incidence and prevalence of severe hypoglycemia in patients with type 1 diabetes, mainly explained by definition of severity, methods of reporting, and patient selection. These findings call...... hypoglycemia are 0.02-0.5 events per patient-year and 1-29%, respectively. When subjects with recurrent severe hypoglycemia in the past or suffering from impaired hypoglycemia awareness are excluded from participation in studies, lower rates are reported. Studies applying anonymous reporting or reporting...

  15. Genetic risk factors for type 1 diabetes

    DEFF Research Database (Denmark)

    Pociot, Flemming; Lernmark, Åke

    2016-01-01

    Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one...... is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one...... of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis....

  16. Metformin in adults with type 1 diabetes

    DEFF Research Database (Denmark)

    Petrie, John R; Chaturvedi, Nish; Ford, Ian

    2017-01-01

    AIMS: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight...... but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D....... Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. MATERIALS AND METHODS: After 12 weeks of single-blind placebo-controlled run-in, participants with ≥ 70% adherence...

  17. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist

    NARCIS (Netherlands)

    van Oosten, B. W.; Killestein, J.; Mathus-Vliegen, E. M. H.; Polman, C. H.

    2004-01-01

    Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence

  18. Functional role of cannabinoid receptors in urinary bladder

    Directory of Open Access Journals (Sweden)

    Pradeep Tyagi

    2010-01-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa (marijuana, and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects of cannabinoids on voiding dysfunction in multiple sclerosis patients. In this review, we shall summarize the literature on the expression of cannabinoid receptors in urinary bladder and the peripheral influence of locally and systemically administered cannabinoids in the bladder. The ongoing search for cannabinoid-based therapeutic strategies devoid of psychotropic effects can be complemented with local delivery into bladder by the intravesical route. A greater understanding of the role of the peripheral CB 1 and CB 2 receptor system in lower urinary tract is necessary to allow the development of new treatment for pelvic disorders.

  19. Cannabinoids in the management of spasticity associated with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Anna Maria Malfitano

    2008-08-01

    Full Text Available Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS. In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.Keywords: cannabinoids, multiple sclerosis, spasticity

  20. Diabetes in young: Beyond type 1

    Directory of Open Access Journals (Sweden)

    Anju Virmani

    2012-01-01

    Full Text Available Although majority of diabetes in children is type1 diabetes, childhood type2 diabetes prevalence is rapidly increasing due to changing lifestyle. Most patients can be definitely grouped into either of the two but some present diagnostic difficulty due to overlapping and non specific clinical features and laboratory findings. MODY and several other diseases affecting the pancreas also result in childhood diabetes. Treatment of diabetes in children presents unique challenges and primary prevention is of prime importance.

  1. Birth Weight in Type 1 Diabetic Pregnancy

    Directory of Open Access Journals (Sweden)

    Jacquemyn Yves

    2010-01-01

    Full Text Available Our aim was to investigate whether birth weight in mothers with diabetes mellitus type 1 is higher as compared to nondiabetic controls. Methods. A retrospective study was performed using an existing database covering the region of Flanders, Belgium. Data included the presence of diabetes type 1, hypertension, parity, maternal age, the use artificial reproductive technology, fetal- neonatal death, congenital anomalies, admission to a neonatal intensive care unit, and delivery by Caesarean section or vaginally. Results. In the period studied, 354 women with diabetes type 1 gave birth and were compared with 177.471 controls. Women with type 1 diabetes more often had a maternal age of over 35 years (16.7% versus 12.0%, P=.008, OR 1.46; 95% CI 1.09–1.95. They more frequently suffered hypertension in pregnancy (19.5% versus 4.7%, P<.0001, OR 4.91; 95% CI 3.73–6.44. Perinatal death was significantly higher in the diabetes mellitus group (3.05% versus 0.73%, P<.0001, OR 4.28; 95% CI 2.22–8.01. Caesarean section was performed almost 5 times as frequently in the diabetes versus the control group (OR 4.57; 95% CI 3.70–5.65. Birth weight was significantly higher in diabetic pregnant women from 33 until 38 weeks included, but those reaching 39 weeks and later were not different with control groups. Conclusion. In Belgium, diabetic pregnancy still carries a high risk for fetal and maternal complications; in general birth weight is significantly higher but for those reaching term there is no significant difference in birth weight.

  2. Exploring diabetes type 1-related stigma.

    Science.gov (United States)

    Abdoli, Samereh; Abazari, Parvaneh; Mardanian, Leila

    2013-01-01

    Empowerment of people with diabetes means integrating diabetes with identity. However, others' stigmatization can influence it. Although diabetes is so prevalent among Iranians, there is little knowledge about diabetes-related stigma in Iran. The present study explored diabetes-related stigma in people living with type 1 diabetes in Isfahan. A conventional content analysis was used with in-depth interview with 26 people with and without diabetes from November 2011 to July 2012. A person with type 1 diabetes was stigmatized as a miserable human (always sick and unable, death reminder, and intolerable burden), rejected marriage candidate (busy spouse, high-risk pregnant), and deprived of a normal life [prisoner of (to must), deprived of pleasure]. Although, young adults with diabetes undergo all aspects of the social diabetes-related stigma; in their opinion they were just deprived of a normal life. It seems that in Isfahan, diabetes-related stigma is of great importance. In this way, conducting an appropriate intervention is necessary to improve the empowerment process in people with type 1 diabetes in order to reduce the stigma in the context.

  3. Synthetic cannabinoid: prevalence, mechanisms of addiction development, mental disorders associated with the use of synthetic cannabinoid

    Directory of Open Access Journals (Sweden)

    Antsyborov A.V.

    2017-04-01

    Full Text Available according to the authors among the new psychoactive substances, the number of which is growing every year, despite the measures aimed at the obstacles to their dissemination there discovered the most frequent violations of psychotic conditions associated with use of synthetic cannabinoid in clinical practice. On the black market, they are distributed through online shops, under the guise of herbal mixtures for Smoking. When ingested, this group of drugs at the peak of intoxication raises a number of mental (different according to the depth of impaired consciousness, auditory and visual hallucinations, panic attacks, acute psychotic paranoid disorders, catatonic stupor, polar affective disorders, acute polythematic delusional symptoms and somatic disorders (disorders of heart rhythm and conduction, acute ischemic disorders, hypertension, depression of respiratory activity, violation of thermoregulation, development of acute renal failure, vomiting, expressed cephalgia, clinic of hypokalemia. In the reviewed literature and authors own observations there have been discovered some cases of mental addiction development to synthetic cannabinoids. The analysis of new literature data and own clinical observations helped the authors to compare the psychotropic effects caused by this group of drugs, relative to other known surfactants. The toxic effects of CSC on the body greatly exceeds the use of plant cannabinoids, and it has almost the same effects as the synthetic cathinone’s. The speed of formation of psychological dependence is lower compared to synthetic cathinone. Developing current strategies for diagnosis, treatment, and rehabilitation of patients who use synthetic cannabinoids remains an important task for practical healthcare.

  4. Safety Issues Concerning the Medical Use of Cannabis and Cannabinoids

    Directory of Open Access Journals (Sweden)

    Mark A Ware

    2005-01-01

    Full Text Available Safety issues are a major barrier to the use of cannabis and cannabinoid medications for clinical purposes. Information on the safety of herbal cannabis may be derived from studies of recreational cannabis use, but cannabis exposure and effects may differ widely between medical and recreational cannabis users. Standardized, quality-controlled cannabinoid products are available in Canada, and safety profiles of approved medications are available through the Canadian formulary. In the present article, the evidence behind major safety issues related to cannabis use is summarized, with the aim of promoting informed dialogue between physicians and patients in whom cannabinoid therapy is being considered. Caution is advised in interpreting these data, because clinical experience with cannabinoid use is in the early stages. There is a need for long-term safety monitoring of patients using cannabinoids for a wide variety of conditions, to further guide therapeutic decisions and public policy.

  5. Cannabinoid hyperemesis syndrome with extreme hydrophilia

    Directory of Open Access Journals (Sweden)

    Enuh HA

    2013-08-01

    Full Text Available Hilary A Enuh,1 Julia Chin,1 Jay Nfonoyim21Department of Medicine, 2Critical Care Unit, Richmond University Medical Center, Staten Island, NY, USAAbstract: Marijuana is the most widely used recreational drug in the US. Hyperemetic hydrophilic syndrome is a previously described but infrequently recognized condition of cannabinoid abuse with hyperemesis and obsessive hot showering. We present a 47-year-old male known marijuana addict with intractable abdominal pain who could not wait for physical examination, meal, or medication, because of obsessive compulsive warm baths. He had a history of epilepsy and addiction to marijuana, which he took on the day of admission. He presented to the hospital with a seizure, complicated by nausea, vomiting, and severe abdominal pain. His examination was unremarkable, except for mild epigastric tenderness. His laboratory and radiological tests were within normal limits, except for a positive urine drug screen for marijuana and opiates. He took himself immediately to the bathroom and remained under a hot shower with the exception of two 15-minute breaks for the rest of the day. He stated that it made him feel better than medication. Receiving medication and even eating was a problem because of this compulsive showering. Abstinence from marijuana during the hospital stay made the patient's nausea and vomiting resolve significantly. Cannabinoid hyperemesis is a differential diagnosis among patients with intractable nausea, vomiting, and obsessive hot bathing. The syndrome is an unmistakable indication of marijuana addiction. A thorough history and observation is very valuable. Recognition of this entity will reduce unnecessary testing and utilization of health care resources.Keywords: cannabinoid, compulsive bathing, cyclic vomiting, hyperemesis, hydrophilia, marijuana

  6. Teleconsultation in type 1 diabetes mellitus (TELEDIABE).

    Science.gov (United States)

    Bertuzzi, Federico; Stefani, Ilario; Rivolta, Benedetta; Pintaudi, Basilio; Meneghini, Elena; Luzi, Livio; Mazzone, Antonino

    2018-02-01

    The growing incidence of diabetes and the need to contain healthcare costs empower the necessity to identify new models of care. Telemedicine offers an acknowledged instrument to provide clinical health care at a distance, increasing patient compliance and the achievement of therapeutical goals. The objective was to test the feasibility and the efficacy in the improvement of the glycemic control of the teleconsultation for patients with type 1 diabetes mellitus. A randomized open-label, parallel arms, controlled trial was conducted in two diabetes centers in Italy. Participants affected by type 1 diabetes mellitus have been randomly (1:1) assigned to receive their visits as standard or a web-based care. Patients in the teleconsultation group can arrange their appointments on a Web site and can also have access to web educational courses or to nutritional and psychological counseling. The primary outcome was the assessment of glycemic control by HbA1c measurement after a 12-month follow-up. Overall 74 participants were followed for 1 year. HbA1c changes were not statistically different within (p = 0.56 for standard care group; p = 0.45 for telemedicine group) and between (p = 0.60) groups when considering differences from baseline to the end of the study. Patients randomized to teleconsultation reported reduced severe hypoglycemic episodes (p = 0.03). In addition, they were largely satisfied with the activities, perceived a good improvement in the self-management of the diabetes, and reported to have a time saving and a cost reduction. In conclusion, TELEDIABE proposes a new system for the management of patients with type 1 diabetes mellitus.

  7. Setting research priorities for Type 1 diabetes.

    Science.gov (United States)

    Gadsby, R; Snow, R; Daly, A C; Crowe, S; Matyka, K; Hall, B; Petrie, J

    2012-10-01

    Research priorities are often set by academic researchers or the pharmaceutical industry. The interests of patients, carers and clinicians may therefore be overlooked and research questions that matter may be neglected. The aims of this study were to collect uncertainties about the treatment of Type 1 diabetes from patients, carers and health professionals, and to collate and prioritize these uncertainties to develop a top 10 list of research priorities, using a structured priority-setting partnership of patients, carers, health professionals and diabetes organizations, as described by the James Lind Alliance. A partnership of interested organizations was set up, and from this a steering committee of 10 individuals was formed. An online and paper survey was used to identify uncertainties. These were collated, and the steering group carried out an interim priority-setting exercise with partner organizations. This group of uncertainties was then voted on to give a smaller list that went forward to the final priority-setting workshop. At this meeting, a final list of the top 10 research priorities was agreed. An initial 1141 uncertainties were described. These were reduced to 88 indicative questions, 47 of which went out for voting. Twenty-four were then taken forward to a final priority-setting workshop. This workshop resulted in a list of top 10 research priorities in Type 1 diabetes. We have shown that it is possible using the James Lind Alliance process to develop an agreed top 10 list of research priorities for Type 1 diabetes from health professionals, patients and carers. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  8. Insulinbehandling af voksne med type 1-diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2015-01-01

    Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin...... treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes...

  9. Insulinbehandling af voksne med type 1-diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2015-01-01

    Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin...... treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes...... of the patient....

  10. Therapeutic perspectives in type-1 diabetes

    CERN Document Server

    SINGH, PRACHI; TUPALLY, KARNAKER R; PODDAR, KINGSHUK; Tan, Aaron; VENKATESAN, VENKY; PAREKH, HARENDRA S; PASTORIN, GIORGIA

    2016-01-01

    This book provides critical insights into and appraisals of recent breakthroughs in type 1 diabetes modulation, with a particular emphasis on the potential impact of current prevention and treatment strategies. It also discusses recent successes and failures in clinical trials. Presenting an comprehensive overview of the disease, it is especially useful for newcomers in the field. It also includes illustrations, which make it easy for the reader to grasp the basic concepts involved. Furthermore, the tables include concise and easy-to-understand information on current clinical trials.

  11. Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

    Science.gov (United States)

    Ovadia, H; Wohlman, A; Mechoulam, R; Weidenfeld, J

    1995-02-01

    In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

  12. Teenage pregnancy in type 1 diabetes mellitus.

    Science.gov (United States)

    Carmody, David; Doyle, Aoife; Firth, Richard G R; Byrne, Maria M; Daly, Sean; Mc Auliffe, Fionnuala; Foley, Micheal; Coulter-Smith, Samuel; Kinsley, Brendan T

    2010-03-01

    Younger maternal age at delivery has been linked to adverse reproductive outcomes. Pregnancy complicated by type 1 diabetes mellitus (T1DM) is also associated with adverse pregnancy outcomes. Optimising diabetic glycaemic control prior to pregnancy is known to reduce the rate of congenital abnormalities and improve pregnancy outcomes. Teenage pregnancies are not usually planned and little data exist on teenage pregnancy complicated by T1DM. We sought to identify the glycemic control achieved in teenage pregnancy with T1DM and to clarify if there is an associated increase in adverse pregnancy outcomes compared to those seen in older women with T1DM. We compared outcomes in 18 teenagers (TG) with 582 older women with T1DM (CON) from 1995-2007. TG booked to the combined diabetes-obstetrical service at a median gestational age of 11 weeks (range 6-22) compared to 7 weeks in CON (range 4-40, p teenage women with T1DM book later to specialised care and have worse glycaemic control in pregnancy compared to older women with T1DM. This group also appear to be more insulin resistant than older women in early pregnancy. Our data would suggest that teenagers with type 1 diabetes mellitus may constitute a high-risk group for adverse pregnancy outcomes.

  13. Cannabinoid CB1 receptor agonists do not decrease, but may increase, acoustic trauma-induced tinnitus in rats

    Directory of Open Access Journals (Sweden)

    Yiwen eZheng

    2015-03-01

    Full Text Available Tinnitus has been suggested to arise from neuronal hyperactivity in auditory areas of the brain and anti-epileptic drugs are sometimes used to provide relief from tinnitus. Recently, the anti-epileptic properties of the cannabinoid drugs have gained increasing interest; however, the use of cannabinoids as a form of treatment for tinnitus is controversial. In the present study, we tested whether a combination of delta-9-tetrahydrocannabinol (delta-9-THC and cannabidiol (CBD, delivered in a 1:1 ratio, could affect tinnitus perception in a rat model of acoustic trauma-induced tinnitus. Following sham treatment or acoustic trauma, the animals were divided into the following groups: 1 sham (i.e. no acoustic trauma with vehicle treatment; 2 sham with drug treatment (i.e. delta-9-THC + CBD; 3 acoustic trauma-exposed exhibiting tinnitus, with drug treatment; and 4 acoustic trauma-exposed exhibiting no tinnitus, with drug treatment. The animals received either the vehicle or the cannabinoid drugs every day, 30 min before the tinnitus behavioural testing. Acoustic trauma caused a significant increase in the auditory brainstem response (ABR thresholds in the exposed animals, indicating hearing loss; however, there was a partial recovery over 6 months. Acoustic trauma did not always result in tinnitus; however among those that did exhibit tinnitus, some of them had tinnitus at multiple frequencies while others had it only at a single frequency. The cannabinoids significantly increased the number of tinnitus animals in the exposed-tinnitus group, but not in the sham group. The results suggest that cannabinoids may promote the development of tinnitus, especially when there is pre-existing hearing damage.

  14. Are cannabinoids effective for HIV wasting syndrome?

    Directory of Open Access Journals (Sweden)

    Alejandra Núñez

    2017-12-01

    Full Text Available Resumen INTRODUCCIÓN El síndrome de emaciación (wasting en VIH/SIDA aún permanece como un problema común, constituyéndose como un factor de mortalidad en esta población. Se ha postulado el uso de cannabinoides como tratamiento de la baja de peso secundaria a la infección por VIH, lo que aún es controvertido. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos ocho revisiones sistemáticas que en conjunto incluyen 10 estudios primarios, de los cuales, seis son ensayos aleatorizados. Concluimos que no está claro si los cannabinoides aumentan el apetito o incrementan el peso en el síndrome de wasting en pacientes con VIH, y probablemente los efectos adversos son frecuentes.

  15. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor.

    Science.gov (United States)

    Rinaldi-Carmona, M; Barth, F; Millan, J; Derocq, J M; Casellas, P; Congy, C; Oustric, D; Sarran, M; Bouaboula, M; Calandra, B; Portier, M; Shire, D; Brelière, J C; Le Fur, G L

    1998-02-01

    Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.

  16. Immune intervention in type 1 diabetes.

    Science.gov (United States)

    Michels, Aaron W; Eisenbarth, George S

    2011-06-01

    Type 1 diabetes (T1D) is a chronic autoimmune disease that results in the specific immune destruction of insulin producing beta cells. Currently there is no cure for T1D and treatment for the disease consists of lifelong administration of insulin. Immunotherapies aimed at preventing beta cell destruction in T1D patients with residual c-peptide or in individuals developing T1D are being evaluated. Networks of researchers such as TrialNet and the Immune Tolerance Network in the U.S. and similar networks in Europe have been established to evaluate such immunotherapies. This review focuses on immune intervention for the prevention and amelioration of human T1D with a focus on potential immune suppressive, antigen specific and environmental therapies. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Type 1 diabetes care updates: Tanzania

    Directory of Open Access Journals (Sweden)

    Kandi Catherine Muze

    2015-01-01

    Full Text Available Tanzania is located in east Africa with a population of 45 million. The country′s population is growing at 2.5% annually. The International Diabetes Federation Child Sponsorship Program was launched in Tanzania in 2005. The number of type 1 diabetes mellitus children enrolled in the changing diabetes in children program in Tanzania has augmented from almost below 50 in 2005 to over 1200 in 2014. The country had an overall trend of HbA1c value of 14% in 2005 while the same has reduced over the years to 10% in 2012-13. The program has been able to reduce the proportion of patients with HbA1c values of 11-14%; from 71.9% in 2008 to 49.8% in 2012-13. The challenges, which CDiC faces are misdiagnosis, low public awareness, and stigma especially in the reproductive age/adolescent groups.

  18. Microcephalic osteodysplastic primordial dwarfism type 1.

    Science.gov (United States)

    Ferrell, Steven; Johnson, Aaron; Pearson, Waylon

    2016-06-16

    Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is an uncommon cause of microcephaly and intrauterine growth retardation in a newborn. Early identifying features include but are not limited to sloping forehead, micrognathia, sparse hair, including of eyebrows and short limbs. Immediate radiological findings may include partial or complete agenesis of the corpus callosum, interhemispheric cyst and shallow acetabula leading to dislocation. Genetic testing displaying a mutation in RNU4ATAC gene is necessary for definitive diagnosis. Early identification is important as MOPD1 is an autosomal recessive condition and could present in subsequent pregnancies. The purpose of this case is to both identify and describe some common physical findings related to MOPD1. We present a case of MOPD1 in a girl born to non-consanguineous parents that was distinct for subglottic stenosis and laryngeal cleft. 2016 BMJ Publishing Group Ltd.

  19. Research progress of spinocerebellar ataxia type 1

    Directory of Open Access Journals (Sweden)

    Lin-wei ZHANG

    2014-05-01

    Full Text Available Spinocerebellar ataxia type 1 (SCA1 is a kind of autosomal dominant genetic neurodegenerative disorder. To date, the pathogenesis of SCA1 remains unclear. Studies in numerous SCA1 experimental models, including transgenic mice, transgenic drosophila and induced pluripotent stem cells, have shown that phosphorylation of S776 in mutant ataxin-1, molecular chaperones, ubiquitin-proteasome system and down-regulation of several components of RAS-MAPK-MSK1 pathway may involve in the pathogenesis of SCA1. In this review, the clinical and pathological features of SCA1, and the latest advances of pathogenesis, model systems and therapeutic exploration will be briefly summarized. doi: 10.3969/j.issn.1672-6731.2014.05.017

  20. Type 1 diabetes and multiple sclerosis

    DEFF Research Database (Denmark)

    Nielsen, N.M.; Westergaard, T.; Frisch, M.

    2006-01-01

    BACKGROUND: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported...... Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil....... OBJECTIVE: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish...

  1. Anophthalmia: an uncommon manifestation of neurofibromatosis type 1.

    Science.gov (United States)

    Chen, Sheng; Pu, Jia-Li; Zhang, Jian-Min; Hong, Yuan

    2011-11-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominant, multisystem disorder, affecting approximately 1 of 3500 people. Ocular disorders, such as Lisch nodules, optic gliomas, and anterior segment defects, are typical with clinical presentation. Anophthalmia, as a rare eye malformation, has never been reported in patients with NF-1. We report a 27-year-old patient in whom clinical manifestations of café au lait spots, neurofibromas, osseous orbital dysplasia, and anophthalmia were observed. The diagnosis of NF-1 was made, according to clinical course and brain computed tomography and magnetic resonance imaging. Because the patient refused aggressive management approaches, she was managed conservatively and is well on follow-up. We suggest that patients presenting with anophthalmia need serious evaluation and that NF-1 needs to be considered in the differential diagnosis.

  2. Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1.

    Science.gov (United States)

    Gutmann, David H

    2014-07-29

    With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. © 2014 American Academy of Neurology.

  3. Teenage pregnancy in type 1 diabetes mellitus.

    LENUS (Irish Health Repository)

    Carmody, David

    2010-03-01

    Younger maternal age at delivery has been linked to adverse reproductive outcomes. Pregnancy complicated by type 1 diabetes mellitus (T1DM) is also associated with adverse pregnancy outcomes. Optimising diabetic glycaemic control prior to pregnancy is known to reduce the rate of congenital abnormalities and improve pregnancy outcomes. Teenage pregnancies are not usually planned and little data exist on teenage pregnancy complicated by T1DM. We sought to identify the glycemic control achieved in teenage pregnancy with T1DM and to clarify if there is an associated increase in adverse pregnancy outcomes compared to those seen in older women with T1DM. We compared outcomes in 18 teenagers (TG) with 582 older women with T1DM (CON) from 1995-2007. TG booked to the combined diabetes-obstetrical service at a median gestational age of 11 weeks (range 6-22) compared to 7 weeks in CON (range 4-40, p < 0.02). Glycaemic was worse in TG compared to CON at 13, 26 and 35 weeks gestation, despite higher insulin doses. First trimester miscarriage rate did not differ between groups. Major congenital anomaly rate was 6.2% (1\\/16) compared to 3.2% in CON. This preliminary study has demonstrated that pregnant teenage women with T1DM book later to specialised care and have worse glycaemic control in pregnancy compared to older women with T1DM. This group also appear to be more insulin resistant than older women in early pregnancy. Our data would suggest that teenagers with type 1 diabetes mellitus may constitute a high-risk group for adverse pregnancy outcomes.

  4. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity.

    Directory of Open Access Journals (Sweden)

    Lisa K Brents

    Full Text Available K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R.JWH-018, five potential monohydroxylated metabolites (M1-M5, and one carboxy metabolite (M6 were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i values that were lower than or equivalent to Δ(9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9

  5. Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use

    Directory of Open Access Journals (Sweden)

    Carissa M. Coulston

    2011-01-01

    Full Text Available Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.

  6. Type 1 diabetes: The Bangladesh perspective

    Directory of Open Access Journals (Sweden)

    Kishwar Azad

    2015-01-01

    Full Text Available Diabetes mellitus (DM is a common endocrine disorder among children and adolescents in Bangladesh. The latest International Diabetes Federation atlas estimated the incidence of type 1 DM (T1DM in Bangladesh as 4.2 new cases of T1DM/100,000 children (0-14 years/year, in 2013. Diabetes, being a lifelong disease, places a huge burden on the economy of the most densely populated, and resource-poor country of the world. The Diabetic Association of Bangladesh (BADAS, the largest of its kind in the world, provides comprehensive care to the biggest number of diabetics at any one centre and is engaged in advocacy. Although sounding grandiose, it′s aims that ′no diabetic shall die untreated, unfed or unemployed, even if poor′ is pursued with a passion. Recently BADAS has been supported in its endeavor for children and adolescents by two programmes; viz the Changing Diabetes in Children program (a joint initiative of BADAS, the World Diabetes Foundation and Novo Nordisk, and the Life for a Child Programme (LFAC supported by the IDF. Numerous studies from the prosperous countries have demonstrated the incidence of T1DM is increasing. Data from the CDiC clinic at BIRDEM shows a rising trend in patients presenting with classical T1DM. In addition, the pattern of DM is changing.

  7. Type 1 diabetes guidelines: Are they enough?

    Directory of Open Access Journals (Sweden)

    Abdul Abdul Zargar

    2015-01-01

    Full Text Available The discovery of insulin by Banting and Best in 1922 changed the landscape of type 1 diabetes mellitus (T1DM. Guidelines on T1DM should be evidence based and should emphasize comprehensive risk management. Guidelines would improve awareness amongst governments, state health care providers and the general public about the serious long-term implications of poorly managed diabetes and of the essential resources needed for optimal care. T1DM requires lifelong daily medication, regular control as well as access to facilities to manage acute and chronic complications. American Diabetes Association 2014 guidelines recommends annual nephropathy screening for albumin levels; random spot urine sample for albumin-to-creatinine ratio at start of puberty or age ≥10 years, whichever is earlier, once the child has had diabetes for 5 years. Hypertension should be screened for in T1DM patients by measuring blood pressure at each routine visit. Dyslipidemia in T1DM patients is important and patients should be screened if there is a family history of hypercholesterolemia or a cardiovascular event before the age of 55 years exists or if family history is unknown. Retinopathy is another important complication of diabetes and patients should be subjected to an initial dilated and comprehensive eye examination. Basic diabetes training should be provided for school staff, and they should be assigned with responsibilities for the care of diabetic children. Self-management should be allowed at all school settings for students.

  8. The Genetic Architecture of Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Samuel T Jerram

    2017-08-01

    Full Text Available Type 1 diabetes (T1D is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D.

  9. Celiac disease in type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Camarca Maria

    2012-03-01

    Full Text Available Abstract Celiac Disease (CD occurs in patients with Type 1 Diabetes (T1D ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD. In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.

  10. [NARCOLEPSY WITH CATAPLEXY: TYPE 1 NARCOLEPSY].

    Science.gov (United States)

    Dauvilliers, Yves; Lopez, Régis

    2016-06-01

    Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy. The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix.

  11. Stem Cell Treatment for Type 1 Diabetes

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    Ming eLi

    2014-03-01

    Full Text Available Type 1 diabetes mellitus (T1DM is a common chronic disease in children, characterized by a loss of  cells, which results in defects in insulin secretion and hyperglycemia. Chronic hyperglycemia causes diabetic complications, including diabetic nephropathy, neuropathy and retinopathy. Curative therapies mainly include diet and insulin administration. Although hyperglycemia can be improved by insulin administration, exogenous insulin injection cannot successfully mimic the insulin secretion from normal  cells, which keeps blood glucose levels within the normal range all the time. Islet and pancreas transplantation achieves better glucose control, but there is a lack of organ donors. Cell based therapies have also been attempted to treat T1DM. Stem cells such as embryonic stem cells, induced pluripotent stem cells and tissue stem cells (TSCs such as bone marrow-, adipose tissue- and cord blood-derived stem cells, have been shown to generate insulin-producing cells. In this review, we summarize the most-recently available information about T1DM and the use of TSCs to treat T1DM.

  12. Pregnancy in women with type 1 diabetes

    DEFF Research Database (Denmark)

    Colstrup, Miriam; Mathiesen, Elisabeth; Damm, Peter

    2013-01-01

    Abstract Objective: In 1989 the St. Vincent declaration set a five-year target for approximating outcomes of pregnancies in women with diabetes to those of the background population. We investigated and quantified the risk of adverse pregnancy outcomes in pregnant women with type 1 diabetes (T1DM......) to evaluate if the goals of the 1989 St. Vincent Declaration have been obtained concerning foetal and neonatal complications. Methods: Twelve population-based studies published within the last 10 years with in total 14 099 women with T1DM and 4 035 373 women from the background population were identified....... The prevalence of four foetal and neonatal complications was compared. Results: In women with T1DM versus the background population, congenital malformations occurred in 5.0% (2.2-9.0) (weighted mean and range) versus 2.1% (1.5-2.9), relative risk (RR) = 2.4, perinatal mortality in 2.7% (2.0-6.6) versus 0.72% (0...

  13. Altered Immune Regulation in Type 1 Diabetes

    Science.gov (United States)

    Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

    2013-01-01

    Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

  14. Altered Immune Regulation in Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    András Zóka

    2013-01-01

    Full Text Available Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

  15. Health Risk Behaviors With Synthetic Cannabinoids Versus Marijuana.

    Science.gov (United States)

    Clayton, Heather B; Lowry, Richard; Ashley, Carmen; Wolkin, Amy; Grant, Althea M

    2017-04-01

    Data are limited on the behavioral risk correlates of synthetic cannabinoid use. The purpose of this study was to compare the behavioral risk correlates of synthetic cannabinoid use with those among marijuana users. Data from the 2015 Youth Risk Behavior Survey, a cross-sectional survey conducted in a nationally representative sample of students in grades 9 through 12 ( N = 15 624), were used to examine the association between self-reported type of marijuana use (ie, never use of marijuana and synthetic cannabinoids, ever use of marijuana only, and ever use of synthetic cannabinoids) and self-report of 36 risk behaviors across 4 domains: substance use, injury/violence, mental health, and sexual health. Multivariable models were used to calculate adjusted prevalence ratios. Students who ever used synthetic cannabinoids had a significantly greater likelihood of engaging in each of the behaviors in the substance use and sexual risk domains compared with students who ever used marijuana only. Students who ever used synthetic cannabinoids were more likely than students who ever used marijuana only to have used marijuana before age 13 years, to have used marijuana ≥1 times during the past 30 days, and to have used marijuana ≥20 times during the past 30 days. Several injury/violence behaviors were more prevalent among students who ever used synthetic cannabinoids compared with students who ever used marijuana only. Health professionals and school-based substance use prevention programs should include strategies focused on the prevention of both synthetic cannabinoids and marijuana. Copyright © 2017 by the American Academy of Pediatrics.

  16. Efectos cardiovasculares debido al consumo de cannabinoides

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    Oscar J. León

    2018-05-01

    Full Text Available Resumen: Objetivo: dar a conocer los efectos cardiovasculares secundarios al consumo de marihuana según lo reportado en la literatura médica. Métodos: se realizó una búsqueda con los términos MESH “Cannabis”, “Marijuana smoking” y “adverse effects” en la base de datos PubMed hasta el año 2016. Se obtuvieron 265 referencias. Se excluyeron cartas de editores, protocolos de investigación en proceso, población pediátrica (menores de 18 años, embarazadas, referencias en idiomas diferentes a inglés y español y se escogieron solo referencias relacionadas con efectos cardiovasculares. Resultados: se han establecido dos tipos de receptores de cannabinoides, los CB1 y los CB2, con localizaciones a nivel del sistema nervioso central, endotelial, renal y músculo liso. En la actualidad el consumo de marihuana ha venido en aumento y los médicos poco conocen de sus efectos y los diferentes nombres comerciales para esta sustancia. Existen efectos protectores a nivel vascular con detención de la progresión de la placa aterosclerótica y a la vez múltiples efectos no deseados como taquicardia, hipotensión y bradicardia. Múltiples reportes de caso documentan la relación de la marihuana con el infarto agudo de miocardio con o sin lesión de las arterias coronarias, así como con hemorragia subaracnoidea, pero no existen mecanismos claramente descritos que expliquen una relación directa con estos desenlaces. Conclusiones: se conoce la fisiopatología y los receptores donde actúan los cannabinoides generando efectos tanto protectores como dañinos. Existe fuerte correlación con enfermedad cardiovascular, principalmente síndrome coronario agudo, pero el mecanismo fisiopatológico aún no es claro. Abstract: Objective: To determine the cardiovascular side-effects of smoking marihuana according to that reported in the medical literature. Methods: A search was performed using the MeSH terms, “Cannabis”, “Marijuana smoking” and

  17. 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.

  18. The geoepidemiology of type 1 diabetes.

    Science.gov (United States)

    Borchers, Andrea T; Uibo, Raivo; Gershwin, M E

    2010-03-01

    Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by absolute insulin deficiency resulting from the progressive immune-mediated destruction of pancreatic islet beta cells. It is thought to be triggered by as yet unidentified environmental factors in genetically susceptible individuals, the major genetic contribution coming from loci within the HLA complex, in particular HLA class II. The worldwide incidence of T1D varies by at least 100-fold, being highest in Finland and Sardinia (Italy) and lowest in Venezuela and China. The incidence has been increasing worldwide at an annual rate of approximately 3%. While genetic factors are thought to explain some of the geographic variability in T1D occurrence, they cannot account for its rapidly increasing frequency. Instead, the declining proportion of newly diagnosed children with high-risk genotypes suggests that environmental pressures are now able to trigger T1D in genotypes that previously would not have developed the disease during childhood. Although comparisons between countries and regions with low and high-incidence rates have suggested that higher socioeconomic status and degree of urbanization are among the environmental factors that play a role in the rising incidence of T1D, the findings are too inconsistent to allow firm conclusions. Morbidity and mortality as well as causes of death also show considerable geographic variation. While glycemic control has been identified as a major predictor of the micro- and macrovascular complications of T1D and shows considerable geographical variability, it does not appear to be the only factor involved in the regional differences in complication rates. The role of genetics in susceptibility to nephropathy, retinopathy and other diabetic complications largely remains to be explored. 2009 Elsevier B.V. All rights reserved.

  19. [Neuropsychological performance in neurofibromatosis type 1].

    Science.gov (United States)

    Hernández Del Castillo, Lilia; Martínez Bermejo, Antonio; Portellano Pérez, José Antonio; Tirado Requero, Pilar; Garriz Luis, Alexandra; Velázquez Fragua, Ramón

    2017-08-01

    Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder. In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children. A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups. The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding. The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Type 1 diabetes in India: Overall insights.

    Science.gov (United States)

    Das, Ashok Kumar

    2015-04-01

    Type 1 diabetes mellitus (T1DM) is also on increase like type 2 diabetes, even though not in the same proportion, but still with a trend of 3-5% increase/year. India has three new cases of T1DM/100,000 children of 0-14 years. Three sets of prevalence data shows 17.93 cases/100,000 children in Karnataka, 3.2 cases/100,000 children in Chennai, and 10.2 cases/100,000 children in Karnal (Haryana). T1DM may be autoimmune or idiopathic in nature and is present in 9% cases of insulin deficiency. T1DM is primarily caused by genetic factors, environmental factors, and disorder of the immune regulatory mechanism. A combination of all these three factors causes autoimmune disease, which may ultimately result in the destruction of pancreatic beta cells leading to hyperglycemia, ketoacidosis and potentially death, if not treated with insulin. Prediabetes is the phase before the onset of T1DM, which provides a window of opportunity for early intervention. All available interventions including steroids, immunosuppressants, and cyclosporins can be possibly applied during the prediabetes phase. The treatment goals for T1DM are simple and include maintaining near normal blood glucose levels and avoiding long-term complications, which is a constant juggle between insulin and maintaining an appropriate lifestyle. The Indian Council of Medical Research funded Registry of People with diabetes in India with young age at onset (YDR) was started in the year 2006 with 10 collaborating centres across India. This registry is focusing on to provide an overview of diabetes in the young.

  1. Type 1 diabetes in India: Overall insights

    Directory of Open Access Journals (Sweden)

    Ashok Kumar Das

    2015-01-01

    Full Text Available Type 1 diabetes mellitus (T1DM is also on increase like type 2 diabetes, even though not in the same proportion, but still with a trend of 3-5% increase/year. India has three new cases of T1DM/100,000 children of 0-14 years. Three sets of prevalence data shows 17.93 cases/100,000 children in Karnataka, 3.2 cases/100,000 children in Chennai, and 10.2 cases/100,000 children in Karnal (Haryana.T1DM may be autoimmune or idiopathic in nature and is present in 9% cases of insulin deficiency. T1DM is primarily caused by genetic factors, environmental factors, and disorder of the immune regulatory mechanism. A combination of all these three factors causes autoimmune disease, which may ultimately result in the destruction of pancreatic beta cells leading to hyperglycemia, ketoacidosis and potentially death, if not treated with insulin. Prediabetes is the phase before the onset of T1DM, which provides a window of opportunity for early intervention. All available interventions including steroids, immunosuppressants, and cyclosporins can be possibly applied during the prediabetes phase. The treatment goals for T1DM are simple and include maintaining near normal blood glucose levels and avoiding long-term complications, which is a constant juggle between insulin and maintaining an appropriate lifestyle. The Indian Council of Medical Research funded Registry of People with diabetes in India with young age at onset (YDR was started in the year 2006 with 10 collaborating centres across India. This registry is focusing on to provide an overview of diabetes in the young.

  2. GABAergic and cortical and subcortical glutamatergic axon terminals contain CB1 cannabinoid receptors in the ventromedial nucleus of the hypothalamus.

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    Leire Reguero

    Full Text Available BACKGROUND: Type-1 cannabinoid receptors (CB(1R are enriched in the hypothalamus, particularly in the ventromedial hypothalamic nucleus (VMH that participates in homeostatic and behavioral functions including food intake. Although CB(1R activation modulates excitatory and inhibitory synaptic transmission in the brain, CB(1R contribution to the molecular architecture of the excitatory and inhibitory synaptic terminals in the VMH is not known. Therefore, the aim of this study was to investigate the precise subcellular distribution of CB(1R in the VMH to better understand the modulation exerted by the endocannabinoid system on the complex brain circuitries converging into this nucleus. METHODOLOGY/PRINCIPAL FINDINGS: Light and electron microscopy techniques were used to analyze CB(1R distribution in the VMH of CB(1R-WT, CB(1R-KO and conditional mutant mice bearing a selective deletion of CB(1R in cortical glutamatergic (Glu-CB(1R-KO or GABAergic neurons (GABA-CB(1R-KO. At light microscopy, CB(1R immunolabeling was observed in the VMH of CB(1R-WT and Glu-CB(1R-KO animals, being remarkably reduced in GABA-CB(1R-KO mice. In the electron microscope, CB(1R appeared in membranes of both glutamatergic and GABAergic terminals/preterminals. There was no significant difference in the percentage of CB(1R immunopositive profiles and CB(1R density in terminals making asymmetric or symmetric synapses in CB(1R-WT mice. Furthermore, the proportion of CB(1R immunopositive terminals/preterminals in CB(1R-WT and Glu-CB(1R-KO mice was reduced in GABA-CB(1R-KO mutants. CB(1R density was similar in all animal conditions. Finally, the percentage of CB(1R labeled boutons making asymmetric synapses slightly decreased in Glu-CB(1R-KO mutants relative to CB(1R-WT mice, indicating that CB(1R was distributed in cortical and subcortical excitatory synaptic terminals. CONCLUSIONS/SIGNIFICANCE: Our anatomical results support the idea that the VMH is a relevant hub candidate in

  3. Natural and experimental infection of sheep with European bat lyssavirus type-1 of Danish bat origin

    DEFF Research Database (Denmark)

    Tjørnehøj, Kirsten; Fooks, A.R.; Agerholm, J.S.

    2006-01-01

    In 1998 and 2002, European bat lyssavirus type-1 (EBLV-1) was demonstrated in brain tissue of five Danish sheep suffering from micrological disorders. Four of the five sheep also had encephalic listeriosis. The animals originated from four flocks on pastures within a limited area of western Jutla...

  4. Equid herpesvirus type 1 activates platelets.

    Directory of Open Access Journals (Sweden)

    Tracy Stokol

    Full Text Available Equid herpesvirus type 1 (EHV-1 causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression and platelet microvesiculation (increased small events double positive for CD41 and Annexin V. Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM. A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis

  5. Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine.

    Science.gov (United States)

    Fattore, Liana; Piva, Alessandro; Zanda, Mary Tresa; Fumagalli, Guido; Chiamulera, Cristiano

    2018-02-01

    Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.

  6. Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory.

    Science.gov (United States)

    Abush, Hila; Akirav, Irit

    2013-07-01

    Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.

  7. Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training

    NARCIS (Netherlands)

    Morena, M.; Roozendaal, B.; Trezza, V.; Ratano, P.; Peloso, A.; Hauer, D.; Atsak, P.; Trabace, L.; Cuomo, V.; McGaugh, J.L.; Schelling, G.; Campolongo, P.

    2014-01-01

    Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The

  8. Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids

    NARCIS (Netherlands)

    Lozovaya, N.; Yatsenko, N.; Beketov, A.; Tsintsadze, T.; Burnashev, N.

    2005-01-01

    At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR)

  9. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

    Directory of Open Access Journals (Sweden)

    Marina Rubio

    Full Text Available Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716 during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

  10. Cell-specific STORM superresolution imaging reveals nanoscale organization of cannabinoid signaling

    Science.gov (United States)

    Szabó, Szilárd I.; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G.; Henstridge, Christopher M.; Balla, Gyula Y.; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

    2014-01-01

    A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell-type-, and subcellular compartment-specific manner. We therefore developed a novel approach combining cell-specific physiological and anatomical characterization with superresolution imaging, and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically-projecting GABAergic interneurons possess increased CB1 receptor number, active-zone complexity, and receptor/effector ratio compared to dendritically-projecting interneurons, in agreement with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked dramatic CB1-downregulation in a dose-dependent manner. Full receptor recovery required several weeks after cessation of Δ9-tetrahydrocannabinol treatment. These findings demonstrate that cell-type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits, and identify novel molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction. PMID:25485758

  11. Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling.

    Science.gov (United States)

    Dudok, Barna; Barna, László; Ledri, Marco; Szabó, Szilárd I; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G; Henstridge, Christopher M; Balla, Gyula Y; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

    2015-01-01

    A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell type- and subcellular compartment-specific manner. We developed a new approach to this problem by combining cell-specific physiological and anatomical characterization with super-resolution imaging and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically projecting GABAergic interneurons possessed increased CB1 receptor number, active-zone complexity and receptor/effector ratio compared with dendritically projecting interneurons, consistent with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ(9)-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked marked CB1 downregulation in a dose-dependent manner. Full receptor recovery required several weeks after the cessation of Δ(9)-tetrahydrocannabinol treatment. These findings indicate that cell type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits and identify previously unknown molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction.

  12. Pregnancy outcome in type 1 diabetic women with microalbuminuria

    DEFF Research Database (Denmark)

    Ekbom, P; Damm, P; Feldt-Rasmussen, B

    2001-01-01

    To determine the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes.......To determine the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes....

  13. 77 FR 12508 - Schedules of Controlled Substances: Placement of Five Synthetic Cannabinoids Into Schedule I

    Science.gov (United States)

    2012-03-01

    ... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures... that is more common in current usage, ``marijuana.'' The emergence of these five synthetic cannabinoids... cannabinoids with a potential for abuse similar to the Schedule I substances marijuana and THC. These synthetic...

  14. 75 FR 71635 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2010-11-24

    ... these THC-like synthetic cannabinoids are marketed as ``legal'' alternatives to marijuana and are being...] Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I... intent to temporarily place five synthetic cannabinoids into the Controlled Substances Act (CSA) pursuant...

  15. Cannabinoid antagonist in nanostructured lipid carriers (NLCs): design, characterization and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Elisabetta; Ravani, Laura [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Drechsler, Markus [BIMF/Soft Matter Electron Microscopy, University of Bayreuth (Germany); Mariani, Paolo [Department of Life and Environmental Sciences and CNISM, Università Politecnica delle Marche, I-60100 Ancona (Italy); Contado, Catia [Department of Chemical and Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Ruokolainen, Janne [Department of Applied Physics, Aalto University, 00076 Aalto (Finland); Ratano, Patrizia; Campolongo, Patrizia [Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Roma (Italy); Trezza, Viviana [Department of Science, Roma Tre University, 00146 Roma (Italy); Nastruzzi, Claudio, E-mail: nas@unife.it [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Cortesi, Rita [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy)

    2015-03-01

    This study describes the preparation, characterization, and in vivo evaluation in rats of nanostructured lipid carriers (NLCs) encapsulating rimonabant (RMN) as prototypical cannabinoid antagonist. A study was conducted in order to optimize NLC production by melt and ultrasonication method. NLCs were prepared by alternatively adding the lipid phase into the aqueous one (direct protocol) or the aqueous phase into the lipid one (reverse protocol). RMN-NLCs have been characterized by cryogenic transmission electron microscopy (cryo-TEM), X-ray, photon correlation spectroscopy (PCS) and sedimentation field flow fractionation (SdFFF). Reverse NLCs were treated with polysorbate 80. RMN release kinetics have been determined in vitro by dialysis method. In vivo RMN biodistribution in rats was evaluated after intranasal (i.n.) administration of reverse RMN-NLC. The reverse protocol enabled to prevent the lost of lipid phase and to achieve higher RMN encapsulation efficacy (EE) with respect to the direct protocol (98% w/w versus 67% w/w). The use of different protocols did not affect NLC morphology and dimensional distribution. An in vitro dissolutive release rate of RMN was calculated. The in vivo data indicate that i.n. administration of RMN by reverse NLC treated with polysorbate 80 increased RMN concentration in the brain with respect to the drug in solution. The nanoencapsulation protocol presented here appears as an optimal strategy to improve the low solubility of cannabinoid compounds in an aqueous system suitable for in vivo administration. - Highlights: • Rimonabant (RMN) can be encapsulated in nanostructured lipid carriers (NLCs). • Nanoencapsulation improves RMN solubility in a stable physiologic aqueous formulation. • RMN is released in vitro from NLC by a controlled dissolutive release modality. • I.n. administration leads to higher RMN concentration in the brain with respect to plasma. • NLC increases RMN concentration in the brain with respect to

  16. Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes.

    Science.gov (United States)

    Alvarez, Edgardo O; Beauquis, Juan; Revsin, Yanina; Banzan, Arturo M; Roig, Paulina; De Nicola, Alejandro F; Saravia, Flavia

    2009-03-02

    Type 1 diabetes (T1D) is accompanied by a "diabetic encephalopathy" including hypersensitivity to stress, increased risk of stroke, dementia and cognitive impairment. In previous works we reported several brain alterations including a strong decrease in hippocampal proliferation and survival in both spontaneous and streptozotocin-induced models of experimental T1D. The aim of this study was to explore in streptozotocin-treated mice and other parameters associated to mild neurodegeneration in the dentate gyrus and the potential correlation with behavioural changes. The neurogenic status, measured by doublecortin (DCX) expression, showed an important decline in the number of positive cells in the subgranular zone (SGZ). However, neuronal migration was not affected. We found a marked enhancement of intracellular lipofuscin deposits, characteristic of increased oxidative stress and aging in both, the hilus and the SGZ and granular cell layer (GCL). Diabetic mice showed a significant impairment in learning and memory tests, exhibiting a higher latency to show an escape response and a poorer learning efficiency of an active avoiding response compared with control mice. Both, exploratory and non-exploratory activities in a conflictive environment in the asymmetric elevated plus maze were not affected by the diabetic condition. In conclusion, experimental diabetes showed clear signs of changes in the dentate gyrus, changes similar to those present in the aging process. Correlatively, these alterations were in line with a reduced performance in learning and memory tests. The mechanism that could potentially link neural and behavioural disturbances is not yet fully comprehended.

  17. Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus

    OpenAIRE

    Poon, Myra; Hussain, Khalid

    2009-01-01

    A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus.

  18. 27 CFR 555.207 - Construction of type 1 magazines.

    Science.gov (United States)

    2010-04-01

    ... constructed of, or covered with, a nonsparking material. (3) Wood frame wall construction. The exterior of... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Construction of type 1... Construction of type 1 magazines. A type 1 magazine is a permanent structure: a building, an igloo or “Army...

  19. Tests for genetic interactions in type 1 diabetes

    DEFF Research Database (Denmark)

    Morahan, Grant; Mehta, Munish; James, Ian

    2011-01-01

    Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1...... diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions....

  20. Evaluation of principal cannabinoids in airborne particulates

    Energy Technology Data Exchange (ETDEWEB)

    Balducci, C [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy); Nervegna, G; Cecinato, A [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy)

    2009-05-08

    The determination of delta(9)-tetrahydrocannabinol ({Delta}{sup 9}-THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm{sup -3} of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  1. Evaluation of principal cannabinoids in airborne particulates

    International Nuclear Information System (INIS)

    Balducci, C.; Nervegna, G.; Cecinato, A.

    2009-01-01

    The determination of delta(9)-tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm -3 of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  2. Stability of cannabinoids in urine in three storage temperatures.

    Science.gov (United States)

    Golding Fraga, S; Díaz-Flores Estévez, J; Díaz Romero, C

    1998-01-01

    Stability of cannabinoid compounds in urine samples were evaluated using several storage temperatures. Appreciable losses (> 22.4 percent) were observed in some urine samples, after being stored at room temperature for 10 days. Lower losses (8.1 percent) were observed when the urine samples were refrigerated for 4 weeks. The behavior of urine samples depended on the analyzed urine. This could be due to the different stability of the cannabinoids present in each urine sample. Important losses of 8.0 +/- 10.6, 15.8 +/- 4.2, and 19.6 +/- 6.7 percent were found when the urine samples were frozen during 40 days, 1 year, and 3 years, respectively. Average losses (> > 5 percent) can be observed after one day which could mainly be due to the decrease of the solubility of 11-nor-U9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) or adsorption process of cannabinoid molecules to the plastic storage containers.

  3. Synthetic cannabinoid and marijuana exposures reported to poison centers.

    Science.gov (United States)

    Forrester, M B; Kleinschmidt, K; Schwarz, E; Young, A

    2012-10-01

    Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high. This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system. Synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010 were identified. The distribution of exposures to the two agents with respect to various demographic and clinical factors were compared by calculating the rate ratio (RR) of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI). The proportion of synthetic cannabinoid and marijuana exposures, respectively, were 87.3% and 46.5% via inhalation (RR 1.88, 95% CI 1.38-2.61), 74.9% and 65.7% in male (RR 1.14, 95% CI 0.87-1.51), 40.2% and 56.6% age ≤ 19 years (RR 0.71, 95% CI 0.52-0.98), 79.2% and 58.6% occurring at a residence (RR 1.35, 95% CI 1.02-1.82), 8.4% and 16.2% managed on-site (RR 0.52. 95% CI 0.28-1.00), and 59.3% and 41.4% with serious medical outcomes (RR 1.43, 95% CI 1.03-2.05). Compared to marijuana, synthetic cannabinoid exposures were more likely to be used through inhalation, to involve adults, to be used at a residence, and to result in serious outcomes.

  4. Cannabinoids enhance gastric X/A-like cells activity.

    Directory of Open Access Journals (Sweden)

    Bogusław Sawicki

    2008-06-01

    Full Text Available It has been reported that cannabinoids may cause overeating in humans and in laboratory animals. Although, endogenous cannabinoids and their receptors (CB1 have been found in the hypothalamus, and recently also in gastrointestinal tract, the precise mechanism of appetite control by cannabinoids remains unknown. Recently, ghrelin--a hormone secreted mainly from the stomach X/A-like cells was proposed to be an appetite stimulating agent. The aim of this study was the evaluation of the influence of a single ip injection of a stable analogue of endogenous cannabinoid--anandamide, R-(+-methanandamide (2.5 mg/kg and CP 55,940 (0.25 mg/kg, an exogenous agonist of CB1 receptors, on ghrelin plasma concentration and on ghrelin immunoreactivity in the gastric mucosa of male Wistar rats. Four hours after a single injection of both cannabinoids or vehicle, the animals were anaesthetized and blood was taken from the abdominal aorta to determinate plasma ghrelin concentration by RIA. Subsequently, the animals underwent resection of distal part of stomach. Immunohistochemical study of gastric mucosa, using the EnVision method and specific monoclonal antibodies against ghrelin was performed. The intensity of ghrelin immunoreactivity in X/A-like cells was analyzed using Olympus Cell D image analysis system. The attenuation of ghrelin-immunoreactivity of gastric mucosa, after a single injection of R-(+-methanandamide and CP 55,940 was accompanied by a significant increase of ghrelin plasma concentration. These results indicate that stimulation of appetite exerted by cannabinoids may be connected with an increase of ghrelin secretion from gastric X/A-like cells.

  5. Cannabinoids and their possible use in the treatment of glaucoma

    OpenAIRE

    Zozaya Aldana, Beatriz; Medina Rodríguez, Isabel; Tamayo Pineda, Nirma

    2011-01-01

    Aunque la planta Cannabis sativa ha sido empleada desde la más remota antigüedad con fines medicinales, uno de sus derivados, la marihuana, se ha convertido en la droga de uso ilegal más consumida en el mundo. Asimismo tanto el Cannabis como sus cannabinoides se emplean como terapéutico en pocas enfermedades generalmente neurológicas. Se realizó una revisión bibliográfica para exponer el posible uso de los cannabinoides en la terapéutica del glaucoma. Para ello se tuvo en cuenta la literatura...

  6. Cannabinoides y su posible uso en el glaucoma Cannabinoids and their possible use in the treatment of glaucoma

    Directory of Open Access Journals (Sweden)

    Beatriz Zozaya Aldana

    2011-09-01

    Full Text Available Aunque la planta Cannabis sativa ha sido empleada desde la más remota antigüedad con fines medicinales, uno de sus derivados, la marihuana, se ha convertido en la droga de uso ilegal más consumida en el mundo. Asimismo tanto el Cannabis como sus cannabinoides se emplean como terapéutico en pocas enfermedades generalmente neurológicas. Se realizó una revisión bibliográfica para exponer el posible uso de los cannabinoides en la terapéutica del glaucoma. Para ello se tuvo en cuenta la literatura disponible sobre el tema, durante el período enero a septiembre de 2010. Se ha comprobado el efecto hipotensor ocular de los cannabinoides al disminuir la producción de humor acuoso, y aumentar la excreción de humor acuoso a través de la malla trabecular y la vía uveoescleral, efecto compatible con el hallazgo de elevadas concentraciones de receptores de cannabinoides rCB1 y rCB2; además, el tetrahidrocannabinol ha demostrado disminuir el efecto neurodegenerativo en modelos de isquemia cerebral en ratas y se evidenció también el efecto beneficioso de los cannabinoides al disminuir la degeneración secundaria asociada al glaucoma mediada por la excitotoxicidad del glutamato. Estos hallazgos sobre el efecto beneficioso de los cannabinoides como hipotensores oculares y por su efecto neuroprotector, transmiten un mensaje esperanzador sobre la función que estos podrían desempeñar en el campo del glaucoma, aunque para mayor seguridad y eficacia serían necesarios ensayos clínicos encaminados a valorar su aplicabilidad en la práctica clínica diaria.Although the Cannabis Sativa plant has been used since the most remote ancient times for medicinal purposes, one of its derivatives, marijuana, has become the most commonly used illegal drug in the world. Similarly, both Cannabis and the cannabinoids are used therapeutically in a small number of general neurological pathologies. Literature review was made to set forth the possible use of

  7. Suspected synthetic cannabinoid toxicosis in a dog.

    Science.gov (United States)

    Williams, Keysa; Wells, Raegan J; McLean, Mary Kay

    2015-01-01

    To describe the effects of suspected synthetic cannabinoid (SC) toxicosis and the response to intravenous lipid emulsion (ILE) therapy in a dog. A 2-year-8-month-old male Boxer dog was evaluated at an emergency hospital for progressive ataxia and inappropriate mentation. The initial physical examination identified marked hypothermia (32.7°C [90.9°F]), intermittent sinus bradycardia (60/min), stuporous mentation with intermittent aggression, and severe ataxia. Neurologic status deteriorated to comatose mentation within 2 hours of presentation. The initial diagnostic evaluation (eg, CBC, serum biochemistry profile, venous blood gas, and electrolyte determination) revealed a respiratory acidosis and thrombocytopenia. The owner reported that the dog was exposed to an SC containing Damiana leaf, Marshmallow leaf, and Athaea leaves. Initial treatment included IV fluids and supplemental oxygen. Mechanical ventilation was provided due to hypoventilation and periods of apnea. Intravenous lipid emulsion therapy was administered as a bolus (1.5 mL/kg) and continued as a continuous rate infusion (0.5 mL/kg/h) for a total of 6 hours. The dog became rousable and was weaned from mechanical ventilation approximately 15 hours following presentation. The dog was eating and walking with no ataxia, had a normal mentation at approximately 33 hours following presentation, and was discharged home at that time. Communication with the owners 5 days following discharge revealed that the dog was apparently normal. Based on this case and other reports in the literature regarding human exposures, SC ingestion may result in more severe clinical signs than marijuana ingestion in dogs. Significant clinical intervention may be necessary. Intravenous lipid emulsion treatment may be beneficial due to the lipophilicity of SC. © Veterinary Emergency and Critical Care Society 2015.

  8. Decision-making in diabetes mellitus type 1.

    Science.gov (United States)

    Rustad, James K; Musselman, Dominique L; Skyler, Jay S; Matheson, Della; Delamater, Alan; Kenyon, Norma S; Cáceda, Ricardo; Nemeroff, Charles B

    2013-01-01

    Decreased treatment adherence in patients with diabetes mellitus type 1 (type 1 DM) may reflect impairments in decision-making and underlying associated deficits in working memory and executive functioning. Other factors, including comorbid major depression, may also interfere with decision-making. The authors sought to review the clinically relevant characteristics of decision-making in type 1 DM by surveying the literature on decision-making by patients with type 1 DM. Deficiencies in decision-making in patients with type 1 DM or their caregivers contribute to treatment nonadherence and poorer metabolic control. Animal models of type 1 DM reveal deficits in hippocampal-dependent memory tasks, which are reversible with insulin. Neurocognitive studies of patients with type 1 DM reveal lowered performance on ability to apply knowledge to solve problems in a new situation and acquired scholarly knowledge, psychomotor efficiency, cognitive flexibility, visual perception, speed of information-processing, and sustained attention. Other factors that might contribute to poor decision-making in patients with type 1 DM, include "hypoglycemia unawareness" and comorbid major depression (given its increased prevalence in type 1 DM). Future studies utilizing novel treatment strategies to help patients with type 1 DM make better decisions about their disease may improve their glycemic control and quality of life, while minimizing the impact of end-organ disease.

  9. [Short-and long-term effects of cannabinoids on memory, cognition and mental illness].

    Science.gov (United States)

    Sagie, Shira; Eliasi, Yehuda; Livneh, Ido; Bart, Yosi; Monovich, Einat

    2013-12-01

    Marijuana is considered the most commonly used drug in the world, with estimated millions of users. There is dissent in the medical world about the positive and negative effects of marijuana, and recently, a large research effort has been directed to that domain. The main influencing drug ingredient is THC, which acts on the cannabinoid system and binds to the CB1 receptor. The discovery of the receptor led to the finding of an endogenous ligand, anandamide, and another receptor-CB2. The researchers also discovered that cannabinoids have extensive biological activity, and its short and long-term effects may cause cognitive and emotional deficiencies. Findings show that the short-term effects, such as shortterm memory and verbal Learning, are reversible. However, despite the accumulation of evidence about long-term cognitive damage due to cannabis use, it is difficult to find unequivocal results, arising from the existence of many variables such as large differences between cannabis users, frequency of use, dosage and endogenous brain compensation. Apart from cognitive damage, current studies investigate how marijuana affects mental illness: a high correlation between cannabis use and schizophrenia was found and a high risk to undergo a psychotic attack. Furthermore, patients with schizophrenia who used cannabis showed a selective neuro-psychological disruption, and similar cognitive deficiencies and brain morphological changes were found among healthy cannabis users and schizophrenia patients. In contrast to the negative effects of marijuana including addiction, there are the medical uses: reducing pain, anxiety and nausea, increasing appetite and an anti-inflammatory activity. Medicalization of marijuana encourages frequent use, which may elevate depression.

  10. Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

    Science.gov (United States)

    Fattore, Liana

    2016-04-01

    Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  11. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset

    DEFF Research Database (Denmark)

    Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine

    2015-01-01

    Type 1 narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive....... In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 type 1 narcolepsy patients...... having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling....

  12. Sodium Oxybate treatment in pediatric type 1 narcolepsy.

    Science.gov (United States)

    Moresco, Monica; Pizza, Fabio; Antelmi, Elena; Plazzi, Giuseppe

    2018-03-05

    Narcolepsy type 1 (NT1) is a rare chronic neurologic disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, usually with onset during childhood/adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. NT1 disease is caused by the selective loss of hypocretin-producing neurons in the lateral hypothalamus, most probably related to an autoimmune pathophysiology. Indeed a strong genetic predisposition including the HLA system and other associations in genes involved in immune responses has been found together with the triggering role of environmental agents such as H1N1 influenza infections and vaccinations. Sodium Oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid that is synthetized by neurons in the brain and functions as neurotransmitter. GHB is a central nervous system depressant and produces dose-dependent sedation. SO is a first line medication for cataplexy and excessive daytime sleepiness in adults with NT1, but can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. Although in the majority of patients narcolepsy develops before 15 years of age, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Current therapy is based only on empirical data shared among expert sleep disorders clinicians. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Cognitive and Behavioral Disorders in Children with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Martha Milade Torres Nupan

    2017-10-01

    Full Text Available AimThe last systematic review of research on the behavior of children with neurofibromatosis type 1 (NF1 was in 2012. Since then, several important findings have been published. Therefore, the study aim was to synthesize recent relevant work related to this issue.MethodWe conducted a systematic review of the literature. Relevant articles were identified using the electronic databases PubMed, PsycINFO, and Scopus and a manual search of references lists. Thirty of 156 articles identified met the inclusion criteria. A quality evaluation of the articles was performed and the information was synthesized using a narrative approach.ResultsCompared with controls, children and adolescents with NF1 present significant alterations in language, reading, visuospatial skills, motor function, executive function, attention, behavior, emotion, and social skills. The prevalence of attention-deficit/hyperactivity disorder (ADHD is important and can affect cognition and executive function variables. A high prevalence of autistic traits and autistic spectrum disorder were reported. The benefits of using statins to treat cognitive deficits are unclear. However, children with NF1 and ADHD seem to benefit from methylphenidate treatment. The presence of hyperintensities in brain magnetic resonance imaging data seem to be related to poor cognitive performance. Analysis of these lesions could help to predict cognitive alterations in children with NF1.InterpretationThere has been important progress to evaluate cognitive characteristics of children with NF1 and to determine the physiological mechanisms of the concomitant disorders. However, discrepancies in relation to intelligence, learning disabilities, attention deficits, and treatment remain. Further investigations on this topic are recommended.

  14. Cognitive and Behavioral Disorders in Children with Neurofibromatosis Type 1.

    Science.gov (United States)

    Torres Nupan, Martha Milade; Velez Van Meerbeke, Alberto; López Cabra, Claudia Alejandra; Herrera Gomez, Paula Marcela

    2017-01-01

    The last systematic review of research on the behavior of children with neurofibromatosis type 1 (NF1) was in 2012. Since then, several important findings have been published. Therefore, the study aim was to synthesize recent relevant work related to this issue. We conducted a systematic review of the literature. Relevant articles were identified using the electronic databases PubMed, PsycINFO, and Scopus and a manual search of references lists. Thirty of 156 articles identified met the inclusion criteria. A quality evaluation of the articles was performed and the information was synthesized using a narrative approach. Compared with controls, children and adolescents with NF1 present significant alterations in language, reading, visuospatial skills, motor function, executive function, attention, behavior, emotion, and social skills. The prevalence of attention-deficit/hyperactivity disorder (ADHD) is important and can affect cognition and executive function variables. A high prevalence of autistic traits and autistic spectrum disorder were reported. The benefits of using statins to treat cognitive deficits are unclear. However, children with NF1 and ADHD seem to benefit from methylphenidate treatment. The presence of hyperintensities in brain magnetic resonance imaging data seem to be related to poor cognitive performance. Analysis of these lesions could help to predict cognitive alterations in children with NF1. There has been important progress to evaluate cognitive characteristics of children with NF1 and to determine the physiological mechanisms of the concomitant disorders. However, discrepancies in relation to intelligence, learning disabilities, attention deficits, and treatment remain. Further investigations on this topic are recommended.

  15. 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.

  16. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.

    Science.gov (United States)

    Petrosino, Stefania; Verde, Roberta; Vaia, Massimo; Allarà, Marco; Iuvone, Teresa; Di Marzo, Vincenzo

    2018-06-01

    Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB 2 ) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD). We investigated if nonpsychotropic cannabinoids, such as cannabidiol (CBD), produced similar effects in this experimental model of ACD. HaCaT cells were stimulated with poly-(I:C), and the release of chemokines and cytokines was measured in the presence of CBD or other phytocannabinoids (such as cannabidiol acid, cannabidivarin, cannabidivarinic acid, cannabichromene, cannabigerol, cannabigerolic acid, cannabigevarin, tetrahydrocannabivarin, and tetrahydrocannabivarinic acid) and antagonists of CB 1 , CB 2 , or transient receptor potential vanilloid type-1 (TRPV1) receptors. HaCaT cell viability following phytocannabinoid treatment was also measured. The cellular levels of endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol] and related molecules (palmitoylethanolamide, oleoylethanolamide) were quantified in poly-(I:C)-stimulated HaCaT cells treated with CBD. We show that in poly-(I:C)-stimulated HaCaT cells, CBD elevates the levels of AEA and dose-dependently inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor- α in a manner reversed by CB 2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5'-iodio-resiniferatoxin (I-RTX), respectively, with no cytotoxic effect. This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Interbirth interval is associated with childhood type 1 diabetes risk

    DEFF Research Database (Denmark)

    Cardwell, Chris R; Svensson, Jannet; Waldhoer, Thomas

    2012-01-01

    to calculate pooled odds ratios (ORs) and investigate heterogeneity between studies. Overall, 2,787 children with type 1 diabetes were included. There was a reduction in the risk of childhood type 1 diabetes in children born to mothers after interbirth intervals...... of childhood type 1 diabetes has not been investigated. A secondary analysis of 14 published observational studies of perinatal risk factors for type 1 diabetes was conducted. Risk estimates of diabetes by category of interbirth interval were calculated for each study. Random effects models were used...

  18. Stigma Perceived and Experienced by Adults with Type 1 Diabetes

    DEFF Research Database (Denmark)

    Hansen, Ulla Møller; Willaing, Ingrid; Ventura, Adriana D

    2017-01-01

    OBJECTIVES: We aimed to (a) culturally and linguistically adapt the Type 1 Diabetes Stigma Assessment Scale (DSAS-1) from English (for Australia) into Danish and (b) examine psychometric properties of the measure among Danish adults with type 1 diabetes. METHODS: We performed a forward......-backward translation, face validity interviews with experts and cognitive debriefing of the Danish version (DSAS-1 DK) with ten adults from the target group. The DSAS-1 DK was then completed by 1594 adults with type 1 diabetes. Electronic clinical records provided age, diabetes duration, diabetes-related complications...... to advance research into the stigma perceived and experienced by adults with type 1 diabetes in a Danish context....

  19. Aortic stiffness is associated with white matter integrity in patients with type 1 diabetes

    International Nuclear Information System (INIS)

    Tjeerdema, Nathanja; Schinkel, Linda D. van; Westenberg, Jos J.; Elderen, Saskia G. van; Buchem, Mark A. van; Grond, Jeroen van der; Roos, Albert de; Smit, Johannes W.

    2014-01-01

    To assess the association between aortic pulse wave velocity (PWV) as a marker of arterial stiffness and diffusion tensor imaging of brain white matter integrity in patients with type 1 diabetes using advanced magnetic resonance imaging (MRI) technology. Forty-one patients with type 1 diabetes (23 men, mean age 44 ± 12 years, mean diabetes duration 24 ± 13 years) were included. Aortic PWV was assessed using through-plane velocity-encoded MRI. Brain diffusion tensor imaging (DTI) measurements were performed on 3-T MRI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated for white and grey matter integrity. Pearson correlation and multivariable linear regression analyses including cardiovascular risk factors as covariates were assessed. Multivariable linear regression analyses revealed that aortic PWV is independently associated with white matter integrity FA (β = -0.777, p = 0.008) in patients with type 1 diabetes. This effect was independent of age, gender, mean arterial pressure, body mass index, smoking, duration of diabetes and glycated haemoglobin levels. Aortic PWV was not significantly related to grey matter integrity. Our data suggest that aortic stiffness is independently associated with reduced white matter integrity in patients with type 1 diabetes. (orig.)

  20. Aortic stiffness is associated with white matter integrity in patients with type 1 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Tjeerdema, Nathanja; Schinkel, Linda D. van [Leiden University Medical Center, Department of Endocrinology and General Internal Medicine (C7-Q), Albinusdreef 2, PO Box 9600, Leiden (Netherlands); Westenberg, Jos J.; Elderen, Saskia G. van; Buchem, Mark A. van; Grond, Jeroen van der; Roos, Albert de [Leiden University Medical Center, Department of Radiology, Leiden (Netherlands); Smit, Johannes W. [Leiden University Medical Center, Department of Endocrinology and General Internal Medicine (C7-Q), Albinusdreef 2, PO Box 9600, Leiden (Netherlands); University Medical Center Nijmegen, Department of General Internal Medicine, Nijmegen (Netherlands)

    2014-09-15

    To assess the association between aortic pulse wave velocity (PWV) as a marker of arterial stiffness and diffusion tensor imaging of brain white matter integrity in patients with type 1 diabetes using advanced magnetic resonance imaging (MRI) technology. Forty-one patients with type 1 diabetes (23 men, mean age 44 ± 12 years, mean diabetes duration 24 ± 13 years) were included. Aortic PWV was assessed using through-plane velocity-encoded MRI. Brain diffusion tensor imaging (DTI) measurements were performed on 3-T MRI. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated for white and grey matter integrity. Pearson correlation and multivariable linear regression analyses including cardiovascular risk factors as covariates were assessed. Multivariable linear regression analyses revealed that aortic PWV is independently associated with white matter integrity FA (β = -0.777, p = 0.008) in patients with type 1 diabetes. This effect was independent of age, gender, mean arterial pressure, body mass index, smoking, duration of diabetes and glycated haemoglobin levels. Aortic PWV was not significantly related to grey matter integrity. Our data suggest that aortic stiffness is independently associated with reduced white matter integrity in patients with type 1 diabetes. (orig.)

  1. Disease awareness in myotonic dystrophy type 1: an observational cross-sectional study

    OpenAIRE

    Baldanzi, Sigrid; Bevilacqua, Francesca; Lorio, Rita; Volpi, Leda; Simoncini, Costanza; Petrucci, Antonio; Cosottini, Mirco; Massimetti, Gabriele; Tognoni, Gloria; Ricci, Giulia; Angelini, Corrado; Siciliano, Gabriele

    2016-01-01

    Background Myotonic dystrophy type 1 (Steinert?s disease or DM1), the most common form of autosomal dominant muscular dystrophy in adults, is a multisystem disorder, affecting skeletal muscle as well as eyes, heart, gastrointestinal tract, endocrine system, and central nervous system, finally responsible of increasing disabilities and secondary social consequences. To date, DM1-related brain involvement represents a challenging field of research. It is well known that DM1 patients frequently ...

  2. Localization and function of the cannabinoid CB1 receptor in the anterolateral bed nucleus of the stria terminalis.

    Directory of Open Access Journals (Sweden)

    Nagore Puente

    Full Text Available BACKGROUND: The bed nucleus of the stria terminalis (BNST is involved in behaviors related to natural reward, drug addiction and stress. In spite of the emerging role of the endogenous cannabinoid (eCB system in these behaviors, little is known about the anatomy and function of this system in the anterolateral BNST (alBNST. The aim of this study was to provide a detailed morphological characterization of the localization of the cannabinoid 1 (CB1 receptor a necessary step toward a better understanding of the physiological roles of the eCB system in this region of the brain. METHODOLOGY/PRINCIPAL FINDINGS: We have combined anatomical approaches at the confocal and electron microscopy level to ex-vivo electrophysiological techniques. Here, we report that CB1 is localized on presynaptic membranes of about 55% of immunopositive synaptic terminals for the vesicular glutamate transporter 1 (vGluT1, which contain abundant spherical, clear synaptic vesicles and make asymmetrical synapses with alBNST neurons. About 64% of vGluT1 immunonegative synaptic terminals show CB1 immunolabeling. Furthermore, 30% and 35% of presynaptic boutons localize CB1 in alBNST of conditional mutant mice lacking CB1 mainly from GABAergic neurons (GABA-CB1-KO mice and mainly from cortical glutamatergic neurons (Glu-CB1-KO mice, respectively. Extracellular field recordings and whole cell patch clamp in the alBNST rat brain slice preparation revealed that activation of CB1 strongly inhibits excitatory and inhibitory synaptic transmission. CONCLUSIONS/SIGNIFICANCE: This study supports the anterolateral BNST as a potential neuronal substrate of the effects of cannabinoids on stress-related behaviors.

  3. Effects of a selective cannabinoid CB2 agonist and antagonist on intravenous nicotine self administration and reinstatement of nicotine seeking.

    Directory of Open Access Journals (Sweden)

    Islam Gamaleddin

    Full Text Available Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2 have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. Our objective was to explore the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed and progressive ratio and on nicotine seeking induced by nicotine priming or by nicotine associated cues. For this, we evaluated the effects of various doses of the selective CB2 antagonist AM630 (1.25 to 5 mg/kg and CB2 agonist AM1241 (1 to 10 mg/kg on these behavioral responses in rats. Different groups of male Long Evans rats were trained to lever press for nicotine at a unit dose of 30 µg/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 ligands did not affect either nicotine-taking nicotine-seeking behavior. Our results do not support the involvement of CB2 receptors in nicotine-taking or nicotine-seeking behavior.

  4. Cannabinoid Receptors: A Novel Target for Therapy for Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2008-01-01

    We have shown that the expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 (WIN...

  5. Cannabinoid Receptors: A Novel Target for Treating Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2006-01-01

    Recently we have shown that expression levels of both cannabinoid receptors CB and CB12 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2...

  6. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2007-01-01

    .... We have shown that the expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 (WIN...

  7. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Mukhtar, Hasan; Afaq, Farrukh; Sarfaraz, Sami

    2005-01-01

    .... Here we show that expression levels of both cannabinoid receptors CB(sub 1) and CB(sub 2) are significantly higher in CA-HPV-10 and other human prostate cells LNCaP, DUI45, PC3, and CWR22RV1 than in human prostate epithelial and PZ-HPV-7 cells...

  8. Clinical pharmacology of cannabinoids in early phase drug development

    NARCIS (Netherlands)

    Zuurman, Hillie Henka

    2008-01-01

    Although cannabis is especially known for its recreational use as a ‘soft drug’, its potential therapeutic properties have been recognized for hundreds of years. Since the isolation of THC from Cannabis sativa L, the discovery of cannabinoid receptors and their natural ligands (endocannabinoids) the

  9. Cannabinoids: New Promising Agents in the Treatment of Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Sabrina Giacoppo

    2014-11-01

    Full Text Available Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.

  10. Type 1 Does The Two-Step: Type 1 Secretion Substrates With A Functional Periplasmic Intermediate.

    Science.gov (United States)

    Smith, Timothy J; Sondermann, Holger; O'Toole, George A

    2018-06-04

    Bacteria have evolved several secretion strategies for polling and responding to environmental flux and insult. Of these, the type 1 secretion system (T1SS) is known to secrete an array of biologically diverse proteins - from small < 10 kDa bacteriocins to gigantic adhesins with a mass over 1 MDa. For the last several decades T1SS have been characterized as a one-step translocation strategy whereby the secreted substrate is transported directly into the extracellular environment from the cytoplasm with no periplasmic intermediate. Recent phylogenetic, biochemical, and genetic evidence point to a distinct sub-group of T1SS machinery linked with a bacterial transglutaminase-like cysteine proteinase (BTLCP), which uses a two-step secretion mechanism. BTLCP-linked T1SS transport a class of repeats-in-toxin (RTX) adhesins that are critical for biofilm formation. The prototype of this RTX adhesin group, LapA of Pseudomonas fluorescens Pf0-1, uses a novel N-terminal retention module to anchor the adhesin at the cell surface as a secretion intermediate threaded through the outer membrane-localized, TolC-like protein LapE. This secretion intermediate is post-translationally cleaved by the BTLCP family LapG protein to release LapA from its cognate T1SS pore. Thus, secretion of LapA and related RTX adhesins into the extracellular environment appears to be a T1SS-mediated, two-step process that involves a periplasmic intermediate. In this review, we contrast the T1SS machinery and substrates of the BLTCP-linked two-step secretion process with those of the classical one-step T1SS to better understand the newly recognized and expanded role of this secretion machinery. Copyright © 2018 American Society for Microbiology.

  11. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation.

    Science.gov (United States)

    De Petrocellis, L; Orlando, P; Moriello, A Schiano; Aviello, G; Stott, C; Izzo, A A; Di Marzo, V

    2012-02-01

    Plant cannabinoids, like Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other 'thermo-TRP's', the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1-4 channels in the gastrointestinal tract. TRP activity was assessed by evaluating elevation of [Ca(2+)](i) in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quantitative RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil. (i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca(2+)](i) with high efficacy (50-70% of the effect of ionomycin) and potency (EC(50∼) 3.7 μm), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca(2+)](i) with moderate-high efficacy (30-60% of the effect of ionomycin) and potency (EC(50) 0.9-6.4 μm), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice. Cannabinoids can affect both the activity and the expression of TRPV1-4 channels, with various potential therapeutic applications, including in the gastrointestinal tract. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

  12. Stimulation of cannabinoid receptor 2 (CB2 suppresses microglial activation

    Directory of Open Access Journals (Sweden)

    Fernandez Francisco

    2005-12-01

    Full Text Available Abstract Background Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD, multiple sclerosis (MS, and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2. Methods In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-γ using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Aβ1–42 peptide using a phagocytosis assay. Results We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.

  13. Lymphocyte apoptosis in the pathogenesis of type 1 diabetes mellitus

    African Journals Online (AJOL)

    EL-HAKIM

    biochemical features.2 It is a coordinated series of events for the ... sex matched subjects with no clinical or laboratory signs or family history of ... Keywords: lymphocyte apoptosis; CD95 system; type 1 DM; prediabetes. Eman M. ..... percentage among complicated and non-complicated cases of type-1 diabetes mellitus.

  14. Management of Type 1 Diabetes in Schools: Whose Responsibility?

    Science.gov (United States)

    Mandali, Swarna L.; Gordon, Theresa A.

    2009-01-01

    The Centers for Disease Control and Prevention (2008) reports that approximately 0.2% of all persons under the age of 20 have been diagnosed with either type 1 or type 2 diabetes. This represents 186,300 children and young adults. Type 1 diabetes has traditionally been a disease of children and adolescents. Although type 2 diabetes has in the past…

  15. Coexistence of coeliac disease and type 1 diabetes

    OpenAIRE

    Szaflarska-Popławska, Anna

    2014-01-01

    There is a selective review of the literature concerning the coexistence of coeliac disease and type 1 diabetes mellitus. This review focuses on the principles of serological tests towards coeliac disease in patients with type 1 diabetes mellitus and metabolic control measures as a result of a gluten-free diet.

  16. Partial sleep restriction decreases insulin sensitivity in type 1 diabetes

    NARCIS (Netherlands)

    Donga, Esther; van Dijk, Marieke [Leiden Univ., LUMC; van Dijk, J. Gert; Biermasz, Nienke R.; Lammers, Gert-Jan; van Kralingen, Klaas; Hoogma, Roel P. L. M.; Corssmit, Eleonora P. M.; Romijn, Johannes A.

    2010-01-01

    Sleep restriction results in decreased insulin sensitivity and glucose tolerance in healthy subjects. We hypothesized that sleep duration is also a determinant of insulin sensitivity in patients with type 1 diabetes. We studied seven patients (three men, four women) with type 1 diabetes: mean age 44

  17. Breast-feeding and childhood-onset type 1 diabetes

    DEFF Research Database (Denmark)

    Cardwell, Chris R; Stene, Lars C; Ludvigsson, Johnny

    2012-01-01

    To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.......To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders....

  18. Human leukocyte antigen (HLA) polymorphism and type 1 diabetes ...

    African Journals Online (AJOL)

    Insulin-dependent diabetes mellitus or type 1 diabetes is an autoimmune multifactorial disease which has a great socio-economic impact. In Morocco, less is known about the contribution of Human leukocyte antigen (HLA) alleles to type 1 diabetes susceptibility. Our study focused on evaluating the distribution of class II ...

  19. Type 1,1-operators defined by vanishing frequency modulation

    DEFF Research Database (Denmark)

    Johnsen, Jon

    This paper presents a general definition of pseudo-differential operators of type 1,1; the definition is shown to be the largest one that is both compatible with negligible operators and stable under vanishing frequency modulation. Elaborating counter-examples of Ching andHörmander, type 1...

  20. The Effect of Type-1 Error on Deterrence

    DEFF Research Database (Denmark)

    Lando, Henrik; Mungan, Murat C.

    2018-01-01

    According to a conventional view, type-1 error (wrongful conviction) is as detrimental to deterrence as type-2 error (wrongful acquittal), because type-1 error lowers the pay-off from acting within the law. This view has led to the claim that the pro-defendant bias of criminal procedure, and its ...

  1. Efficacy of standardised herbal extracts in type 1 diabetes - an ...

    African Journals Online (AJOL)

    In the present study, the hypoglycemic activity of Withania somnifera Dunal, Allium sativum Linn., Gymnema sylvestre (Retz.) Schult, Ferula foetida (Bunge.) Reg. and Murraya koenigii (L.) Spreng. extracts have been studied in an experimental model of type 1 diabetes. Type 1 diabetes was induced in albino rats by a single ...

  2. The epidemiology and pathogenesis of type 1 diabetes mellitus in ...

    African Journals Online (AJOL)

    Type 1 diabetes is a serious, debilitating disease, with life-threatening complications, and the financial burden associated with the management of this disease is enormous. Early diagnosis and intervention can improve morbidity and mortality. Unfortunately, in Africa, type 1 diabetes is poorly characterised, and there is ...

  3. Audit on stillbirths in women with pregestational type 1 diabetes

    DEFF Research Database (Denmark)

    Lauenborg, Jeannet; Mathiesen, Elisabeth Reinhardt; Ovesen, Per Glud

    2003-01-01

    To audit stillbirth cases in women with type 1 diabetes to search for specific characteristics in order to improve antenatal care and treatment.......To audit stillbirth cases in women with type 1 diabetes to search for specific characteristics in order to improve antenatal care and treatment....

  4. Experimental Therapy Shows Promise for Type 1 Diabetes

    Science.gov (United States)

    ... triggers cells to take up sugar from the blood. In type 1 diabetes, the immune system The cells and tissues that ... people to eat or drink to raise their blood sugar levels. However, many people with type 1 diabetes can’t tell when their blood sugar is ...

  5. Type 1 diabetes: New horizons in prediction and prevention.

    Science.gov (United States)

    Razack, Natasha N; Wherrett, Diane K

    2005-01-01

    Significant advances have been made in our understanding of the pathogenesis of type 1 diabetes and our ability to predict risk for the condition. This knowledge is being used to develop new and innovative strategies to prevent type 1 diabetes or to prevent further destruction of beta cells in those who are newly diagnosed. Several multicentre studies are underway investigating the natural history of the disease, the genetics behind the disease and ways to stop the autoimmune reaction against beta cells (Type 1 Diabetes TrialNet, Type 1 Diabetes Genetics Consortium and the Trial to Reduce Diabetes in the Genetically at Risk [TRIGR] Study Group). The stage is set to find an agent or strategy to prevent type 1 diabetes or to preserve the residual beta cell mass in new-onset patients.

  6. Prelabor Cesarean Section and Risk of Childhood Type 1 Diabetes

    DEFF Research Database (Denmark)

    Clausen, Tine Dalsgaard; Bergholt, Thomas; Eriksson, Frank

    2016-01-01

    BACKGROUND: Unfavorable conditions associated with cesarean section may influence the risk of type 1 diabetes in offspring, but results from studies are conflicting. We aimed to evaluate the association between prelabor cesarean section and risk of childhood type 1 diabetes. METHODS: A Danish...... nationwide cohort study followed all singletons born during 1982-2010. Five national registers provided information on mode of delivery, outcome, and confounders. The risk of childhood type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 1,760,336 singletons...... contributed 20,436,684 person-years, during which 4,400 were diagnosed with childhood type 1 diabetes. RESULTS: The hazard ratio for childhood type 1 diabetes was increased in children delivered by prelabor cesarean section compared with vaginal delivery when adjusted for year of birth, parity, sex, parental...

  7. Fulminant type 1 diabetes mellitus: a case report

    Science.gov (United States)

    Yunir, E.; Nenfiati

    2018-03-01

    Type 1 diabetes mellitus is a metabolic disease caused by insulin deficiency that results from destruction of β-cells in the pancreas. Based on American Diabetes Association, there are two types of type 1 diabetes mellitus: type 1A (autoimmune) and 1B (idiopathic). In this case, we are presenting a new archetype of type 1 diabetes named fulminant type 1 diabetes mellitus. This disease results from quick destruction of β-cells byanautoimmune mechanism. The manifestation of this disease consists of unspecific flu-like symptoms, abdominal symptoms, to specific hyperglycemia symptoms such as fatigue, malaise, change in mental status that are attributable to high blood glucose and ketosis. Laboratory examination reveals high blood glucose, normal glycosylated hemoglobin, ketosis or ketoacidosis, potassium depletion and elevation of liver function tests. Treatment consists of intravenous infusion followed by insulin injection for blood glucose control, followed by treatment of metabolic derangements such as acid-base and electrolyte disorder.

  8. Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease.

    Science.gov (United States)

    Jayant, Shalini; Sharma, Brij Mohan; Bansal, Rani; Sharma, Bhupesh

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world. Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition. The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition. We have induced experimental AD in mice by using two induction models viz., intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose. Morris water maze (MWM) and attentional set shifting test (ASST) were used to assess learning and memory. Hematoxylin-eosin and Congo red staining were used to examine the structural variation in brain. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), nitric oxide levels (nitrites/nitrates), acetyl cholinesterase activity, myeloperoxidase and calcium levels were also estimated. i.c.v. STZ as well as AlCl3+d-galactose have impaired spatial and reversal learning with executive functioning, increased brain oxidative and nitrosative stress, cholinergic activity, inflammation and calcium levels. Furthermore, these agents have also enhanced the burden of Aβ plaque in the brain. Treatment with 1-phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of learning-memory, brain biochemistry and brain damage. Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Candidate PET radioligands for cannabinoid CB{sub 1} receptors: [{sup 18}F]AM5144 and related pyrazole compounds

    Energy Technology Data Exchange (ETDEWEB)

    Zizhong, Li [Center for Translational Neuroimaging, Brookhaven National Laboratory, Upton, NY 11973 (United States); Gifford, Andrew [Center for Translational Neuroimaging, Brookhaven National Laboratory, Upton, NY 11973 (United States); Qian, Liu [Center for Drug Discovery, Northeastern University, Boston, MA 02115 (United States); Thotapally, Rajesh [Center for Drug Discovery, Northeastern University, Boston, MA 02115 (United States); Yushin, Ding [Center for Translational Neuroimaging, Brookhaven National Laboratory, Upton, NY 11973 (United States); Makriyannis, Alexandros [Center for Drug Discovery, Northeastern University, Boston, MA 02115 (United States); Gatley, S John [Center for Translational Neuroimaging, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Center for Drug Discovery, Northeastern University, Boston, MA 02115 (United States)

    2005-05-01

    Introduction: The mammalian brain contains abundant G protein-coupled cannabinoid CB{sub 1} receptors that respond to {delta}{sup 9}-tetrahydrocannabinol, the active ingredient of cannabis. The availability of a positron emission tomography (PET) radioligand would facilitate studies of the addictive and medicinal properties of compounds that bind to this receptor. Among the known classes of ligands for CB{sub 1} receptors, the pyrazoles are attractive targets for radiopharmaceutical development because they are antagonists and are generally less lipophilic than the other classes. Methods: A convenient high-yield synthesis of N-(4-[{sup 18}F]fluorophenyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)- 1H-pyrazole-3-carboxamide (AM5144) was devised by coupling the appropriate pyrazole-3-carboxyl chloride compound with 4-[{sup 18}F]fluoroaniline. The labeled precursor was synthesized from 1-[{sup 18}F]fluoro-4-nitrobenzene in 60% radiochemical yield for 10 min using an improved procedure involving sodium borohydride reduction with cobalt chloride catalysis. The product was purified by HPLC to give a specific activity >400 mCi/{mu}mol and a radiochemical purity >95%, and a PET study was conducted in a baboon. Results: Although the regional uptake of AM5144 in baboon brain was consistent with binding to cannabinoid CB{sub 1} receptors, absolute uptake at <0.003% injected radioactivity per cubic centimeter was lower than the previously reported uptake of the radioiodinated pyrazole AM281. Conclusions: The relatively poor brain uptake of AM5144 and other pyrazole CB{sub 1} receptor ligands is not surprising because of their high lipophilicity as compared with most brain PET radiotracers. However, for nine pyrazole compounds for which rodent data are available, brain uptake and calculated logP values are not correlated. Thus, high logP values should not preclude evaluation of radiotracers for targets such as the CB{sub 1} receptor that may require very lipophilic ligands.

  10. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    Science.gov (United States)

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

  11. Atrial Natriuretic Peptide (ANP) in early pregnancy is associated with development of preeclampsia in type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lene Ringholm; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2011-01-01

    The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting that preecla......The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting...... that preeclampsia is associated with cardiovascular changes in early pregnancy....

  12. Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice

    International Nuclear Information System (INIS)

    Baireddy, Praveena; Liu, Jing; Hinsdale, Myron; Pope, Carey

    2011-01-01

    Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (−/−) mice. Mice of both genotypes (n = 5–6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82–95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 μM) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20–23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: ► C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. ► Wild type and cannabinoid CB1 receptor knockout littermates

  13. Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice

    Energy Technology Data Exchange (ETDEWEB)

    Baireddy, Praveena; Liu, Jing; Hinsdale, Myron; Pope, Carey, E-mail: carey.pope@okstate.edu

    2011-11-15

    Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n = 5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 {mu}M) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: Black-Right-Pointing-Pointer C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. Black-Right-Pointing-Pointer Wild type and

  14. Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

    Science.gov (United States)

    Miederer, I; Uebbing, K; Röhrich, J; Maus, S; Bausbacher, N; Krauter, K; Weyer-Elberich, V; Lutz, B; Schreckenberger, M; Urban, R

    2017-05-01

    Δ 9 -Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain. The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain. 21 male Sprague Dawley rats (12-13 w) were examined and received five different doses of THC ranging from 0.01 to 1 mg/kg. For data acquisition a Focus 120 small animal PET scanner was used and 24.1-28.0 MBq of [ 18 F]-fluoro-2-deoxy-d-glucose were injected. The data were acquired for 70 min and arterial blood samples were collected throughout the scan. THC, THC-OH and THC-COOH were determined at 55 min p.i. Nine volumes of interest were defined, and the cerebral glucose uptake was calculated for each brain region. Low blood THC levels of glucose uptake (6-30 %), particularly in the hypothalamus (p = 0.007), while blood THC levels > 10 ng/ml (injected dose: ≥ 0.05 mg/kg) coincided with a decreased glucose uptake (-2 to -22 %), especially in the cerebellar cortex (p = 0.008). The effective concentration in this region was estimated 2.4 ng/ml. This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose - an effect that may be of relevance in behavioural studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. The Neuroglial Dialog Between Cannabinoids and Hemichannels

    Science.gov (United States)

    Labra, Valeria C.; Santibáñez, Cristian A.; Gajardo-Gómez, Rosario; Díaz, Esteban F.; Gómez, Gonzalo I.; Orellana, Juan A.

    2018-01-01

    The formation of gap junctions was initially thought to be the central role of connexins, however, recent evidence had brought to light the high relevance of unopposed hemichannels as an independent mechanism for the selective release of biomolecules during physiological and pathological conditions. In the healthy brain, the physiological opening of astrocyte hemichannels modulates basal excitatory synaptic transmission. At the other end, the release of potentially neurotoxic compounds through astroglial hemichannels and pannexons has been insinuated as one of the functional alterations that negatively affect the progression of multiple brain diseases. Recent insights in this matter have suggested encannabinoids (eCBs) as molecules that could regulate the opening of these channels during diverse conditions. In this review, we discuss and hypothesize the possible interplay between the eCB system and the hemichannel/pannexon-mediated signaling in the inflamed brain and during event of synaptic plasticity. Most findings indicate that eCBs seem to counteract the activation of major neuroinflammatory pathways that lead to glia-mediated production of TNF-α and IL-1β, both well-known triggers of astroglial hemichannel opening. In contrast to the latter, in the normal brain, eCBs apparently elicit the Ca2+-activation of astrocyte hemichannels, which could have significant consequences on eCB-dependent synaptic plasticity. PMID:29662436

  16. The Neuroglial Dialog Between Cannabinoids and Hemichannels

    Directory of Open Access Journals (Sweden)

    Valeria C. Labra

    2018-03-01

    Full Text Available The formation of gap junctions was initially thought to be the central role of connexins, however, recent evidence had brought to light the high relevance of unopposed hemichannels as an independent mechanism for the selective release of biomolecules during physiological and pathological conditions. In the healthy brain, the physiological opening of astrocyte hemichannels modulates basal excitatory synaptic transmission. At the other end, the release of potentially neurotoxic compounds through astroglial hemichannels and pannexons has been insinuated as one of the functional alterations that negatively affect the progression of multiple brain diseases. Recent insights in this matter have suggested encannabinoids (eCBs as molecules that could regulate the opening of these channels during diverse conditions. In this review, we discuss and hypothesize the possible interplay between the eCB system and the hemichannel/pannexon-mediated signaling in the inflamed brain and during event of synaptic plasticity. Most findings indicate that eCBs seem to counteract the activation of major neuroinflammatory pathways that lead to glia-mediated production of TNF-α and IL-1β, both well-known triggers of astroglial hemichannel opening. In contrast to the latter, in the normal brain, eCBs apparently elicit the Ca2+-activation of astrocyte hemichannels, which could have significant consequences on eCB-dependent synaptic plasticity.

  17. NHSBSP type 1 interval cancers: a scientifically valid grouping?

    International Nuclear Information System (INIS)

    Porter, G.J.R.; Evans, A.J.; Burrell, H.C.; Lee, A.H.S.; Chakrabarti, J.

    2007-01-01

    Aim: To assess whether there are differences in the pathological features or survival between the new National Health Service Breast Screening Programme (NHSBSP) interval cancer classification system category of type 1 interval cancers, and the previously used, separate categories of occult, unclassified, and true interval cancers. Materials and methods: The prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor status, and histological type) and survival of 428 type 1 interval invasive breast cancers were analysed by subgroup (occult, unclassified and true interval). Results: Occult cancers compared with other type 1 interval cancers were of significantly lower grade [38 of 52 (73%) versus 151 of 340 (44%) grade 1 or 2, p = 0.0005], more likely to be smaller size [37 of 51 (73%) versus 158 of 341 (46%) <20 mm, p = 0.0003] and more frequently of lobular type at histology [14 of 42 (32%) versus 50 of 286 (17%), p = 0.03]. There was no significant difference in pathological features of unclassified tumours compared with other type 1 tumours. There was no significant survival difference between different type 1 subgroups (p = 0.12). Conclusion: The NHSBSP type 1 interval cancers are a heterogeneous grouping with markedly differing pathological features. However, no significant survival difference is seen between the different type 1 subgroups

  18. NHSBSP type 1 interval cancers: a scientifically valid grouping?

    Energy Technology Data Exchange (ETDEWEB)

    Porter, G.J.R. [Nottingham Breast Institute, City Hospital, Nottingham (United Kingdom)]. E-mail: garethporter@doctors.org.uk; Evans, A.J. [Nottingham Breast Institute, City Hospital, Nottingham (United Kingdom); Burrell, H.C. [Nottingham Breast Institute, City Hospital, Nottingham (United Kingdom); Lee, A.H.S. [Nottingham Breast Institute, City Hospital, Nottingham (United Kingdom); Chakrabarti, J. [Nottingham Breast Institute, City Hospital, Nottingham (United Kingdom)

    2007-03-15

    Aim: To assess whether there are differences in the pathological features or survival between the new National Health Service Breast Screening Programme (NHSBSP) interval cancer classification system category of type 1 interval cancers, and the previously used, separate categories of occult, unclassified, and true interval cancers. Materials and methods: The prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor status, and histological type) and survival of 428 type 1 interval invasive breast cancers were analysed by subgroup (occult, unclassified and true interval). Results: Occult cancers compared with other type 1 interval cancers were of significantly lower grade [38 of 52 (73%) versus 151 of 340 (44%) grade 1 or 2, p = 0.0005], more likely to be smaller size [37 of 51 (73%) versus 158 of 341 (46%) <20 mm, p = 0.0003] and more frequently of lobular type at histology [14 of 42 (32%) versus 50 of 286 (17%), p = 0.03]. There was no significant difference in pathological features of unclassified tumours compared with other type 1 tumours. There was no significant survival difference between different type 1 subgroups (p = 0.12). Conclusion: The NHSBSP type 1 interval cancers are a heterogeneous grouping with markedly differing pathological features. However, no significant survival difference is seen between the different type 1 subgroups.

  19. [Endurance capabilities of triathlon competitors with type 1 diabetes mellitus].

    Science.gov (United States)

    Boehncke, S; Poettgen, K; Maser-Gluth, C; Reusch, J; Boehncke, W-H; Badenhoop, K

    2009-04-01

    Treatment of type 1 diabetes mellitus (DM) aims to prevent complications by strictly optimizing blood glucose levels. Although physical exercise is an important part of metabolic control, endurance sports are considered hazardous for patients with type 1 diabetes because of the extreme physiological stress they represent. To further elucidate the metabolic challenge this form of exercise presented we investigated the performance of triathlon competitors with type 1 diabetes. Ten patients (32-61 years) with type 1 diabetes (disease duration 2-35 years) were followed for three years, during which each year they participated in one triathlon long-distance competitions (2.4 miles swimming, 26.2 miles running and 112 miles cycling; Ironman Germany 2005-2007). Glucose, cortisol, aldosterone, renin, thyroid hormones, testosterone, growth hormone and catecholamines were measured in blood and saliva. Five non-diabetic competitors served as controls. The performance equalled those of age-matched healthy athletes. Several participants experienced hyperglycemia early in the bike leg, whereas all of them developed low blood glucose levels during the marathon leg. Basal insulin supply was reduced up to 50 % on race day. Hormone levels in athletes with type 1 DM and healthy controls were similar. Patients with type 1 DM can successfully sustain extreme endurance challenges. Physiological alterations of the metabolic state complicated by type 1 DM can readily be compensated by adapting intensified insulin therapy and nutritional modifications. Thus 1 DM should not be regarded a contraindication to participating in high endurance sports.

  20. ROLE OF NEUROSPECIFIC PROTEINS IN THE DEVELOPMENT OF COGNITIVE DYSFUNCTION IN PATIENTS WITH TYPE 1 DIABETES

    Directory of Open Access Journals (Sweden)

    M. V. Novosyolova

    2014-01-01

    Full Text Available Type 1 (type 1 DM diabetes mellitus is one of the common chronic metabolic diseases, which currently is a significant problem due to disability at a young age and reduce life expectancy. Despite the fact that type 1 diabetes accounts for only 10% of all patients with diabetes, it occurs particularly hard, with a tendency to progression. One of the targets of type 1 diabetes is the central nervous system with the further formation of cognitive dysfunction in young age leads to diminished quality of life. Cognitive deficits may be the result not only of structural lesions of the brain, but it may be due to the development of metabolic disorders. In the case of timely diagnosis and treatment of cognitive impairment associated with metabolic changes that can partially or completely regress. The aim of this study was to identify biomarkers of the brain damage in young patients with type 1 diabetes. The study involved 58 patients with  type  1  diabetes,  the  control  group  comprised  29  healthy  controls.  The  complex  included a neuropsychological examination which was used for testing the Montreal scale (MoCA test rapid screening of cognitive impairment, assessment of quality of life using a common questionnaire Medical Outcomes Study Short Form (MOS SF-36 and the specific audit – dependent quality of life (ADDQoL. To evaluateearly markersin the developmentof cognitive dysfunctionwere identifiedneurospecific proteins – S100 protein and glial fibrillary acidic protein (GFAP, myelin basic protein (MBP. Found an increased level of neurospecific protein that was correlated with parameters of carbohydrate metabolism, poor quality of life and severe cognitive deficiency (MoCA test lower than 26 points.

  1. The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

    Science.gov (United States)

    Bow, Eric W.; Rimoldi, John M.

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

  2. [The child from families with type 1 diabetes].

    Science.gov (United States)

    Wasikowa, Renata; Suchańska, Dorota; Suchańska, Danuta; Basiak, Aleksander; Noczyńska, Anna; Stasińska, Teresa

    2005-01-01

    Diabetes type 1 is observed in individuals with a genetic predisposition to the disease. Observed is a 3-5 fold risk for congenital defects, therefore diabetes type 1 is one of the highest known teratogenic risk factor. The main factor responsible for the development of congenital defects is hyperglycemia. Observed are congenital defects of the central nervous system, the bones, urinary and digestive tract. Characteristic is macrosomia. Observed are hypocalcemia, hypomagnesemia, polycythemia, hyperbilirubinemia, hypertrophic cardiomyopathy, respiratory disturbances. Children from families with diabetes type 1 are at high risk for the development of the disease in the newborn period, additional diseases. They must be in permanent medical control.

  3. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.

    Science.gov (United States)

    Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

    2007-11-01

    Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.

  4. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development

    OpenAIRE

    Gustafsson, Sofia

    2012-01-01

    Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis. In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentr...

  5. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials

    OpenAIRE

    Lynch, Mary E; Campbell, Fiona

    2011-01-01

    Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabi...

  6. SWGELLA DYSENTERIAE TYPE 1 IN KwAZuLU-NATAL

    African Journals Online (AJOL)

    -control. 1995: 15. ure co. LABORATORY SURV~ILLAN.CEOF. SWGELLA DYSENTERIAE TYPE 1 IN. KwAZuLU- ... freeze-dried quality-eontrol specimens were prepared containing ... (National Committee for Clinical Laboratory Standards,.

  7. Type 1 or Type 2 Diabetes and Pregnancy

    Science.gov (United States)

    ... and Pregnancy Articles Type 1 or Type 2 Diabetes and Pregnancy Language: English (US) Español (Spanish) Recommend on Facebook Tweet Share Compartir Problems of Diabetes in Pregnancy Blood sugar that is not well ...

  8. Fertility treatment and childhood type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Kettner, Laura Ozer; Matthiesen, Niels Bjerregaard; Ramlau-Hansen, Cecilia Høst

    2016-01-01

    OBJECTIVE: To investigate the association between specific types of fertility treatment and childhood type 1 diabetes mellitus. DESIGN: Nationwide birth cohort study. SETTING: Not applicable. PATIENT(S): All pregnancies resulting in a live-born singleton child in Denmark from 1995 to 2003....... INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Childhood type 1 diabetes mellitus identified from redeemed prescriptions for insulin until 2013. RESULT(S): The study included 565,116 singleton pregnancies. A total of 14,985 children were conceived by ovulation induction or intrauterine insemination......, and 8,490 children were conceived by in vitro fertilization or intracytoplasmic sperm injection. During the follow-up period, 2,011 (0.4%) children developed type 1 diabetes mellitus. The primary analyses showed no association between fertility treatment and childhood type 1 diabetes mellitus...

  9. On Generalized Type 1 Logistic Distribution | Ahsanullah | Afrika ...

    African Journals Online (AJOL)

    Some distributional properties of the generalized type 1 logistic distribution are given. Based on these distributional property a characterization of this distribution is presented. Key words: Conditional Expectation; Reversed Hazard Rate; Characterization.

  10. Metabolomic Biomarkers in the Progression to Type 1 Diabetes

    DEFF Research Database (Denmark)

    Overgaard, Anne Julie; Kaur, Simranjeet; Pociot, Flemming

    2016-01-01

    diabetes has been studied using this technique, although in relatively small cohorts and at limited time points. Overall, three observations have been consistently reported; phospholipids at birth are lower in children developing type 1 diabetes early in childhood, methionine levels are lower in children......Metabolomics is the snapshot of all detectable metabolites and lipids in biological materials and has potential in reflecting genetic and environmental factors contributing to the development of complex diseases, such as type 1 diabetes. The progression to seroconversion to development of type 1...... at seroconversion, and triglycerides are increased at seroconversion and associated to microbiome diversity, indicating an association between the metabolome and microbiome in type 1 diabetes progression....

  11. Epidemiology of type 1 (insulin-dependent) diabetes mellitus

    DEFF Research Database (Denmark)

    Green, Anders

    1999-01-01

    Recent estimates suggest that more than 100,000 inhabitants in the Middle East suffer from type 1 diabetes and that about 6000 subjects in the region develop the disease each year. This paper illustrates how epidemiological principles and methods may assist in a rational assessment of the public...... health impact of type 1 diabetes in the Middle East. Making a series of assumptions, it is estimated that the future prevalence of type 1 diabetes in the region will increase slightly, but that the increase may be more pronounced if the disease incidence is increasing and the prognosis improved....... It is recommended that more valid information is established on the basic epidemiological features of type 1 diabetes in the Middle East, as this will provide the basis of more rational planning of the current and future diabetes healthcare in the region....

  12. Long-term mortality and retinopathy in type 1 diabetes

    DEFF Research Database (Denmark)

    Grauslund, Jakob

    2010-01-01

    The incidence of type 1 diabetes is increasing in Denmark as well as the rest of the world. Due to diabetes-related micro- and macrovascular complications, the morbidity and the mortality is higher among type 1 diabetic patients. The aim of this thesis was to examine a population-based cohort...... of 727 type 1 diabetic patients from Fyn County, Denmark, with an onset of diabetes before 1 July 1973 in order to: (1) Evaluate the all-cause mortality rates and the influence of sex, duration of diabetes and calendar year of diagnosis in a 33-year follow-up (Paper I). (2) Examine glycaemic regulation...... of DR was graded higher in the digital photos. Among these, PDR was detected in three eyes using digital photos but remained undetected on all films. This suggests that digital photos with wide fields are the best way to detect DR in long-term type 1 diabetic patients. Overall, it is concluded...

  13. Interleukin-1 antagonism in type 1 diabetes of recent onset

    DEFF Research Database (Denmark)

    Moran, Antoinette; Bundy, Brian; Becker, Dorothy J

    2013-01-01

    Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1...... antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes....

  14. Omkostningseffektivitet ved behandling af type 1-diabetes med insulinpumpe

    DEFF Research Database (Denmark)

    Nørgaard, Kirsten; Sohlberg, Anna; Goodall, Gordan

    2010-01-01

    This study's aim was to project the long-term clinical and economic outcomes of continuous subcutaneous insulin infusion (CSII) treatment compared to multiple daily injections (MDI) in type 1 diabetes patients in Denmark.......This study's aim was to project the long-term clinical and economic outcomes of continuous subcutaneous insulin infusion (CSII) treatment compared to multiple daily injections (MDI) in type 1 diabetes patients in Denmark....

  15. Candidate PET radioligands for cannabinoid CB1 receptors: [18F]AM5144 and related pyrazole compounds

    International Nuclear Information System (INIS)

    Li Zizhong; Gifford, Andrew; Liu Qian; Thotapally, Rajesh; Ding Yushin; Makriyannis, Alexandros; Gatley, S. John

    2005-01-01

    Introduction: The mammalian brain contains abundant G protein-coupled cannabinoid CB 1 receptors that respond to Δ 9 -tetrahydrocannabinol, the active ingredient of cannabis. The availability of a positron emission tomography (PET) radioligand would facilitate studies of the addictive and medicinal properties of compounds that bind to this receptor. Among the known classes of ligands for CB 1 receptors, the pyrazoles are attractive targets for radiopharmaceutical development because they are antagonists and are generally less lipophilic than the other classes. Methods: A convenient high-yield synthesis of N-(4-[ 18 F]fluorophenyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)- 1H-pyrazole-3-carboxamide (AM5144) was devised by coupling the appropriate pyrazole-3-carboxyl chloride compound with 4-[ 18 F]fluoroaniline. The labeled precursor was synthesized from 1-[ 18 F]fluoro-4-nitrobenzene in 60% radiochemical yield for 10 min using an improved procedure involving sodium borohydride reduction with cobalt chloride catalysis. The product was purified by HPLC to give a specific activity >400 mCi/μmol and a radiochemical purity >95%, and a PET study was conducted in a baboon. Results: Although the regional uptake of AM5144 in baboon brain was consistent with binding to cannabinoid CB 1 receptors, absolute uptake at 1 receptor ligands is not surprising because of their high lipophilicity as compared with most brain PET radiotracers. However, for nine pyrazole compounds for which rodent data are available, brain uptake and calculated logP values are not correlated. Thus, high logP values should not preclude evaluation of radiotracers for targets such as the CB 1 receptor that may require very lipophilic ligands

  16. Longterm visual prognosis in Usher syndrome types 1 and 2.

    Science.gov (United States)

    Sadeghi, André M; Eriksson, Kristina; Kimberling, William J; Sjöström, Anders; Möller, Claes

    2006-08-01

    To estimate the age at diagnosis of retinitis pigmentosa and to determine visual acuity deterioration, visual field impairment and the frequency of cataracts in Usher syndrome types 1 and 2. We carried out a retrospective study of 328 affected subjects with Usher syndrome types 1 and 2. Study subjects were divided into seven different age groups by decade. Data were analysed using descriptive statistics, general linear model anova and survival analysis. Retinitis pigmentosa was diagnosed significantly earlier in subjects with Usher syndrome type 1 than in those with type 2. Visual acuity was significantly more impaired in affected subjects with Usher syndrome type 1 than in those with type 2 from 50 years of age onwards. Survival analysis revealed a significant difference in visual field loss (type 2 subjects tending to be more impaired, while comparison indicated no significant differences between the groups in any of the other visual field categories. Cataract was found to be generally more common in Usher syndrome type 1 than type 2. Progressive loss of visual acuity and visual field begins to be substantial between the second and third decades of life in both Usher types. The rate of degeneration varies between individuals in both groups. The data are useful for the counselling of affected subjects with Usher syndrome types 1 and 2.

  17. Are cannabinoids effective for Parkinson’s disease?

    Directory of Open Access Journals (Sweden)

    Gonzalo A Bravo-Soto

    2017-06-01

    Full Text Available Resumen Se postula que los cannabinoides pudieran tener beneficios en la enfermedad de Parkinson. No obstante, su real efectividad clínica aún es discutida. Para responder a esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos seis revisiones sistemáticas que en conjunto incluyen ocho estudios, de los cuales cuatro corresponden a ensayos aleatorizados. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que los cannabinoides probablemente no disminuyen los síntomas ni las discinesias, y se asocian a efectos adversos frecuentes en pacientes con enfermedad de Parkinson

  18. The Wide and Unpredictable Scope of Synthetic Cannabinoids Toxicity

    Directory of Open Access Journals (Sweden)

    Jose Orsini

    2015-01-01

    Full Text Available Drug use and abuse continue to be a large public health concern worldwide. Over the past decade, novel or atypical drugs have emerged and become increasingly popular. In the recent past, compounds similar to tetrahydrocannabinoid (THC, the active ingredient of marijuana, have been synthetically produced and offered commercially as legal substances. Since the initial communications of their abuse in 2008, few case reports have been published illustrating the misuse of these substances with signs and symptoms of intoxication. Even though synthetic cannabinoids have been restricted, they are still readily available across USA and their use has been dramatically increasing, with a concomitant increment in reports to poison control centers and emergency department (ED visits. We describe a case of acute hypoxemic/hypercapnic respiratory failure as a consequence of acute congestive heart failure (CHF developed from myocardial stunning resulting from a non-ST-segment elevation myocardial infarction (MI following the consumption of synthetic cannabinoids.

  19. Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

    Directory of Open Access Journals (Sweden)

    Despina Kokona

    2016-01-01

    Full Text Available The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP. This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

  20. Rhabdomyolysis and Renal Insufficiency Due to Synthetic Cannabinoid Intoxication

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    Semiha Orhan

    2017-12-01

    Full Text Available Bonsai is the street name of synthetic marijuana, which is a psychoactive substance. Since synthetic cannabinoids are easily accessible and cheap, their use is becoming widespread day by day. It can cause not only various clinical symptoms but also severe rhabdomyolysis. In this case, with severe rhabdomyolysis, we tried to discuss the treatment challenges of the patient examined in intensive care unit with the history of bonsai use.

  1. Overvej cannabinoid hyperemesis-syndrom ved recidiverende opkastninger

    DEFF Research Database (Denmark)

    Nordholm-Carstensen, Andreas

    2014-01-01

    Cannabinoid hyperemesis syndrome (CHS) is characterised by unrelenting nausea, recurrent vomiting, abdominal pain and compulsive, hot bathing behaviour. The symptoms contrast the traditional effects associated with cannabis use. We report a "textbook example" of a 26-year-old man with CHS. CHS...... is an important differential diagnosis to consider in patients with similar symptoms and the distinctive symptom relief in hot water. Early recognition may prevent extensive, unnecessary medical examinations and frequent hospital admissions....

  2. Cannabinoid-like anti-inflammatory compounds from flax fiber.

    Science.gov (United States)

    Styrczewska, Monika; Kulma, Anna; Ratajczak, Katarzyna; Amarowicz, Ryszard; Szopa, Jan

    2012-09-01

    Flax is a valuable source of fibers, linseed and oil. The compounds of the latter two products have already been widely examined and have been proven to possess many health-beneficial properties. In the course of analysis of fibers extract from previously generated transgenic plants overproducing phenylpropanoids a new terpenoid compound was discovered.The UV spectra and the retention time in UPLC analysis of this new compound reveal similarity to a cannabinoid-like compound, probably cannabidiol (CBD). This was confirmed by finding two ions at m/z 174.1 and 231.2 in mass spectra analysis. Further confirmation of the nature of the compound was based on a biological activity assay. It was found that the compound affects the expression of genes involved in inflammatory processes in mouse and human fibroblasts and likely the CBD from Cannabis sativa activates the specific peripheral cannabinoid receptor 2 (CB2) gene expression. Besides fibers, the compound was also found in all other flax tissues. It should be pointed out that the industrial process of fabric production does not affect CBD activity.The presented data suggest for the first time that flax products can be a source of biologically active cannabinoid-like compounds that are able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties.

  3. Pharmacological effects of cannabinoids on learning and memory in Lymnaea.

    Science.gov (United States)

    Sunada, Hiroshi; Watanabe, Takayuki; Hatakeyama, Dai; Lee, Sangmin; Forest, Jeremy; Sakakibara, Manabu; Ito, Etsuro; Lukowiak, Ken

    2017-09-01

    Cannabinoids are hypothesized to play an important role in modulating learning and memory formation. Here, we identified mRNAs expressed in Lymnaea stagnalis central nervous system that encode two G-protein-coupled receptors ( Lymnaea CBr-like 1 and 2) that structurally resemble mammalian cannabinoid receptors (CBrs). We found that injection of a mammalian CBr agonist WIN 55,212-2 (WIN 55) into the snail before operant conditioning obstructed learning and memory formation. This effect of WIN 55 injection persisted for at least 4 days following its injection. A similar obstruction of learning and memory occurred when a severe traumatic stimulus was delivered to L. stagnalis In contrast, injection of a mammalian CBr antagonist AM 251 enhanced long-term memory formation in snails and reduced the duration of the effects of the severe traumatic stressor on learning and memory. Neither WIN 55 nor AM 251 altered normal homeostatic aerial respiratory behaviour elicited in hypoxic conditions. Our results suggest that putative cannabinoid receptors mediate stressful stimuli that alter learning and memory formation in Lymnaea This is also the first demonstration that putative CBrs are present in Lymnaea and play a key role in learning and memory formation. © 2017. Published by The Company of Biologists Ltd.

  4. Atrial Natriuretic Peptide (ANP) in early pregnancy is associated with development of preeclampsia in type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lene Ringholm; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2011-01-01

    The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting...... that preeclampsia is associated with cardiovascular changes in early pregnancy....

  5. Oral-facial-digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum

    NARCIS (Netherlands)

    Bouman, Arjan; Alders, Mariëlle; Oostra, Roelof Jan; van Leeuwen, Elisabeth; Thuijs, Nikki; van der Kevie-Kersemaekers, Anne-Marie; van Maarle, Merel

    2017-01-01

    Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is

  6. Cannabinoid receptor CB2 modulates axon guidance

    DEFF Research Database (Denmark)

    Duff, Gabriel; Argaw, Anteneh; Cecyre, Bruno

    2013-01-01

    on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2 (-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted...... CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R....

  7. Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient.

    Science.gov (United States)

    Laohathai, Christopher; Weber, Daniel J; Hayat, Ghazala; Thomas, Florian P

    2016-02-01

    Chronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection. A 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV-1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up. Chronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes.

  8. Molecular Mechanisms of Cannabis Signaling in the Brain.

    Science.gov (United States)

    Ronan, Patrick J; Wongngamnit, Narin; Beresford, Thomas P

    2016-01-01

    Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative. Copyright © 2016. Published by Elsevier Inc.

  9. Insulin gene therapy for type 1 diabetes mellitus.

    Science.gov (United States)

    Handorf, Andrew M; Sollinger, Hans W; Alam, Tausif

    2015-04-01

    Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or whole pancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.

  10. Efecto neuroprotector de los cannabinoides en las enfermedades neurodegenerativas

    Directory of Open Access Journals (Sweden)

    Carlos Suero-García

    2015-01-01

    Full Text Available Objetivos: Se analiza la situación actual de las investigaciones relacionadas con las sustancias cannabinoides, así como su interacción con el organismo, clasificación, efectos terapéuticos y su uso en las enfermedades neurodegenerativas. Métodos: Se realiza una exhaustiva revisión bibliográfica relacionada con las sustancias cannabinoides y sus derivados sintéticos, haciendo especial hincapié en la forma de interactuar con el organismo y los efectos que provocan dichas interacciones. Concretamente, se estudiarán sus efectos neuroantiinflamatorio y analgésico lo que conlleva al efecto neuroprotector en enfermedades neurodegenerativas tales como Alzheimer, Parkinson, Huntington, esclerosis múltiple y esclerosis lateral amiotrófica. Resultados: Desde hace miles de años la planta Cannabis Sativa ha sido utilizada por muchas culturas con distintos fines, de ocio, textiles, analgésicos, pero no es hasta finales del siglo XX cuando se empieza a incentivar los estudios científicos relacionados con ésta. La planta posee una mezcla de unos 400 componentes, de los cuales 60 pertenecen al grupo de los cannabinoides siendo los principales el cannabinol, cannabidiol y tetrahidrocannabinol. Con el descubrimiento de las sustancias cannabinoides, sus derivados, y los receptores que interactúan, se amplían las posibilidades terapéuticas teniendo un especial interés el efecto neuroprotector que estas sustancias contienen. Conclusiones. Se ha demostrado el gran potencial de los cannabinoides como sustancias terapéuticas más allá de su uso analgésico o antiemético, esto es, en enfermedades neurodegenerativas en las que pueden no solo disminuir los síntomas, sino frenar el proceso de la enfermedad. Otra posible aplicación puede ser en el campo oncológico, siendo particularmente intensa la actividad investigadora realizada en los últimos 15 años.

  11. A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

    Directory of Open Access Journals (Sweden)

    Anene Ukaigwe

    2014-01-01

    Full Text Available Cannabinoid Hyperemesis Syndrome (CHS was first described in 2004. Due to its novelty, CHS is often unrecognized by clinicians leading to expensive workup of these patients with cyclical symptoms. It may take up to 9 years to diagnose CHS. CHS is characterized by cyclical nausea and vomiting, abdominal pain, and an unusual compulsion to take hot showers in the presence of chronic use of cannabinoids. Cannabicyclohexanol is a synthetic cannabinoid, popularly known as K2 spice. It is a popular marijuana alternative among teenagers and young adults since it is readily available as herbal incense. Unlike marijuana, many users know that K2 is not detected in conventional urine drug screens, allowing those users to conceal their intake from typical detection methods. Serum or urine gas chromatography mass spectrophotometry is diagnostic, though not widely available. Thus, it is imperative for clinicians to recognize CHS, even with negative UDS, to provide cost-effective care. We present a 38-year-old man with a 10-year history of cannabis, and 1-year history of K2 abuse admitted with 1-week history of episodes of nausea, vomiting of clear fluids, and epigastric discomfort. Symptoms are relieved only by hot showers. Extensive laboratory, radiologic, and endoscopic evaluation was unrevealing. CHS was diagnosed, based on proposed criteria by Simonetti et al.

  12. Early cannabinoid exposure influences neuroendocrine and reproductive functions in male mice: I. Prenatal exposure.

    Science.gov (United States)

    Dalterio, S; Steger, R; Mayfield, D; Bartke, A

    1984-01-01

    Maternal exposure to delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent in marihuana, or to the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) alters endocrine functions and concentrations of brain biogenic amines in their male offspring. Prenatal CBN exposure on day 18 of gestation resulted in decreased plasma FSH levels, testicular testosterone (T) concentrations, and seminal vesicles weights, but increased plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) post-castration in adulthood. Prenatal exposure to THC significantly enhanced the responsiveness of the testes to intratesticular LH injection in vivo and tended to increase human chorionic gonadotropin (hCG)-stimulated T production by decapsulated testes in vitro. In the CBN-exposed mice, hCG-stimulated T production was enhanced, while CBD exposure had no effect. Prenatal THC exposure altered the negative feedback effects of exogenous gonadal steroids in castrated adults, with lower plasma T and FSH levels after 20 micrograms T than in castrated controls. In contrast, CBD-exposed mice had higher levels of LH in plasma post-castration. In CBN-exposed adults, two weeks post-castration the concentration of norepinephrine (NE) and dopamine (DA) in hypothalamus and remaining brain were reduced, while levels of serotonin (5-HT) and its metabolite, 5-HIAA, were elevated compared to that in castrated OIL-controls. Prenatal CBD-exposure also reduced NE and elevated 5-HT and 5-HIAA, but did not affect DA levels post-castration. Concentrations of brain biogenic amines were not influenced by prenatal THC exposure in the present study. A single prenatal exposure to psychoactive or non-psychoactive components of marihuana results in long term alterations in the function of the hypothalamo-pituitary-gonadal axis. Changes in the concentrations of brain biogenic amines may be related to these effects of prenatal cannabinoids on endocrine function in adult male mice.

  13. Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.

    Science.gov (United States)

    Busquets-Garcia, Arnau; Gomis-González, Maria; Srivastava, Raj Kamal; Cutando, Laura; Ortega-Alvaro, Antonio; Ruehle, Sabine; Remmers, Floortje; Bindila, Laura; Bellocchio, Luigi; Marsicano, Giovanni; Lutz, Beat; Maldonado, Rafael; Ozaita, Andrés

    2016-08-30

    Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH(+) cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.

  14. Glutaric aciduria type 1--importance of early diagnosis and treatment.

    Science.gov (United States)

    Afroze, Bushra; Yunus, Zabedah Mohammad

    2014-05-01

    Glutaric aciduria type 1 is a rare inherited organic academia. Untreated patients characteristically develop dystonia secondary to striatal injury during early childhood, which results in high morbidity and mortality. In patients diagnosed during neonatal period, striatal injury can be prevented by metabolic treatment including low lysine diet, carnitine supplementation and aggressive emergency treatment during acute episode of inter current illnesses. However, after the onset of neurological damage initiation of treatment is generally not effective. Therefore; glutaric aciduria type 1 is included in newborn screening panel for inherited metabolic diseases in many countries. We describe two children in a family with glutaric aciduria type 1 and their different long term outcomes. The first child was diagnosed late leading to severe neurological damage. The second child was diagnosed in the neonatal period as a result of selective high-risk screening and was treated appropriately giving a normal growth.

  15. Adolescents developing life skills for managing type 1 diabetes

    DEFF Research Database (Denmark)

    Husted, Gitte R; Esbensen, Bente Appel; Hommel, Eva

    2014-01-01

    AIM: To explore and illustrate how the Guided Self-Determination-Youth method influences the development of life skills in adolescents with type 1 diabetes supported by their parents and healthcare providers. BACKGROUND: Evidence-based methods that accomplish constructive cooperation between...... adolescents with poorly controlled type 1 diabetes, their parents and healthcare providers are needed. We adjusted an adult life skills intervention comprising reflection sheets and advanced communication for use by adolescent-parent-professional triads in outpatient visits. DESIGN: A qualitative realistic...... with type 1 diabetes for ≥1 year and having poor glycaemic control participated together with 17 parents and eight healthcare providers. Data were collected from December 2009-March 2012 and consisted of digitally recorded outpatient Guide Self-Determination-Youth visits collected during the intervention...

  16. ARX MPC for people with type 1 diabetes

    DEFF Research Database (Denmark)

    Boiroux, Dimitri; Finan, Daniel Aaron; Jørgensen, John Bagterp

    Type 1 diabetes is a chronic disease characterized by a lack of production of pancreatic insulin, consequently leading to high blood glucose concentrations (hyperglycemia). Hyperglycemia has negative health effects in the long term such as eye, nerve, and kidney disease. Exogenous insulin must......, or even death. Currently, insulin administration is performed by the subject with type 1 diabetes based on infrequent glucose measurements (in the form of finger-sticks), often resulting in an unsatisfactory blood glucose control. An artificial pancreas is a medical device that injects exogenous insulin...... and insulin injection information to compute the optimal insulin administration for the current conditions. We use model predictive control (MPC) to compute the optimal insulin administration for 20 virtual type 1 diabetes subjects. The system (i.e., subject) has one manipulated input (insulin infusion rate...

  17. The pregnancy journey for women with type 1 diabetes

    DEFF Research Database (Denmark)

    Edwards, Helen; Speight, Jane; Bridgman, Heather

    2016-01-01

    The purpose of this study is to describe and develop a model of the pregnancy journey for women with type 1 diabetes. We undertook a thematic analysis of written interactions (n = 200; n = 2060 text excerpts) with an online counselling support service from 93 women with type 1 diabetes. Seven...... reassurance during Pregnancy; however, some women still worried, with peer support offering the most reassurance. In conclusion, women with type 1 diabetes potentially experience seven distinct phases of the pregnancy journey, with eight themes varying in significance across phases. Contemplation begins well...... possible discrete phases in the pregnancy journey were revealed: Contemplation, Pregnancy planning, Conception, Pregnancy, Delivery/birth, and Motherhood or Pregnancy loss. Eight common themes were identified, varying in importance across phases. Diabetes-specific distress was most evident during...

  18. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Pramming, Stig; Heller, Simon R

    2004-01-01

    BACKGROUND: Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate...... the influence of risk markers, clinical setting and selection. METHODS: Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe......, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. CONCLUSION: Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers...

  19. Hypoglycaemia during pregnancy in women with Type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lene Ringholm; Pedersen-Bjergaard, U; Thorsteinsson, B

    2012-01-01

    Diabet. Med. 29, 558-566 (2012) ABSTRACT: Aims To explore incidence, risk factors, possible pathophysiological factors and clinical management of hypoglycaemia during pregnancy in women with Type 1 diabetes. Methods Literature review. Results In women with Type 1 diabetes, severe hypoglycaemia......% of the pregnant women account for 60% of all recorded events. Risk factors for severe hypoglycaemia during pregnancy include a history with severe hypoglycaemia in the year preceding pregnancy, impaired hypoglycaemia awareness, long duration of diabetes, low HbA(1c) in early pregnancy, fluctuating plasma glucose...... should have high priority among clinicians with the persistent aim of improving pregnancy outcome among women with Type 1 diabetes. Pre-conception counselling, carbohydrate counting, use of insulin analogues, continuous subcutaneous insulin infusion (insulin pump) therapy and real-time continuous glucose...

  20. New technologies in the treatment of type 1 diabetes

    DEFF Research Database (Denmark)

    Schmidt, Signe

    2013-01-01

    Type 1 diabetes is a chronic condition characterized by insufficient production of insulin, a hormone needed for proper control of blood glucose levels. People with type 1 diabetes must monitor their blood glucose throughout the day using a glucose meter or a continuous glucose monitor, calculate...... how much insulin is needed to maintain normal blood glucose levels, and administer the insulin dose by pen injection or insulin pump infusion into the subcutaneous tissue. In recent years, several new technologies for the treatment of type 1 diabetes have been developed. This PhD thesis covers two...... studies of the effects of commercially available technologies--sensor-augmented pump therapy and automated insulin bolus calculators--when used in clinical practice. Both studies demonstrated that these technologies have the potential to improve diabetes care. In addition, two in-clinic studies related...

  1. Type 1 Tyrosinemia with Hypophosphatemic Rickets; a Case Report

    Directory of Open Access Journals (Sweden)

    Peyman Eshraghi

    2014-09-01

    Full Text Available Background: Tyrosinemia type 1 is an autosomal recessive metabolic disorder, which typically affects liver and kidneys. It is caused by a defect in fumarylacetoacetate hydrolase or fumarylacetoacetase (FAH enzyme, the final enzyme in the tyrosine degradation pathway. The disease typically manifests as early onset type in early infancy with acute hepatic crisis with hepatomegaly and bleeding tendency. In 1992, a new drug orfadin (NTBC, Nitisinone which is a potent inhibitor of 4 hydroxy phenyl pyrovate dioxygenase has revolutionized the treatment of tyrosinemia type 1 and is now the mainstry of therapy. Case presentation: Our case was a girl in midchidhood period with profound rickets and slowly progressing liver disease who presented with difficulty walking and weakness of muscles. She had an elevated serum tyrosine and urinary succinylacetone, which confirmed the diagnosis of tyrosinemia type 1 and after treatment with NTBC significant remission, was achieved.

  2. Hand functions in type 1 and type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Akpinar Pinar

    2017-01-01

    Full Text Available Introduction/Objective. Hand functions have an enormous impact on activities of daily living in patients with diabetes mellitus (DM, such as self-care, administering insulin injections, and preparing and eating meals. The aim of the study was to evaluate hand functions and grip strength in patients with type 1 and type 2 DM. Methods. This was an observational case-control study investigating the hand functions and grip strength in patients with type 1 and type 2 DM. The study comprised 41 patients with type 1 DM aged 25–50 years sex- and age-matched, 40 non-diabetic controls, and 91 patients with type 2 DM aged 40–65 years sex- and age-matched 60 non-diabetic controls. Patients with documented history of diabetic sensorimotor neuropathy and adhesive capsulitis were excluded. The Duruoz Hand Index was used to assess the functional hand disability. Grip strength was tested with a calibrated Jamar dynamometer. Results. The Duruoz Hand Index scores in patients with type 2 DM were significantly higher than in persons in the control group (p 0.05. Grip strength values of patients with type 1 DM were significantly lower compared to those in the control group (p < 0.05, whereas there was no significant difference between patients with type 2 DM and their control group. There was a negatively significant correlation between grip strength and the Duruoz Hand Index scores in patients with both type 1 and type 2 DM (p < 0.05. Conclusion. Patients with type 1 DM and type 2 DM have different degrees of hand disability as compared to healthy control groups.

  3. Metabolomics and bioanalysis of terpenoid derived secondary metabolites : Analysis of Cannabis sativa L. metabolite production and prenylases for cannabinoid production

    NARCIS (Netherlands)

    Muntendam, Remco

    2015-01-01

    Cannabinoid research has gained a renenewed interest by both the public and scientist. Focus is mainly directed to the medicinal activities, as reported for various cannabinoid structures. This thesis focusses on prenyl-derived secondary metabolites with main focus on cannabinoids. Firstly the

  4. Cannabinoid Receptor Type 2, but Not Type 1, Is Up-Regulated in Peripheral Blood Mononuclear Cells of Children Affected by Autistic Disorders

    Science.gov (United States)

    Siniscalco, Dario; Sapone, Anna; Giordano, Catia; Cirillo, Alessandra; de Magistris, Laura; Rossi, Francesco; Fasano, Alessio; Bradstreet, James Jeffrey; Maione, Sabatino; Antonucci, Nicola

    2013-01-01

    Autistic disorders (ADs) are heterogeneous neurodevelopmental disorders arised by the interaction of genes and environmental factors. Dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours are common features of ADs. There are no defined mechanisms of pathogenesis, rendering…

  5. Confirmation of novel type 1 diabetes risk loci in families

    DEFF Research Database (Denmark)

    Cooper, J D; Howson, J M M; Smyth, D

    2012-01-01

    Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we......, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study....

  6. US Army Soldiers With Type 1 Diabetes Mellitus.

    Science.gov (United States)

    Choi, Y Sammy; Cucura, Jon

    2018-04-01

    US Army soldiers diagnosed with type 1 diabetes were previously considered unfit for duty. For highly motivated soldiers, current advanced technologies allow the possibility of not only retention on active duty, but military deployment. We present our experience at Fort Bragg, North Carolina, taking care of soldiers newly diagnosed with type 1 diabetes mellitus. Through intensive diabetes education, extensive military and physical training, optimization of diabetes technology, and remote real-time monitoring, soldiers are able to continue to serve their country in the most specialized roles.

  7. A Quasi-Type-1 Phase-Locked Loop Structure

    DEFF Research Database (Denmark)

    Golestan, Saeed; Fernandez, Francisco Daniel Freijedo; Vidal, Ana

    2014-01-01

    The grid voltage phase and frequency are crucial information in control of most grid connected power electronic based equipment. Most often, a phase-locked loop (PLL) is employed for this purpose. A PLL is a closed-loop feedback control system that the phase of its output signal is related...... to the phase of its input signal. Arguably, the simplest PLL is a type-1 PLL. The type-1 PLLs are characterized by having only one integrator in their control loop and therefore having a high stability margin. However, they suffer from a serious drawback: they cannot achieve zero average steady-state phase...

  8. 76 FR 11075 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2011-03-01

    ... constituent of marijuana. ``Synthetic cannabinoids'' are a large family of chemically unrelated structures functionally (biologically) similar to THC, the active principle of marijuana. Two of the five synthetic...-like synthetic cannabinoids are perceived as ``legal'' alternatives to marijuana despite the fact that...

  9. Cannabinoids for Medical Use A Systematic Review and Meta-analysis

    NARCIS (Netherlands)

    Whiting, Penny F.; Wolff, Robert F.; Deshpande, Sohan; Di Nisio, Marcello; Duffy, Steven; Hernandez, Adrian V.; Keurentjes, J. Christiaan; Lang, Shona; Misso, Kate; Ryder, Steve; Schmidlkofer, Simone; Westwood, Marie; Kleijnen, Jos

    2015-01-01

    IMPORTANCE Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES Twenty-eight databases from

  10. Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Christoph W Michalski

    2008-02-01

    Full Text Available While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC are unknown.The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP tissues. In vitro, effects of blockade and activation of cannabinoid receptors on pancreatic stellate cells were characterized. In CP, cannabinoid receptors were detected predominantly in areas with inflammatory changes, stellate cells and nerves. Levels of endocannabinoids were decreased compared with normal pancreas. Cannabinoid-receptor-1 antagonism effectuated a small PSC phenotype and a trend toward increased invasiveness. Activation of cannabinoid receptors, however, induced de-activation of PSC and dose-dependently inhibited growth and decreased IL-6 and MCP-1 secretion as well as fibronectin, collagen1 and alphaSMA levels. De-activation of PSC was partially reversible using a combination of cannabinoid-receptor-1 and -2 antagonists. Concomitantly, cannabinoid receptor activation specifically decreased invasiveness of PSC, MMP-2 secretion and led to changes in PSC phenotype accompanied by a reduction of intracellular stress fibres.Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis.

  11. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity

    NARCIS (Netherlands)

    Campolongo, P.; Morena, M.; Scaccianoce, S.; Trezza, V.; Chiarotti, F.; Schelling, G.; Cuomo, V.; Roozendaal, B.

    2013-01-01

    Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2

  12. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

    Science.gov (United States)

    McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

    2015-06-01

    As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Understanding the Growing Threat of Synthetic Cannabinoids and Its Implications on University-Based Counselors

    Science.gov (United States)

    Golubovic, Nedeljko; Dew, Brian J.

    2017-01-01

    The rise in synthetic cannabinoid use has been one of the nation's most alarming drug-related trends. Considering the popularity of use among young adults, college counselors are likely to be among the 1st professionals to treat clients who use these drugs. In this article, the unique aspects of synthetic cannabinoids are reviewed, implications…

  15. Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

    Science.gov (United States)

    Xu, Yuanzhong; Tong, Qingchun

    2017-07-01

    Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Cannabis, Cannabinoids, and Cerebral Metabolism: Potential Applications in Stroke and Disorders of the Central Nervous System.

    Science.gov (United States)

    Latorre, Julius Gene S; Schmidt, Elena B

    2015-09-01

    No compound has generated more attention in both the scientific and recently in the political arena as much as cannabinoids. These diverse groups of compounds referred collectively as cannabinoids have both been vilified due to its dramatic and potentially harmful psychotropic effects and glorified due to its equally dramatic and potential application in a number of acute and chronic neurological conditions. Previously illegal to possess, cannabis, the plant where natural form of cannabinoids are derived, is now accepted in a growing number of states for medicinal purpose, and some even for recreational use, increasing opportunities for more scientific experimentation. The purpose of this review is to summarize the growing body of literature on cannabinoids and to present an overview of our current state of knowledge of the human endocannabinoid system in the hope of defining the future of cannabinoids and its potential applications in disorders of the central nervous system, focusing on stroke.

  17. Leprosy type 1 reactions and erythema nodosum leprosum

    OpenAIRE

    Kahawita,Indira P.; Walker,Stephen L.; Lockwood,Diana N.J.

    2008-01-01

    Leprosy reactions are a major cause of nerve damage and morbidity in a significant proportion of leprosy patients. Reactions are immunologically mediated and can occur even after successful completion of multi-drug therapy. This review focuses on the epidemiology, pathology and treatment of leprosy type 1 reactions, erythema nodosum leprosum and silent neuropathy.

  18. Isolation of Ancestral Sylvatic Dengue Virus Type 1, Malaysia

    Science.gov (United States)

    Teoh, Boon-Teong; Sam, Sing-Sin; Abd-Jamil, Juraina

    2010-01-01

    Ancestral sylvatic dengue virus type 1, which was isolated from a monkey in 1972, was isolated from a patient with dengue fever in Malaysia. The virus is neutralized by serum of patients with endemic DENV-1 infection. Rare isolation of this virus suggests a limited spillover infection from an otherwise restricted sylvatic cycle. PMID:21029545

  19. Improving School Experiences for Adolescents with Type 1 Diabetes

    Science.gov (United States)

    Kise, Saori S.; Hopkins, Amanda; Burke, Sandra

    2017-01-01

    Background: Diabetes mellitus (diabetes) is one of the most common metabolic diseases in children worldwide and the incidence of type 1 diabetes (T1D) is growing. T1D is complicated to manage and adolescents with diabetes face unique, age-specific challenges. The purpose of this article is to discuss ways in which schools can create a positive…

  20. Peptide and protein biomarkers for type 1 diabetes mellitus

    Science.gov (United States)

    Zhang, Qibin; Metz, Thomas O.

    2016-08-30

    A method for identifying persons with increased risk of developing type 1 diabetes mellitus, or having type I diabetes mellitus, utilizing selected biomarkers described herein either alone or in combination. The present disclosure allows for broad based, reliable, screening of large population bases. Also provided are arrays and kits that can be used to perform such methods.

  1. Caring for Students with Type 1 Diabetes: School Nurses' Experiences

    Science.gov (United States)

    Wang, Yueh-Ling; Volker, Deborah L.

    2013-01-01

    This qualitative study used a Husserlian phenomenological approach to obtain an understanding of the essences of five experienced Taiwanese school nurses' lived experience of caring for students with type 1 diabetes mellitus (T1DM). Audio-recorded, semi-structured, in-depth interviews were conducted. Data analysis entailed a modified method from…

  2. Determinants of daily insulin use in Type 1 diabetes

    NARCIS (Netherlands)

    Muis, Marian J.; Bots, Michiel L.; Bilo, Henk J. G.; Hoogma, Roel P. L. M.; Hoekstra, Joost B. L.; Grobbee, Diederick E.; Stolk, Ronald P.

    2006-01-01

    OBJECTIVE: Insulin need for a given degree of glucose control varies markedly among individuals. We examined which factors determine daily insulin use in patients with Type 1 diabetes. METHODS: A cross-sectional study was performed in 416 patients. Clinical parameters, medication use, physical

  3. Antigenic variation and resistance to neutralization in poliovirus type 1.

    NARCIS (Netherlands)

    D.C. Diamond; B.A. Jameson; J. Bonin; M. Kohara; S. Abe; H. Itoh; T. Komatsu; M. Arita; S. Kuge; A. Nomoto; A.D.M.E. Osterhaus (Albert); R. Crainic; E. Wimmer

    1985-01-01

    textabstractMutations have been identified in variants of poliovirus, type 1 (Mahoney) on the basis of their resistance to neutralization by individual monoclonal antibodies. The phenotypes of these variants were defined in terms of antibody binding; the pattern of epitopes expressed or able to be

  4. Increased basal glucose production in type 1 Gaucher's disease

    NARCIS (Netherlands)

    Corssmit, E. P.; Hollak, C. E.; Endert, E.; van Oers, M. H.; Sauerwein, H. P.; Romijn, J. A.

    1995-01-01

    To evaluate the metabolic effects of Gaucher's disease, glucose metabolism and parameters of fat metabolism were studied by indirect calorimetry and primed continuous infusion of [3-3H]glucose in seven clinically stable untreated patients with type 1 Gaucher's disease and in seven healthy matched

  5. Motor problems in children with neurofibromatosis type 1

    NARCIS (Netherlands)

    A.B. Rietman (André); R. Oostenbrink (Rianne); Bongers, S. (Sanne); Gaukema, E. (Eddy); Van Abeelen, S. (Sandra); J.G.M. Hendriksen; C.W.N. Looman (Caspar); P.F.A. de Nijs (Pieter); M.C.Y. de Wit (Marie Claire)

    2017-01-01

    textabstractBackground: Children with the neurogenetic disorder neurofibromatosis type 1 (NF1) often have problems with learning and behaviour. In both parent reports and neuropsychological assessment, motor problems are reported in approximately one third to one half of the children with NF1.

  6. [Adolescents with diabetes type 1 in adolescent psychiatry and psychotherapy].

    Science.gov (United States)

    Walter, Joachim

    2013-01-01

    Psychiatric comorbidity, family and biographical risk factors, and individual motivational aspects influence the therapeutic adherence and treatment motivation in Diabetes Type 1. The article provides basis diabetological knowledge for adolescent psychotherapists and describes practical out- and inpatient experiences and deliberations with especially problematic comorbid patients. In psychiatrically comorbid patients family conflicts and individual psychopathology is often reflected and manifested in selfharming diabetes management.

  7. Type 1 diabetes mellitus and atopic diseases in children.

    African Journals Online (AJOL)

    Ehab

    Nancy S. Elbarbary. Assistant Professor of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Background. Diabetes mellitus type 1 (T1DM) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors.1 Worldwide,. T1DM epidemic represents an increasing global.

  8. The vaccines for Bovine Herpesvirus Type 1: A review | Zhao ...

    African Journals Online (AJOL)

    Bovine herpesvirus type 1 (BoHV-1) is the pathogen of Infectious Bovine Rhinothracheitis (IBR) disease, causing great economic losses in the livestock industry. Vaccine is a powerful means to control the virus. Here, the review described the currently available knowledge regarding to the advance in the field of BoHV-1 ...

  9. Type 1,1-operators defined by vanishing frequency modulation

    DEFF Research Database (Denmark)

    Johnsen, Jon

    2009-01-01

    This paper presents a general definition of pseudo-differential operators of type 1,1; the definition is shown to be the largest one that is both compatible with negliible operators and stable under vanishing frequency modulation. Elaborating counter-examples of Ching, Hörmander and Parenti...

  10. Case report: type 1 diabetes in monozygotic quadruplets

    Czech Academy of Sciences Publication Activity Database

    Štechová, K.; Halbhuber, Z.; Hubáčková, M.; Kayserová, J.; Petruželková, L.; Včeláková, J.; Koloušková, S.; Ulmannová, T.; Faresjo, M.; Neuwirth, Aleš; Spíšek, R.; Šedivá, A.; Filipp, Dominik; Sumnik, Z.

    2012-01-01

    Roč. 20, č. 4 (2012), s. 457-462 ISSN 1018-4813 R&D Projects: GA MŠk 2B08066 Institutional research plan: CEZ:AV0Z50520514 Keywords : autoimmunity * type 1 diabetes * beta cell s Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.319, year: 2012

  11. Viral infections as potential triggers of type 1 diabetes

    NARCIS (Netherlands)

    van der Werf, Nienke; Kroese, Frans G. M.; Rozing, Jan; Hillebrands, Jan-Luuk

    During the last decades, the incidence of type 1 diabetes (T1D) has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetical factors environmental perturbations (including viral infections) are also involved in the pathogenesis of T1D. T1D

  12. Neuroendocrine Tumour in a Patient with Neurofibromatosis Type 1 ...

    African Journals Online (AJOL)

    We report the case of an HIV-positive female patient with neurofibromatosis type 1 who was treated for recurrent peptic ulcer disease and later developed diabetes mellitus and chronic diarrhoea. A metastasising somatostatinoma was histologically proven and evidence of a concomitant gastrin-producing neuroendocrine ...

  13. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1

    African Journals Online (AJOL)

    Enrique

    with MRI every 3 months and the bone marrow oedema disappeared after 6 months. Introduction ... SA JOURNAL OF RADIOLOGY • August 2004. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1 ... may be either trauma of external origin or iatrogenic, post surgery. In some patients particularly children ...

  14. Human immunodeficiency virus type-1 (HIV-1) genetic diversity and ...

    African Journals Online (AJOL)

    The presence of human immunodeficiency virus (HIV) type-1 diversity has an impact on vaccine efficacy and drug resistance. It is important to know the circulating genetic variants and associated drug-resistance mutations in the context of scale up of antiretroviral therapy (ART) in Nigeria. The objective of this study was to ...

  15. Immunological Adaptations to Pregnancy in Women with Type 1 Diabetes

    NARCIS (Netherlands)

    Groen, Bart; van der Wijk, Anne-Eva; van den Berg, Paul P.; Lefrandt, Joop D.; van den Berg, Gerrit; Sollie, Krystina M.; de Vos, Paul; Links, Thera P.; Faas, Marijke M.

    2015-01-01

    Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations

  16. Non HLA genetic markers association with type-1 diabetes mellitus ...

    African Journals Online (AJOL)

    The currently available data identified IDDM1 and IDDM2 as 2 susceptibility loci for type 1 diabetes (T1D). The major histocompatibility complex (MHC)/HLA region referred to as IDDM1 contains several 100 genes known to have a great influence on T1D risk. Within IDDM2, a minisatellite variable number of tandem repeats ...

  17. Type 1 diabetes and obesity in children : Focus on inflammation

    NARCIS (Netherlands)

    Verrijn Stuart, A.A.

    2013-01-01

    Type 1 diabetes (T1D) is an inflammatory disorder as is obesity. This thesis addresses inflammatory features in both conditions, with focus on inflammatory mediators and the role of adipose tissue (AT). The first part, specific aspects of immune tolerance in T1D,focuses on immune (dys) regulation

  18. Personality profiles of children and adolescents with neurofibromatosis type 1

    NARCIS (Netherlands)

    Prinzie, P.; Descheemaeker, M.J.; Vogels, A.; Cleymans, T.; Haselager, G.J.T.; Curfs, L.M.G.; Hellinckx, W.; Onghena, P.; Legius, E.; Lieshout, C.F.M. van; Fryns, J.P.

    2003-01-01

    The personality profile of 44 youngsters (24 males, 20 females; mean age 11 years, 3 months) with neurofibromatosis type 1 (NF1) was compared with a group of 220 non-NF1 control youngsters (matched on age and gender). Personality characteristics of each youngster were rated by both parents, using

  19. Sensor Augmented Pump Therapy Use in Type 1 Diabetes Mellitus

    LENUS (Irish Health Repository)

    Carolan, E

    2016-11-01

    Tight metabolic control in Type 1 Diabetes Mellitus (T1DM) reduces incidence and delays progression of micro-vascular complications. Severe hypoglycaemia remains a significant barrier to achieving optimal diabetes control. Continuous subcutaneous insulin infusion (CSII) systems refine insulin delivery with programmable basal rates and mealtime bolusing

  20. Exercise management in type 1 diabetes: a consensus statement.

    Science.gov (United States)

    Riddell, Michael C; Gallen, Ian W; Smart, Carmel E; Taplin, Craig E; Adolfsson, Peter; Lumb, Alistair N; Kowalski, Aaron; Rabasa-Lhoret, Remi; McCrimmon, Rory J; Hume, Carin; Annan, Francesca; Fournier, Paul A; Graham, Claudia; Bode, Bruce; Galassetti, Pietro; Jones, Timothy W; Millán, Iñigo San; Heise, Tim; Peters, Anne L; Petz, Andreas; Laffel, Lori M

    2017-05-01

    Type 1 diabetes is a challenging condition to manage for various physiological and behavioural reasons. Regular exercise is important, but management of different forms of physical activity is particularly difficult for both the individual with type 1 diabetes and the health-care provider. People with type 1 diabetes tend to be at least as inactive as the general population, with a large percentage of individuals not maintaining a healthy body mass nor achieving the minimum amount of moderate to vigorous aerobic activity per week. Regular exercise can improve health and wellbeing, and can help individuals to achieve their target lipid profile, body composition, and fitness and glycaemic goals. However, several additional barriers to exercise can exist for a person with diabetes, including fear of hypoglycaemia, loss of glycaemic control, and inadequate knowledge around exercise management. This Review provides an up-to-date consensus on exercise management for individuals with type 1 diabetes who exercise regularly, including glucose targets for safe and effective exercise, and nutritional and insulin dose adjustments to protect against exercise-related glucose excursions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Charcot-Marie-Tooth disease type 1A

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Børglum, A D; Brandt, C A

    1994-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients...

  2. Osteomyelitis in leukocyte adhesion deficiency type 1 syndrome

    DEFF Research Database (Denmark)

    Jabbari Azad, Farahzad; Ardalan, Maryam; H.Rafati, Ali

    2010-01-01

    Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, inherited immunodeficiency that affects one per million people yearly and usually presents with recurrent, indolent bacterial infections of the skin, mouth, and respiratory tract and impaired pus formation and wound healing. A 13-year-old girl...

  3. [Complex regional pain syndrome type 1: negating the myth

    NARCIS (Netherlands)

    Frolke, J.P.M.; Dongen, R.T.M. van; Meent, H. van de

    2015-01-01

    Complex regional pain syndrome type 1 (CRPS-1) was identified in the Netherlands more than 30 years ago, but since then the arguments supporting this diagnosis have become weaker. Incidence has decreased, it is often not possible to make a definite diagnosis, the pathophysiology remains unclear and

  4. Chronic comorbidities in children and adolescents with type 1 diabetes

    NARCIS (Netherlands)

    Fazelifarsani, Soulmaz; Souverein, Patrick C.; Van Der Vorst, Marja M.J.; Knibbe, Catherijne A.J.; De Boer, Anthonius; Mantel-Teeuwisse, Aukje K.

    2014-01-01

    Background: Limited quantitative data exist on the burden of chronic comorbidities in children and adolescents with type 1 diabetes (T1D). Such knowledge is necessary for the development of guidelines and prevention programs. Objectives: To determine the incidence of chronic comorbidities in

  5. Overnight glucose control in people with type 1 diabetes

    DEFF Research Database (Denmark)

    Boiroux, Dimitri; Duun-Henriksen, Anne Katrine; Schmidt, Signe

    2018-01-01

    This paper presents an individualized model predictive control (MPC) algorithm for overnight blood glucose stabilization in people with type 1 diabetes (T1D). The MPC formulation uses an asymmetric objective function that penalizes low glucose levels more heavily. We compute the model parameters...

  6. Continuous glucose monitoring systems for type 1 diabetes mellitus

    NARCIS (Netherlands)

    Langendam, Miranda; Luijf, Yoeri M.; Hooft, Lotty; DeVries, J. Hans; Mudde, Aart H.; Scholten, Rob J. P. M.

    2012-01-01

    Background Self-monitoring of blood glucose is essential to optimise glycaemic control in type 1 diabetes mellitus. Continuous glucose monitoring (CGM) systems measure interstitial fluid glucose levels to provide semi-continuous information about glucose levels, which identifies fluctuations that

  7. Insulin analogues and severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Hansen, L S; Jespersen, M J

    2012-01-01

    The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed...

  8. Imaging Finding of Multiple Endocrine Neoplasia Type 1: Case Report

    International Nuclear Information System (INIS)

    Yum, Tae Jun; Cho, Hee Woo

    2012-01-01

    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome with characteristic clinical and radiological manifestations. Many reports on MEN1 have been published; however, no cases of radiologically diagnosed MEN1 have been reported. Therefore, we report on a radiologically diagnosed case of MEN1 with clinical symptoms of gastroduodenal ulcer.

  9. Characteristics of children presenting with newly diagnosed type 1 ...

    African Journals Online (AJOL)

    The clinical presentation of type 1 diabetes in children can be acute or insidious, and symptoms may be subtle ... weakness, together with simple bedside tests such as urine dipsticks ... a recent worldwide focus on programmes to reduce the incidence .... by parents, asking the correct questions by medical personnel, and.

  10. Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

    NARCIS (Netherlands)

    Dreijerink, K.M.A.

    2009-01-01

    Multiple Endocrine Neoplasia type 1 (MEN1) is an inherited syndrome that is characterized by the occurrence of tumours of the parathyroid glands, gastroenteropancreatic tumours, pitui-tary gland adenomas, as well as adrenal adenomas and neuro-endocrine tumours, often at a young age. MEN1 tumours can

  11. Speech Disorders in Neurofibromatosis Type 1: A Sample Survey

    Science.gov (United States)

    Cosyns, Marjan; Vandeweghe, Lies; Mortier, Geert; Janssens, Sandra; Van Borsel, John

    2010-01-01

    Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder with an estimated prevalence of two to three cases per 10 000 population. While the physical characteristics have been well documented, speech disorders have not been fully characterized in NF1 patients. Aims: This study serves as a pilot to identify key…

  12. Reproduction and fertility in human immunodeficiency virus type-1 infection

    NARCIS (Netherlands)

    van Leeuwen, E.; Prins, J. M.; Jurriaans, S.; Boer, K.; Reiss, P.; Repping, S.; van der Veen, F.

    2007-01-01

    Human immunodeficiency virus type-1 (HIV-1) affects mostly men and women in their reproductive years. For those who have access to highly active antiretroviral therapy (HAART), the course of HIV-1 infection has shifted from a lethal to a chronic disease. As a result of this, many patients with HIV-1

  13. Genetics Home Reference: acute necrotizing encephalopathy type 1

    Science.gov (United States)

    ... encephalopathy type 1 typically appears in infancy or early childhood, although some people do not develop the condition ... status and number of prior infections, may also influence risk. Related ... it mean if a disorder seems to run in my family? What are the different ways in which a ...

  14. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis

    OpenAIRE

    Muratori, L; Cataleta, M; Muratori, P; Lenzi, M; Bianchi, F

    1998-01-01

    Background—Liver/kidney microsomal antibody type 1 (LKM1) and liver cytosol antibody type 1 (LC1) are the serological markers of type 2 autoimmune hepatitis (AIH). 
Aims—Since LKM1 and LC1 react against two distinct liver specific autoantigens (cytochrome P450IID6 (CYP2D6) and a 58 kDa cytosolic polypeptide respectively), the aim was to see whether LKM1 and LC1 concentrations correlate with liver disease activity. 
Patients—Twenty one patients with type 2 AIH were studied. 
Methods—A...

  15. Risk factors for necrobiosis lipoidica in Type 1 diabetes mellitus.

    Science.gov (United States)

    Hammer, E; Lilienthal, E; Hofer, S E; Schulz, S; Bollow, E; Holl, R W

    2017-01-01

    To compare the clinical and metabolic characteristics of patients with Type 1 diabetes and necrobiosis lipoidica with those of patients with Type 1 diabetes who do not have necrobiosis lipoidica. A multicentre analysis was performed. Clinical and laboratory data were obtained from 64 133 patients (aged 0-25 years) with Type 1 diabetes with and without necrobiosis lipoidica who were registered in the German/Austrian Diabetes Prospective Documentation Initiative registry. Data were analysed using multivariable regression modelling. Age, diabetes duration, treatment year and sex were considered as confounding factors. Results adjusted for demographic variables are presented. In patients with necrobiosis lipoidica, metabolic control was worse (HbA 1c 72 vs. 67 mmol/mol, 8.7% vs. 8.3%; P = 0.0065) and the duration of diabetes was longer [6.24 (3.28-9.97) vs. 5.11 (2.08-8.83) years; P = 0.014; not adjusted]. Patients with necrobiosis lipoidica required higher insulin doses than those without (1.02 vs. 0.92 U/kg/day; P 1). There was no significant difference in the frequency of microvascular complications (microalbuminuria and retinopathy) between the groups. Furthermore, 24.8% and 17.5% of patients with Type 1 diabetes with and without necrobiosis lipoidica, respectively, had elevated thyroid antibodies (P = 0.051). Necrobiosis lipoidica was correlated with coeliac disease in patients with Type 1 diabetes (3.4% vs. 1.0%; P = 0.0035). Our data indicate a strong correlation between hyperglycaemia and the development of necrobiosis lipoidica. We postulate that the underlying pathogenic processes differ from those leading to microalbuminuria and retinopathy, and additional immunological mechanisms may play a role. © 2016 Diabetes UK.

  16. Cardiorenal Syndrome Type 1: Definition, Etiopathogenesis, Diagnostics and Treatment

    Directory of Open Access Journals (Sweden)

    Nikolic Tomislav

    2018-03-01

    Full Text Available Cardiorenal Syndrome Type 1 (CRS-1 is defined as an acute worsening of heart function leading to acute kidney injury and/or dysfunction. It is an important cause of hospitalization which affects the diagnosis as well as the prognosis and treatment of patients. The purpose of this paper is to analyze causes that lead to the development of cardiorenal syndrome type 1 and its clinical consequences, as well as to emphasize the clinical importance of its early detection. The clinical studies and professional papers dealing with etiopathogenesis, diagnosis and treatment of cardiorenal syndrome type 1, have been analyzed. The most important role in the occurrence of cardio renal syndrome type 1 is played by hemodynamic mechanisms, activation of neurohumoral systems, inflammation and imbalance between the production of reactive oxygen species (ROS and nitric oxide (NO. Diagnosis of cardiorenal syndrome type 1 involves biomarkers of acute renal injury among which the most important are: neutrophil gelatinaseassociated lipocalin (NGAL, cystatin C, kidney injury molecule 1 (KIM-1, liver-type fatty acid binding protein (L-FABP, IL-18 and the values of nitrogen compounds in serum. In addition to a pharmacological therapy, various modalities of extracorporeal ultrafiltration are applied in treatment of CRS-1, particularly if there is resistance to the use of diuretic therapy. As opposed to the experimental models, in clinical practice acute renal injury is often diagnosed late so that the measures taken do not give the expected results and the protective role shown in experimental conditions do not give the same results. For all these reasons, it is necessary to analyze the pathophysiology of renal impairment in cardiorenal syndrome as well as detect early indicators of kidney injury that could have clinical benefit and positive impact on reducing the cost of treatment.

  17. Enhancing the activity of cannabidiol and other cannabinoids in vitro through modifications to drug combinations and treatment schedules.

    Science.gov (United States)

    Scott, Katherine Ann; Shah, Sini; Dalgleish, Angus George; Liu, Wai Man

    2013-10-01

    Cannabinoids are the bioactive components of the Cannabis plant that display a diverse range of therapeutic qualities. We explored the activity of six cannabinoids, used both alone and in combination in leukaemic cells. Cannabinoids were cytostatic and caused a simultaneous arrest at all phases of the cell cycle. Re-culturing pre-treated cells in drug-free medium resulted in dramatic reductions in cell viability. Furthermore, combining cannabinoids was not antagonistic. We suggest that the activities of some cannabinoids are influenced by treatment schedules; therefore, it is important to carefully select the most appropriate strategy in order to maximise their efficacy.

  18. Synthetic cannabinoid JWH-018 and psychosis: an explorative study.

    Science.gov (United States)

    Every-Palmer, Susanna

    2011-09-01

    Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

    Science.gov (United States)

    Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

    2014-09-01

    This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

  20. Consensus guidelines for management of glycogen storage disease type 1b - European Study on Glycogen Storage Disease Type 1

    NARCIS (Netherlands)

    Visser, G; Rake, JP; Labrune, P; Leonard, JV; Moses, S; Ullrich, K; Wendel, U; Smit, GPA

    2002-01-01

    Life expectancy in glycogen storage disease type 1 (GSD-1) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and therefore experience with long-term management and follow-up at each centre is limited. There is wide variation in

  1. Abnormal islet sphingolipid metabolism in type 1 diabetes.

    Science.gov (United States)

    Holm, Laurits J; Krogvold, Lars; Hasselby, Jane P; Kaur, Simranjeet; Claessens, Laura A; Russell, Mark A; Mathews, Clayton E; Hanssen, Kristian F; Morgan, Noel G; Koeleman, Bobby P C; Roep, Bart O; Gerling, Ivan C; Pociot, Flemming; Dahl-Jørgensen, Knut; Buschard, Karsten

    2018-04-18

    Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. The RNA expression data is

  2. Toxic Effects of Cannabis and Cannabinoids: Animal Data

    Directory of Open Access Journals (Sweden)

    Pierre Beaulieu

    2005-01-01

    Full Text Available The present article reviews the main toxic effects of cannabis and cannabinoids in animals. Toxic effects can be separated into acute and chronic classifications. Acute toxicity studies show that it is virtually impossible to die from acute administration of marijuana or tetrahydrocannabinol, the main psychoactive component of cannabis. Chronic toxicity involves lesions of airway and lung tissues, as well as problems of neurotoxicity, tolerance and dependence, and dysregulations in the immune and hormonal systems. Animal toxicity data, however, are difficult to extrapolate to humans.

  3. Altered Integration of Structural Covariance Networks in Young Children With Type 1 Diabetes.

    Science.gov (United States)

    Hosseini, S M Hadi; Mazaika, Paul; Mauras, Nelly; Buckingham, Bruce; Weinzimer, Stuart A; Tsalikian, Eva; White, Neil H; Reiss, Allan L

    2016-11-01

    Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early-onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large-scale brain networks. In the present study, we applied graph-theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization-an architecture that is simultaneously highly segregated and integrated-the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early-onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp 37:4034-4046, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Cannabinoid mitigation of neuronal morphological change important to development and learning: insight from a zebra finch model of psychopharmacology.

    Science.gov (United States)

    Soderstrom, Ken; Gilbert, Marcoita T

    2013-03-19

    Normal CNS development proceeds through late-postnatal stages of adolescent development. The activity-dependence of this development underscores the significance of CNS-active drug exposure prior to completion of brain maturation. Exogenous modulation of signaling important in regulating normal development is of particular concern. This mini-review presents a summary of the accumulated behavioral, physiological and biochemical evidence supporting such a key regulatory role for endocannabinoid signaling during late-postnatal CNS development. Our focus is on the data obtained using a unique zebra finch model of developmental psychopharmacology. This animal has allowed investigation of neuronal morphological effects essential to establishment and maintenance of neural circuitry, including processes related to synaptogenesis and dendritic spine dynamics. Altered neurophysiology that follows exogenous cannabinoid exposure during adolescent development has the potential to persistently alter cognition, learning and memory. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Bariatric Surgery in Type 1 Diabetes Mellitus: A Systematic Review.

    Science.gov (United States)

    Mahawar, Kamal K; De Alwis, Nimantha; Carr, William R J; Jennings, Neil; Schroeder, Norbert; Small, Peter K

    2016-01-01

    Bariatric surgery is recognised as an effective treatment strategy for obese patients with type 2 diabetes mellitus. An increasing number of patients with type 1 diabetes mellitus also suffer with obesity and obesity-associated comorbidities but the role of bariatric and metabolic surgery in this group of patients is unclear. This systematic review investigates published English language scientific literature to understand the results of bariatric surgery in obese patients with type 1 diabetes mellitus. We found that these patients can experience significant weight loss and comorbidity resolution with bariatric surgery. Though most patients also see a decline in total insulin requirement, glycaemic control remains difficult. Most of the patients reported in literature have undergone gastric bypass but data is insufficient to recommend any particular procedure.

  6. Solar wind interaction with type-1 comet tails

    International Nuclear Information System (INIS)

    Ershkovich, A.I.

    1977-01-01

    A comet tail is considered as a plasma cylinder separated by a tangential discontinuity surface from the solar wind. Under typical conditions a comet tail boundary is shown to undergo the Kelvin-Helmholtz instability. With infinite amplitude the stabilizing effect of the magnetic field increases, and waves become stable. The proposed model supplies the detailed quantitative description of helical waves observed in type-1 comet tails. This theory enables the evaluation of the comet tail magnetic field by means of the observations of helical waves. The magnetic field in the comet tail turns out to be of the order of the interplanetary field. This conclusion seems to be in accordance with Alfven's idea that the magnetic field in type-1 comet tails is a captured interplanetary field. (Auth.)

  7. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Kinsley, Brendan; Amiel, Stephanie A

    2007-01-01

    OBJECTIVE: To assess the safety and efficacy of insulin aspart (IAsp) versus regular human insulin (HI) in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS: Subjects (n = 322) who were pregnant or planning pregnancy were randomized to IAsp...... in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes and may potentially offer some benefits in terms of postprandial glucose control and preventing severe hypoglycemia....... or HI as meal-time insulin in an open-label, parallel-group, multicenter study. Subjects had A1C pregnancy. Insulin doses were titrated toward predefined glucose targets and A1C 1C, plasma glucose...

  8. Abnormal islet sphingolipid metabolism in type 1 diabetes

    DEFF Research Database (Denmark)

    Holm, Laurits J; Krogvold, Lars; Hasselby, Jane P

    2018-01-01

    AIMS/HYPOTHESIS: Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis....... Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we...... diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1...

  9. Clustering of microvascular complications in Type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Bjerg, Lasse; Hulman, Adam; Charles, Morten

    2018-01-01

    AIMS: To describe to what extent microvascular complications exhibit clustering in persons with Type 1 diabetes, and to assess whether the presence of one complication modified the strength of the association between the other two. METHODS: We conducted a cross-sectional analysis of the electronic...... medical records of 2276 persons with Type 1 diabetes treated in a specialized care hospital in Denmark in 2013. We used log-linear analysis to describe associations between diabetic kidney disease, neuropathy and retinopathy and logistic regression models to quantify the magnitude of associations...... adjusting for potential confounders. RESULTS: The median duration of diabetes was 24 years and median HbA1c was 63 mmol/mol (7.9%). We found strong indication of clustering and found no evidence that presence of one complication modified the association between the other two. In models adjusted for diabetes...

  10. Behavioral interventions for adolescents with type 1 diabetes

    DEFF Research Database (Denmark)

    Hampson, S. E.; Skinner, T. C.; Hart, J.

    2000-01-01

    OBJECTIVE - To evaluate the effectiveness of behavioral interventions for adolescents with type 1 diabetes based on a systematic review of the literature. RESEARCH DESIGN AND METHODS - The literature was identified by searching 11 electronic databases, hand-searching 3 journals from their start...... dates, and contacting individual researchers. Only articles that reported evaluations of behavioral (including educational and psychosocial) interventions for adolescents (age range 9-21 years) with type 1 diabetes that included a control group were included in the present review. Data summarizing...... were RCTs. Effect sizes could be calculated for 18 interventions. The overall mean effect size calculated across all outcomes was 0.33 (median 0.21), indicating that these interventions have a small- to medium-sized beneficial effect on diabetes management. Interventions that were theoretically based...

  11. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

    Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... or with HbA1c. In conclusion, no major abnormalities in glucocorticoid receptor binding characteristics could be demonstrated in Type 1 diabetes mellitus....... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0...

  12. Intervening before the onset of Type 1 diabetes

    DEFF Research Database (Denmark)

    Reimers, Jesper Irving

    2003-01-01

    AIMS/HYPOTHESIS: To set up a clinical trial to establish whether nicotinamide can prevent or delay clinical onset of Type 1 diabetes. METHOD: The European Nicotinamide Diabetes Intervention Trial is a randomised, double-blind, placebo-controlled intervention trial undertaken in 18 European...... countries, Canada and the USA. Entry criteria were a first-degree family history of Type 1 diabetes, age 3-40 years, confirmed islet cell antibody (ICA) levels greater than or equal to 20 JDF units, and a non-diabetic OGTT; the study group was further characterised by intravenous glucose tolerance testing......) centile in 34%. Additional islet autoantibodies were identified in 354 trial entrants. Diabetes-associated HLA class II haplotypes were found in 84% of the younger age group and 80% of the older group. The protective haplotype HLA-DQA1*0102-DQB1*0602 was found in 10% overall. CONCLUSIONS...

  13. Insulin Administration for People with Type 1 diabetes

    DEFF Research Database (Denmark)

    Boiroux, Dimitri; Finan, Daniel Aaron; Poulsen, Niels Kjølstad

    2011-01-01

    considers meal announcement at mealtimes only. They give a quantitative upper bound on the achievable control performance. The third control strategy is a feedforward-feedback control strategy. This strategy uses a time-varying setpoint to reduce the risk of hypoglycemia. The feedback controller computes......In this paper, we apply model predictive control (MPC) for control of blood glucose in people with type 1 diabetes. The two first control strategies are based on nonlinear model predictive control (NMPC). The first control strategy is based on meal announcement in advance, while the second one...... the optimal basal insulin infusion rate. The feedforward controller consists of a bolus calculator. It computes the optimal bolus, along with the time-varying glucose setpoint. We test these three strategies on a virtual patient with type 1 diabetes. The numerical results demonstrate the robustness...

  14. Bartter Syndrome Type 1 Presenting as Nephrogenic Diabetes Insipidus

    Directory of Open Access Journals (Sweden)

    Gianluca Vergine

    2018-01-01

    Full Text Available Bartter syndrome (BS type 1 (OMIM #601678 is a hereditary salt-losing renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, polyuria, recurrent vomiting, and growth retardation. It is caused by loss-of-function mutations of the SLC12A1 gene, encoding the furosemide-sensitive Na-K-Cl cotransporter. Recently, a phenotypic variability has been observed in patients with genetically determined BS, including absence of nephrocalcinosis, hypokalemia, and/or metabolic alkalosis in the first year of life as well as persistent metabolic acidosis mimicking distal renal tubular acidosis. We report the case of a child with a genetically determined diagnosis of Bartter syndrome type 1 who presented with a phenotype of nephrogenic diabetes insipidus, with severe hypernatremia and urinary concentrating defect. In these atypical cases, molecular analysis is mandatory to define the diagnosis, in order to establish the correct clinical and therapeutic management.

  15. Bartter Syndrome Type 1 Presenting as Nephrogenic Diabetes Insipidus.

    Science.gov (United States)

    Vergine, Gianluca; Fabbri, Elena; Pedini, Annalisa; Tedeschi, Silvana; Borsa, Niccolò

    2018-01-01

    Bartter syndrome (BS) type 1 (OMIM #601678) is a hereditary salt-losing renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, polyuria, recurrent vomiting, and growth retardation. It is caused by loss-of-function mutations of the SLC12A1 gene, encoding the furosemide-sensitive Na-K-Cl cotransporter. Recently, a phenotypic variability has been observed in patients with genetically determined BS, including absence of nephrocalcinosis, hypokalemia, and/or metabolic alkalosis in the first year of life as well as persistent metabolic acidosis mimicking distal renal tubular acidosis. We report the case of a child with a genetically determined diagnosis of Bartter syndrome type 1 who presented with a phenotype of nephrogenic diabetes insipidus, with severe hypernatremia and urinary concentrating defect. In these atypical cases, molecular analysis is mandatory to define the diagnosis, in order to establish the correct clinical and therapeutic management.

  16. Therapeutic management of type 1 diabetes before and during pregnancy

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Damm, Peter; Nielsen, Lene Ringholm

    2011-01-01

    before and during pregnancy is crucial and the prevalence of severe hypoglycemia during pregnancy needs to be reduced. Rapid-acting insulin analogues are regarded as safe to use in pregnancy and studies on long-acting insulin analogues are in the pipeline. Supplementation with folic acid may reduce......Introduction: Pregnancy increases the risks of adverse outcomes for mother and infant in women with type 1 diabetes. Obtaining and maintaining adequate glycemic control during pregnancy is crucial for optimizing outcomes. Areas covered: The importance of prepregnancy planning and treatment during...... pregnancy is reviewed. The use of insulin analogues and antihypertensive drugs in diabetic pregnancy are in focus. The reader is presented with evidence discussing the importance of prepregnancy counseling and treatment during pregnancy in women with type 1 diabetes. Expert opinion: Tight glycemic control...

  17. The long-term treatment of a patient with type 1 diabetes mellitus and glutaric aciduria type 1: the effect of insulin.

    Science.gov (United States)

    Del Rizzo, Monica; Galderisi, Alfonso; Celato, Andrea; Furlan, Francesca; Giordano, Laura; Cazzorla, Chiara; Fasan, Ilaria; Moretti, Carlo; Zschocke, Johannes; Burlina, Alberto B

    2016-08-01

    The coexistence of two diseases associated with different metabolic disorders is a very rare event. Some associations, although sporadic, can be particularly challenging both in terms of diagnostic and therapeutic management and in terms of theoretical perspective. Here, we report a child affected by type 1 diabetes mellitus (T1DM) and glutaric aciduria type 1 (GA1). The child was diagnosed with classical T1DM at 15 months of age, with a tendency toward hypoglycemia. A few months later, during an acute intercurrent infective episode, the child displayed acute hypotonia of the lower limbs and limbs dystonia. A brain MRI showed bilateral striatal necrosis, suggesting GA1 diagnosis. Treatment with a low-lysine dietary regimen and carnitine supplementation was started and resulted in an improvement in metabolic control and a reduction of hypoglycemic episodes along with an increasing in insulin daily dose. After 2 years, the neurological outcome consisted of a reduction in dystonic movements and a metabolic stability of both diseases. This case provides some insight into the reciprocal interconnections between the two metabolic disorders. Similar pathogenic mechanisms responsible for the neuronal injury might have impacted each other, and a strict relationship between a specific aspect of GA1-impaired metabolism and glucose homeostasis might explain how the tailored management of GA1 was not only effective in controlling the disease, but it also resulted in an improvement in the control of the glycemic profile. What in known: • Glutaric aciduria type 1 (GA1) usually presents in childhood with severe and possibly irreversible neuronal damage, triggered by a catabolic stress • The association of GA1 with other diseases, including type 1 diabetes mellitus (T1DM), is a rare event, complicating the treatment management What is new: • Insulin treatment has a role in preventing GA1 metabolic decompensation, even in the catabolic condition of hypoglycemia • Promoting

  18. Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Simon, Stéphanie; Lugan, Séverine; Bilheude, Jean-Marc; Perret-Liaudet, Armand; Ironside, James W.; Haik, Stéphane; Basset-Leobon, Christelle; Lacroux, Caroline; Peoch', Katell; Streichenberger, Nathalie; Langeveld, Jan; Head, Mark W.; Grassi, Jacques; Hauw, Jean-Jacques; Schelcher, Francois; Delisle, Marie Bernadette; Andréoletti, Olivier

    2008-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability. PMID:18389084

  19. Multimodal imaging of choroidal nodules in neurofibromatosis type-1

    Directory of Open Access Journals (Sweden)

    Vinod Kumar

    2018-01-01

    Full Text Available Choroidal nodules in neurofibromatosis type-1 are common and are best imaged with near-infrared reflectance (NIR imaging. The authors describe swept-source optical coherence tomography angiography (SSOCTA of choroidal nodules. These nodules are seen as hyperflow areas on SSOCTA and correlate well to bright patches on NIR imaging. The utility of multicolor scanning laser imaging in detecting these abnormalities is also described.

  20. Can Type 1 Diabetes patients safely fast during Ramadan?

    Directory of Open Access Journals (Sweden)

    M. Hamed Farooqi

    2016-09-01

    Full Text Available The issue whether people with Type 1 Diabetes can safely fast during Ramadan has been the subject of quite a few debates over the years. Had it been a simple "yes" or "no" issue, there would have been no reason to debate. However, like a lot of other topics in medical management, this particular subject overlaps both the science and the art of medicine.

  1. Preventing microvascular complications in type 1 diabetes mellitus

    OpenAIRE

    Viswanathan, Vijay

    2015-01-01

    Patients with complications of diabetes such as retinopathy, nephropathy, and cardiovascular complications have increased hospital stay with greater economic burden. Prevention of complications should be started before the onset of type 1 diabetes mellitus (T1DM) by working on risk factors and thereafter by intervention upon confirmatory diagnosis which can prevent further damage to β-cells. The actual risk of getting microvascular complications like microalbuminuria and retinopathy progressi...

  2. Type 1 diabetes : The autoimmune process and islet transplantation

    OpenAIRE

    Jacobson, Stella

    2010-01-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective loss of the insulin-producing β-cells residing in the islets of Langerhans in the pancreas. Cytokines are involved in diabetes development in the nonobese diabetic (NOD) mouse model. NOD mice over-expressing the suppressor of cytokine signaling (SOCS-1) specifically in the β-cells are protected from T1D. Previous studies showed that immune cells infiltrated the pancreas of SOCS-1-transgenic (tg)...

  3. Kenny-Caffey syndrome type 1 in an Egyptian girl

    Directory of Open Access Journals (Sweden)

    Kotb Abbass Metwalley

    2012-01-01

    Full Text Available Kenny-Caffey syndrome type 1 (KCS1 (OMIM 244460 is a rare syndrome characterized by growth retardation, uniformly small slender long bones with medullary stenosis, thickened cortex of the long bones, hypocalcemia possibly with tetany at an early age and normal intelligence. The primary outcome of KCS1 is short stature. We present here an Egyptian girl aged 32 months with typical feature of KCS1.

  4. Ocular manifestations of Type 1 diabetes mellitus in pediatric population

    Directory of Open Access Journals (Sweden)

    Handan Akil

    2016-01-01

    Full Text Available Context: To evaluate the necessity of ocular screening in Type 1 diabetes mellitus (DM. Aims: This study aims to investigate the diabetes-related ocular changes according to the glycosylated hemoglobin (HbA1c level and duration of diabetes in children and compare the results with nondiabetic healthy children. Settings and Design: Observational cross-sectional study designed by ophthalmology and pediatric endocrinology clinics. Subjects and Methods: Forty-two children with Type 1 DM, 42 healthy gender- and age-matched children as controls were enrolled. All patients underwent ophthalmic and physical examination, with a review of medical history and current medication. HbA1c level, best corrected visual acuity, intraocular pressure (IOP, central corneal thickness (CCT, tear break-up time (BUT, Schirmer test, dilated fundus examination findings, central retinal thickness (CRT, and total macular volume (TMV measurements were noted. Statistical Analysis: Descriptive statistics, Student's t-test, Mann–Whitney U-test, Chi-square test for comparison of the group parameters and correlation analyses (Spearman analysis were performed with SPSS statistical software 17.0 (SPSS Inc., Chicago, IL, USA. Results: Type 1 DM group exhibited significantly reduced Schirmer test, increased IOP and decreased retinal thickness relative to the age-matched control group (P < 0.05 but no statistically significant difference was found for the BUT (P = 0.182 and for the CCT (P = 0.495. The correlations between the age, duration, HbA1c and IOP, BUT, Schirmer test, TMV, CRT measurements did not reach statistical significance. Conclusions: More frequent screening may be needed for complications, including neuropathy-related dry eye syndrome, IOP changes, and diabetic retinopathy in children with Type 1 DM.

  5. Varenicline may trigger severe hypoglycaemia in Type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P.L.; Pedersen-Bjergaard, U.; Thorsteinsson, B.

    2008-01-01

    is important to reduce risk of cardiovascular morbidity, especially in diabetes, use of effective drugs indicated for smoking cessation is rational. Case report We report multiple episodes of severe hypoglycaemia after starting varenicline in a 53-year-old woman with Type 1 diabetes. Since onset of diabetes......, intensified blood glucose monitoring and careful education of patients with diabetes treated with varenicline. Further investigation of the use of varenicline in patients with diabetes is warranted Udgivelsesdato: 2008/5...

  6. Genetic heterogeneity in patients with Bartter syndrome type 1.

    Science.gov (United States)

    Sun, Mingran; Ning, Jing; Xu, Weihong; Zhang, Han; Zhao, Kaishu; Li, Wenfu; Li, Guiying; Li, Shibo

    2017-02-01

    Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss‑of‑function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease‑causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insertions and deletions ranging from 1 to 4 nucleotides. A large deletion encompassing a whole exon in the SLC12A1 gene has not yet been reported. The current study initially identified an undocumented homozygous frameshift mutation (c.1833delT) by Sanger sequencing analysis of a single infant with BS type 1. However, in a subsequent analysis, the mutation was detected only in the father's DNA. Upon further investigation using a next‑generation sequencing approach, a deletion in exons 14 and 15 in both the patient and patient's mother was detected. The deletion was subsequently confirmed by use of a long‑range polymerase chain reaction and was determined to be 3.16 kb in size based on sequencing of the junction fragment. The results of the present study demonstrated that pathogenic variants of SLC12A1 are heterogeneous. Large deletions appear to serve an etiological role in BS type 1, and may be more prevalent than previously thought.

  7. Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1.

    Science.gov (United States)

    Gundogdu, Baris; Yolbas, Servet; Yildirim, Ahmet; Gonen, Murat; Koca, Suleyman Serdar

    2016-01-01

    Ankylosing spondylitis (AS) is a systemic disease primarily characterized by the inflammation of sacroiliac joints and axial skeleton. Neurofibromatosis type 1 (NF1) is a multisystem genetic disease which is characterized by cutaneous findings, most importantly café-au-lait spots and axillary freckling, by skeletal dysplasia, and by the growth of both benign and malignant nervous system neoplasms, most notably benign neurofibromas. In this case report, we present a 43-year-old male with AS and NF1.

  8. Type 1 diabetes mellitus and exercise in competitive athletes.

    Science.gov (United States)

    Ratjen, I; Weber, K S; Roden, M; Herrmann, M-E; Müssig, K

    2015-07-01

    The number of patients with type 1 diabetes mellitus who are actively participating in competitive sports is increasing. Here, we aimed to assess individual experiences of competitive athletes with type 1 diabetes and to compare these experiences with current recommendations. A survey of 20 competitive athletes with type 1 diabetes, categorized as endurance (n=10) and non-endurance (n=10) athletes, was performed. Endurance and non-endurance athletes did not differ in gender distribution, age, body mass index, and known diabetes duration. Self-reported target blood glucose values prior to exercise were lower in non-endurance than in endurance athletes (195±34 vs. 137±28 mg/dl, P=0.001). The majority of all athletes experienced activity-induced hypo- and hyperglycemic events, independently of exercise type. However, endurance athletes used additional carbohydrate units to prevent activity-induced hypoglycemic events more frequently without monitoring their blood glucose levels than non-endurance athletes (50% vs. 0%, P=0.01). The reduction of the insulin dose on training and competition days compared to days without exercise was similar for endurance and non-endurance athletes. These results point to a very individual adaption of the athlete's therapy during training and competition. However, there are distinct differences in diabetes management between endurance and non-endurance athletes. © Georg Thieme Verlag KG Stuttgart · New York.

  9. [Prerenal kidney failure in type 1 diabetes mellitus].

    Science.gov (United States)

    Schloot, N C; Hübinger, A; Scherbaum, W A

    2003-12-05

    A 22-year-old man was admitted in a severely reduced condition. Type 1 diabetes mellitus had been diagnosed when he was 13 years old, hypothyroidism was treated with L-thyroxine for 2 years. For the past 3 years he suffered from repetitive hypoglycemia, combined with vertigo, weakness and low blood pressure. He presented with hypotension and hyperpigmentation of the skin. Pathological laboratory results were: serum creatinine 2.5 mg/dl; urea 145 mg/dl; sodium 124 mmol/l; potassium 8.3 mmol/l, HbA (1c) 9.1%. The ECG showed large T waves. Additionally, plasma aldosterone was decreased (diabetes mellitus type 1 and hypothyroidism (Schmidt-Carpenter-Syndrome) were diagnosed. Initially, the patient was treated with sodium chloride 0.9% i. v. and oral sodium 5 g 4 times/day. In addition, he was given hydrocortisone 100 mg i. v., and then switched to 40 mg per day (20-10-10 mg), fludrocortisone 0.05 mg/ day and L-thyroxine 75 microg/ day orally the clinical condition improved dramatically within 24 hours. Intensified conventional insulin therapy was continued. In patients with type 1 diabetes, especially in combination with associated organ-specific autoimmune diseases, autoimmune polyglandular syndrome should be considered and adequately treated with those hormones that are reduced.

  10. Diabetes Distress Among Persons With Type 1 Diabetes.

    Science.gov (United States)

    Powers, Margaret A; Richter, Sara A; Ackard, Diann M; Craft, Cheryl

    2017-02-01

    Purpose The purpose of this study is to evaluate associations between diabetes distress and a range of psychological health behaviors and concerns among persons with type 1 diabetes for the benefit of enhancing early identification and intervention of at-risk individuals. Methods Persons with type 1 diabetes (n = 268; 57.1% female, 91.0% white, 76.8% satisfaction with life, self-esteem, self-efficacy, depression, perfectionism, body image satisfaction, dietary restraint and eating, and shape and weight concerns. Each subscale score was compared within age groups (depression scores and eating, and shape and weight concerns than those with low or moderate distress. For patients satisfaction with life, self-esteem, and self-efficacy and higher on dietary restraint and several areas of perfectionism than those with low or moderate distress. Conclusions Individuals with type 1 diabetes who have high diabetes distress also report higher A1C values and poorer psychological health concerns. A brief diabetes distress questionnaire can help to identify those who need additional screening, education and support, and treatment for overall health and well-being.

  11. Usher syndrome type 1: early detection of electroretinographic changes.

    Science.gov (United States)

    Flores-Guevara, Roberto; Renault, Francis; Loundon, Natalie; Marlin, Sandrine; Pelosse, Béatrice; Momtchilova, Martha; Auzoux-Chevé, Monique; Vermersch, Anne Isabelle; Richard, Pascal

    2009-11-01

    Usher syndrome type 1 needs to be diagnosed at early age in order to timely manage speech therapy, cochlear implantation, and genetic counseling. Few data are available regarding electroretinographic testing before the age of six years. To describe electroretinographic changes in young children with Usher syndrome type 1. Retrospective study of fourteen patients. Age at first neurophysiologic testing was between 17 months and 5 years 4 months. Electroretinogram was performed using flash stimulation in mesopic conditions in the conscious child. Analysis was focused on the amplitudes and latencies of a- and b-waves. Whatever the age, an abnormal fundus was always confirmed with an absent electroretinogram. The youngest patient with absent electroretinogram was 17 month-old. When recorded on and after the 29th month of age, electroretinogram was absent in all cases, including 6 patients with normal fundus. In three patients a low-amplitude electroretinogram was present at first recording within the 26th and 27th months. Electroretinogram showed retinopathy in young children with Usher syndrome type 1, even in the absence of fundoscopic signs of retinal degeneration.

  12. Trabecular bone histomorphometry in humans with Type 1 Diabetes Mellitus.

    Science.gov (United States)

    Armas, Laura A G; Akhter, Mohammed P; Drincic, Andjela; Recker, Robert R

    2012-01-01

    Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone microarchitecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex-matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. [1]. Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Glutaric aciduria type 1: neuroimaging features with clinical correlation

    Energy Technology Data Exchange (ETDEWEB)

    Mohammad, Shaimaa Abdelsattar; Ahmed, Khaled A. [Ain-Shams University, Department of Radiodiagnosis, Faculty of Medicine, Cairo (Egypt); Abdelkhalek, Heba Salah; Zaki, Osama K. [Ain-Shams University, Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Cairo (Egypt)

    2015-10-15

    Glutaric aciduria type 1 is a rare neurometabolic disease with high morbidity. To describe the MR imaging abnormalities in glutaric aciduria type 1 and to identify any association between the clinical and imaging features. MRI scans of 29 children (mean age: 16.9 months) with confirmed diagnosis of glutaric aciduria type 1 were retrospectively reviewed. Gray matter and white matter scores were calculated based on a previously published pattern-recognition approach of assessing leukoencephalopathies. Hippocampal formation and opercular topography were assessed in relation to the known embryological basis. MRI scores were correlated with morbidity score. The most consistent MRI abnormality was widened operculum with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes. Incomplete hippocampal inversion was also seen. The globus pallidus was the most frequently involved gray matter structure (86%). In addition to the central tegmental tract, white matter abnormalities preferentially involved the central and periventricular regions. The morbidity score correlated with the gray matter abnormality score (P = 0.004). Patients with dystonia had higher gray matter and morbidity scores. Morbidity is significantly correlated with abnormality of gray matter, rather than white matter, whether secondary to acute encephalopathic crisis or insidious onset disease. (orig.)

  14. Efficacy and safety of sotagliflozin in treating diabetes type 1.

    Science.gov (United States)

    Rendell, Marc S

    2018-02-01

    Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. Sotagliflozin blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1 and PYY. Urinary glucose excretion is lower than with other agents as a result of decreased glucose absorption. The primary development effort to date has been in Type 1 diabetes. Areas covered: The published information on sotagliflozin is reviewed, along with the recent results of several pivotal Type 1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and reduces glucose variability, with a trend to less hypoglycemic events. In the Type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An additional safety issue arises from the as yet unknown potential risks in women of child bearing potential in whom DKA is of utmost concern. The sotagliflozin development program has now been extended to trials in Type 2 diabetes, and long term studies will be needed to assess the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

  15. Introduction of Molecular Diagnosis of Hemochromatosis Type 1 in Cuba

    Directory of Open Access Journals (Sweden)

    Ismael Aramís Cervera García

    2013-06-01

    Full Text Available Background: hemochromatosis type 1 is an autosomal recessive genetic disorder, which should be diagnosed during its preclinical phase in order to prevent severe organ damage. Objective: to establish the diagnosis of hemochromatosis type 1 in Cuba, and calculate its frequencies in patients with hepatopathies. Methods: an analytic cross-sectional study was conducted including 65 patients with liver disease, who were referred to the laboratory of Molecular Biology of the National Medical Genetics Center by clinical geneticists. A PCR-RFLP analysis was used for detecting the C282Y and H63D mutations in the HFE gene. Results: PCR-RFLP analysis was standardized for the detection of C282Y and H63D mutations. Frequencies of C282Y and H63D mutations in the HFE gene in patients with hepatopathies were 6.3% and 18.2% respectively. Conclusions: molecular diagnosis of C282Y and H63D mutations in the HFE gene causing hemochromatosis type 1 contributed to the identification of 28 carriers in the 65 patients who were studied, as well as a homozygous individual for the H63D mutation, which shows the high prevalence of these mutations in Cuban patients with liver disease.

  16. Frequency of Ketoacidosis in Newly Diagnosed Type 1 Diabetic Children

    Science.gov (United States)

    Razavi, Zahra

    2010-01-01

    Objectives Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Many patients with newly diagnosed type 1 diabetes present with DKA. The aim of this study is to determine the frequency and the clinical presentation of diabetic ketoacidosis at the diagnosis of type 1 diabetes mellitus in youths in hamadan, Western Province of Iran. Methods The Clinical and laboratory data of a total of 200 patients under 19 years of age with newly diagnosed type 1 diabetes mellitus between 1995-2005 were retrospectively reviewed. Statistical analysis was performed using SPSS 11. Results 48 (24%)of the children were presented in a state of ketoacidosis. Sever form of DKA (pH≤7.2) was observed in 54.5% of patients. The mean age at diagnosis was 7.3±5.15 years in DKA group and 8.59±3.07 in non-DKA group (p=0.22). 60.4% of patient with DKA were female whereas in the non-DKA group, 53.3% of patients were female, the difference was not significant (p=0.38). The duration of symptoms before diagnosis was 14.84±8.19 days in patients with DKA and 22.39±2.27 in the non-DKA group, (p=0.11). No significant difference was found between the age, sex and duration of the symptoms and occurance of DKA. Polydipsia (85.4) polyuria (83.3%), weakness (68.8%) and abdominal pain (52.1%) were the most frequently notified symptoms among the patients. In two cases, diagnosis of DKA was preceded by as appendicitis and the patient underwent appendectomy. Conclusion Frequency of DKA at onset of type 1 diabetes mellitus was significant in the studied region. However, it was lower than other regions in Asia. Polydipsia, polyuria, fatigue and abdominal pain were the most common symptoms on presentation. PMID:22125712

  17. Frequency of Ketoacidosis in Newly Diagnosed Type 1 Diabetic Children

    Directory of Open Access Journals (Sweden)

    Zahra Razavi

    2010-04-01

    Full Text Available ABSTRACTObjectives: Diabetic ketoacidosis (DKA is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM. Many patients with newly diagnosed type 1 diabetes present with DKA. The aim of this study is to determine the frequency and the clinical presentation of diabetic ketoacidosis at the diagnosis of type 1 diabetes mellitus in youths in hamadan, Western Province of Iran.Methods: The Clinical and laboratory data of a total of 200 patients under 19 years of age with newly diagnosed type 1 diabetes mellitus between 1995-2005 were retrospectively reviewed. Statistical analysis was performed using SPSS 11.Results: 48 (24%of the children were presented in a state of ketoacidosis. Sever form of DKA (pH≤7.2 was observed in 54.5% of patients. The mean age at diagnosis was 7.3±5.15 years in DKA group and 8.59±3.07 in non-DKA group (p=0.22. 60.4% of patient with DKA were female whereas in the non-DKA group, 53.3% of patients were female, the difference was not significant (p=0.38. The duration of symptoms before diagnosis was 14.84±8.19 days in patients with DKA and 22.39±2.27 in the non-DKA group, (p=0.11. No significant difference was found between the age, sex and duration of the symptoms and occurance of DKA. Polydipsia (85.4 polyuria (83.3%, weakness (68.8% and abdominal pain (52.1% were the most frequently notified symptoms among the patients. In two cases, diagnosis of DKA was preceded by as appendicitis and the patient underwent appendectomy.Conclusion: Frequency of DKA at onset of type 1 diabetes mellitus was significant in the studied region. However, it was lower than other regions in Asia. Polydipsia, polyuria, fatigue and abdominal pain were the most common symptoms on presentation.

  18. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

    Directory of Open Access Journals (Sweden)

    Timothy W Lefever

    2017-03-01

    Full Text Available Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana” in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018 in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia, regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  19. Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents

    Directory of Open Access Journals (Sweden)

    Daniel A. Ladin

    2016-10-01

    Full Text Available Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated through the endocannabinoid system, which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer development and reduction. However, many studies investigated these roles using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical models and to examine the current standing of cannabinoids currently being tested in human cancer patients.

  20. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

    Science.gov (United States)

    Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

    2017-01-01

    Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  1. Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

    Directory of Open Access Journals (Sweden)

    Ken Soderstrom

    2017-10-01

    Full Text Available Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets.

  2. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

    Science.gov (United States)

    Fantegrossi, William E.; Moran, Jeffery H.; Radominska-Pandya, Anna; Prather, Paul L.

    2013-01-01

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. PMID:24084047

  3. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

    Science.gov (United States)

    Fantegrossi, William E; Moran, Jeffery H; Radominska-Pandya, Anna; Prather, Paul L

    2014-02-27

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. © 2013.

  4. Cannabinoids concentration variability in cannabis olive oil galenic preparations.

    Science.gov (United States)

    Carcieri, Chiara; Tomasello, Cristina; Simiele, Marco; De Nicolò, Amedeo; Avataneo, Valeria; Canzoneri, Luca; Cusato, Jessica; Di Perri, Giovanni; D'Avolio, Antonio

    2018-01-01

    Knowledge of the exact concentration of active compounds in galenic preparations is crucial to be able to ensure their quality and to properly administer the prescribed dose. Currently, the need for titration of extracts is still debated. Considering this, together with the absence of a standard preparation method, the aim of this study was to evaluate cannabinoids concentrations variability in galenic olive oil extracts, to evaluate the interlot and interlaboratory variability in the extraction yield and in the preparation composition. Two hundred and one extracts (123 (61.2%) from Bedrocan ® , 54 (26.9%) from Bediol ® , 11 (5.5%) from Bedrolite ® , and 13 (6.5%) from mixed preparations) were analysed by liquid chromatography coupled with tandem mass spectrometry, quantifying cannabinoids (THC, CBD, THCA, CBDA and CBN) concentrations. The RSD% of THC and CBD concentrations resulted higher than 50%. Specifically for Bedrocan ® , Bediol ® , Bedrolite ® (5 g/50 ml), these were THC 82%, THC 53% and CBD 91%, THC 58% and CBD 59%, respectively. The median extraction yields were greater than 75% for all preparations. Our results highlighted a wide variability in THC and CBD concentrations that justify the need for titration and opens further questions about other pharmaceutical preparations without regulatory indication for this procedure. © 2017 Royal Pharmaceutical Society.

  5. Do cannabinoids constitute a therapeutic alternative for anorexia nervosa?

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    Tania Contreras

    2017-12-01

    Full Text Available Resumen INTRODUCCIÓN Se ha planteado que la estimulación del apetito con cannabinoides podría constituir una alternativa terapéutica en anorexia nerviosa. Sin embargo, su utilidad clínica y seguridad genera controversia. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos cuatro revisiones sistemáticas que en conjunto incluyen dos estudios primarios, ambos correspondientes a ensayos aleatorizados. Concluimos que los cannabinoides podrían no aumentar el peso ni mejorar la sintomatología en la anorexia nerviosa, y se asocian a efectos adversos frecuentes.

  6. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.

    Science.gov (United States)

    Scavone, J L; Sterling, R C; Van Bockstaele, E J

    2013-09-17

    Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.

    Science.gov (United States)

    Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H

    2017-10-01

    The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Δ 9 -tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the α 1 adrenergic antagonist prazosin. Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. Published by Elsevier B.V.

  8. The influence of cannabinoids on learning and memory processes of the dorsal striatum.

    Science.gov (United States)

    Goodman, Jarid; Packard, Mark G

    2015-11-01

    Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Mechanism of the Interaction of Cannabinoid System in Central Amygdale with Opioid System

    Directory of Open Access Journals (Sweden)

    S. Sarahroodi

    2008-01-01

    Full Text Available Background and objectivesCannabinoids which are active compounds of marijuana show some pharmacological effects similar to the opioids. There are also functional interactions between both cannabinoid and opioid systems. In this study we investigated the role of cannabinoid receptors in central amygdala and its interaction with opioid system.MethodsIn the present study, we investigated the effects of intraperitoneal injection of opioid drugs on response-induced by intra-amygdala (intra-Amyg microinjection of cannabinoid agents in rats, using elevated plus-maze test of anxiety. ResultsIntraperitoneal injection of morphine (3, 6 and 9 mg/kg increased %OAT and %OAE, but not locomotor activity, showing an anxiolytic response. However, some doses of the opioid receptor antagonist, naloxone reduced %OAT and locomotor activity as well. Intra-Amyg administration of CB1 cannabinoid receptor agonist, ACPA (at the dose of 1.25 and 5 ng/rat increased %OAT and %OAE but not locomotor activity, thus showing an anxiolytic response, which was increased by morphine (6 mg/kg, i.p. without any interaction. Naloxone also reduced ACPA effects. Intra-Amyg administration of CB1 cannabinoid receptor antagonist, AM251 (2.5, 25 and 100 ng/rat did not alter %OAT and %OAE but higher doses of drug (25 and 100 ng/rat reduced locomotor activity. However, the drug in combination of morphine anxiolytic response and with naloxone decreased anxiety.ConclusionThe results may indicate an anxiolytic for CB1 cannabinoid. Our results also showed that opioid system may have interaction with cannabinoid receptor in the amygdale. Keywords: Cannabinoids, Morphine; Naloxone, Anxiety, Elevated Plus-Maze

  10. Prediction of First Cardiovascular Disease Event in Type 1 Diabetes Mellitus: The Steno Type 1 Risk Engine.

    Science.gov (United States)

    Vistisen, Dorte; Andersen, Gregers Stig; Hansen, Christian Stevns; Hulman, Adam; Henriksen, Jan Erik; Bech-Nielsen, Henning; Jørgensen, Marit Eika

    2016-03-15

    Patients with type 1 diabetes mellitus are at increased risk of developing cardiovascular disease (CVD), but they are currently undertreated. There are no risk scores used on a regular basis in clinical practice for assessing the risk of CVD in type 1 diabetes mellitus. From 4306 clinically diagnosed adult patients with type 1 diabetes mellitus, we developed a prediction model for estimating the risk of first fatal or nonfatal CVD event (ischemic heart disease, ischemic stroke, heart failure, and peripheral artery disease). Detailed clinical data including lifestyle factors were linked to event data from validated national registers. The risk prediction model was developed by using a 2-stage approach. First, a nonparametric, data-driven approach was used to identify potentially informative risk factors and interactions (random forest and survival tree analysis). Second, based on results from the first step, Poisson regression analysis was used to derive the final model. The final CVD prediction model was externally validated in a different population of 2119 patients with type 1 diabetes mellitus. During a median follow-up of 6.8 years (interquartile range, 2.9-10.9) a total of 793 (18.4%) patients developed CVD. The final prediction model included age, sex, diabetes duration, systolic blood pressure, low-density lipoprotein cholesterol, hemoglobin A1c, albuminuria, glomerular filtration rate, smoking, and exercise. Discrimination was excellent for a 5-year CVD event with a C-statistic of 0.826 (95% confidence interval, 0.807-0.845) in the derivation data and a C-statistic of 0.803 (95% confidence interval, 0.767-0.839) in the validation data. The Hosmer-Lemeshow test showed good calibration (P>0.05) in both cohorts. This high-performing CVD risk model allows for the implementation of decision rules in a clinical setting. © 2016 American Heart Association, Inc.

  11. Cannabinoids and centrak neuropathic pain. A review (Cannabinoidi e dolore neuropatico centrale. Una rassegna

    Directory of Open Access Journals (Sweden)

    Francesco Crestani

    2014-03-01

    Full Text Available Only recently, the medical community highlighted the pharmacological scientific bases of the effects of Cannabis. The most important active principle, Delta-9-tetrahydrocannabinol was identified in the second half of the last century, and receptors were subsequently identified and endogenous ligands, called endocannabinoids, were characterized. The effectiveness of the cannabinoids in the treatment of nausea and vomit due to anti-neoplastic chemotherapy and in the wasting-syndrome during AIDS is recognized. Moreover, the cannabinoids have shown analgesic properties, particularly interesting with regard to the central neuropathic pain. This article will review the current knowledge and will give practical guidance on how to proceed in prescribing cannabinoids.

  12. Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease

    Science.gov (United States)

    Harris, Steven A.; Harris, Elizabeth A.

    2018-01-01

    This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical

  13. Relation of left ventricular function, mass, and volume to NT-proBNP in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Astrup, A.S.; Kim, W.Y.; Tarnow, L.

    2008-01-01

    OBJECTIVES: To measure left ventricular mass (LVM), left ventricular volumes, and left ventricular function (LVF) in a cohort of type 1 diabetic patients and to correlate measures of imaging to NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP). RESEARCH DESIGN AND METHODS: In a cross......-sectional study, all patients with type 1 diabetes underwent cardiovascular magnetic resonance imaging. We included 63 patients with diabetic nephropathy and 73 patients with normoalbuminuria. RESULTS: All patients had normal global LVF. LVM was increased in patients with diabetic nephropathy compared...... is identified in asymptomatic type 1 diabetic patients with nephropathy compared with normoalbuminuric patients. Elevated levels of NT-proBNP were associated with increased LVM, which are both markers of increased cardiovascular risk Udgivelsesdato: 2008/5...

  14. An unfortunate challenge: Ketogenic diet for the treatment of Lennox-Gastaut syndrome in tyrosinemia type 1.

    Science.gov (United States)

    De Lucia, Silvana; Pichard, Samia; Ilea, Adina; Greneche, Marie-Odile; François, Laurent; Delanoë, Catherine; Schiff, Manuel; Auvin, Stéphane

    2016-07-01

    The ketogenic diet is an evidence-based treatment for resistant epilepsy including Lennox-Gastaut syndrome. This diet is based on low carbohydrate-high fat intakes. Dietary treatment is also therapeutic for inborn errors of metabolism such as aminoacdiopathies. We report a child with both Lennox-Gastaut syndrome and tyrosinemia type 1. This epilepsy syndrome resulted form a porencephalic cyst secondary to brain abscesses that occurred during the management of malnutrition due to untreated tyrosinemia type 1. We used a ketogenic diet as treatment for Lennox-Gastaut syndrome taking into account dietary requirements for tyrosinemia type 1. The patient was transiently responder during a 6-month period. This report illustrates that ketogenic diet remains a therapeutic option even when additional dietary requirements are needed. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  15. Smooth muscle antibodies and type 1 autoimmune hepatitis.

    Science.gov (United States)

    Muratori, Paolo; Muratori, Luigi; Agostinelli, Daniela; Pappas, Georgios; Veronesi, Lorenza; Granito, Alessandro; Cassani, Fabio; Terlizzi, Paolo; Lenzi, Marco; Bianchi, Francesco B

    2002-12-01

    Smooth muscle antibodies (SMA) characterize type 1 autoimmune hepatitis. Our aim was to evaluate sensitivity and specificity of different immunofluorescence substrates for the detection of SMA. Sera from 55 patients with type 1 AIH 20 with primary biliary cirrhosis, 20 with HCV-related chronic hepatitis and 25 blood donors were studied for SMA and anti-microfilaments reactivity by immunofluorescence on rat tissue sections, cultured fibroblasts and commercially available HEp-2 cells (collectively revealing the so called anti-actin pattern), and for the XR1 system by counterimmunoelectrophoresis. SMA was classified on the basis of its immunofluorescence pattern (V--vessels, G--glomerular, T--tubular). As further control group, we studied 26 patients with a diagnosis other than AIH, selected on the basis of a SMA-non-T/XR1 positivity. In patients with AIH the SMA-T pattern on rodent tissue, and anti-MF on fibroblasts and on HEp-2 cells were present in 80, 82 and 80%, respectively. Five out of 11 SMA-non T positive AIH patients were anti-MF positive. None of the pathological and healthy controls was positive for SMA-T or anti-MF reactivity. XR1 system was present in 84% of AIH patients and in 5% of pathological controls (p = 0.01). Two out of 26 SMA-non-T/XR1 positive sera were positive for anti-MF by fibroblasts and HEp-2 cells. A significant correlation was found between SMA-T pattern and anti-MF reactivity; no correlation was found between XR1 system and SMA-T pattern or anti-MF reactivity. SMA-T pattern is highly sensitive and specific first diagnostic test for type 1 AIH; anti-MF can be used as additional tool for the diagnosis, particularly when, despite the absence of the SMA-T pattern, AIH is strongly suspected.

  16. Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs.

    Science.gov (United States)

    Chase, Peter B; Hawkins, Jeff; Mosier, Jarrod; Jimenez, Ernest; Boesen, Keith; Logan, Barry K; Walter, Frank G

    2016-01-01

    Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n = 100) or marijuana (n = 33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9-tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography-mass spectrometry. Statistical significance was determined by using Fisher's exact test or Student's t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n = 16, 15 males) was 20 years (IQR 19-23 years). Median age for the marijuana group (n = 25, 21

  17. Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Baris Gundogdu

    2016-01-01

    Full Text Available Ankylosing spondylitis (AS is a systemic disease primarily characterized by the inflammation of sacroiliac joints and axial skeleton. Neurofibromatosis type 1 (NF1 is a multisystem genetic disease which is characterized by cutaneous findings, most importantly café-au-lait spots and axillary freckling, by skeletal dysplasia, and by the growth of both benign and malignant nervous system neoplasms, most notably benign neurofibromas. In this case report, we present a 43-year-old male with AS and NF1.

  18. Early risk stratification in pediatric type 1 diabetes

    DEFF Research Database (Denmark)

    Broe, Rebecca

    2015-01-01

    In the late 1980s all Danish children with type 1 diabetes were invited for a nationwide evaluation of glycemic control. Approximately 75% (n = 720) participated and have later been referred to as The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). The results were surprisingly poor glycemic...... control among these young patients which lead to a great emphasis on glycemic control in the Danish Pediatric Departments. In 1995 the participants were invited for yet another evaluation but this time with main focus on early signs of microvascular complications - 339 participated. The mean HbA1c had...

  19. Overnight glucose control in people with type 1 diabetes

    DEFF Research Database (Denmark)

    Boiroux, Dimitri; Duun-Henriksen, Anne Katrine; Schmidt, Signe

    2018-01-01

    This paper presents an individualized model predictive control (MPC) algorithm for overnight blood glucose stabilization in people with type 1 diabetes (T1D). The MPC formulation uses an asymmetric objective function that penalizes low glucose levels more heavily. We compute the model parameters...... algorithm uses frequent glucose measurements from a continuous glucose monitor (CGM) and its decisions are implemented by a continuous subcutaneous insulin infusion (CSII) pump. We provide guidelines for tuning the control algorithm and computing the Kalman gain in the linear state space model in innovation...

  20. [SPECIFIC CLINICAL FEATURES OF TYPE 1 AUTOIMMUNE POLYGLANDULAR SYNDROME].

    Science.gov (United States)

    Mikhina, M S; Molashenko, N V; Troshina, E A; Orlova, E M; Sozaeva, L S; Eystein, S H; Breivik, S

    2015-01-01

    Autoimmune polyglandular syndrome is a primary autoimmune disorder affecting two or more peripheral endocrine glands and responsible for their incompetence. It is frequently combined with various organ-specific non-endocrine diseases. Patients with this pathology need life-long replacement therapy and dynamic observation by endocrinologists and other specialists to monitor the effectiveness of the treatment and detect new components of the disease. We report a variant of type 1 autoimmune polyglandular syndrome. Special emphasis is laid on the importance of succession of actions of endocrinologists and specialists in related medical disciplines dealing with children and adult patients.