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Sample records for prevents progressive dopamine

  1. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease

    PubMed Central

    Sánchez-Pernaute, Rosario; Ferree, Andrew; Cooper, Oliver; Yu, Meixiang; Brownell, Anna-Liisa; Isacson, Ole

    2004-01-01

    Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration. PMID:15285796

  2. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  3. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  4. Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction.

    PubMed

    Rivera, Alicia; Gago, Belén; Suárez-Boomgaard, Diana; Yoshitake, Takashi; Roales-Buján, Ruth; Valderrama-Carvajal, Alejandra; Bilbao, Ainhoa; Medina-Luque, José; Díaz-Cabiale, Zaida; Craenenbroeck, Kathleen Van; Borroto-Escuela, Dasiel O; Kehr, Jan; Rodríguez de Fonseca, Fernando; Santín, Luis; de la Calle, Adelaida; Fuxe, Kjell

    2016-05-22

    Morphine is one of the most effective drugs used for pain management, but it is also highly addictive. Morphine elicits acute and long-term adaptive changes at cellular and molecular level in the brain, which play a critical role in the development of tolerance, dependence and addiction. Previous studies indicated that the dopamine D4 receptor (D4 R) activation counteracts morphine-induced adaptive changes of the μ opioid receptor (MOR) signaling in the striosomes of the caudate putamen (CPu), as well as the induction of several Fos family transcription factors. Thus, it has been suggested that D4 R could play an important role avoiding some of the addictive effects of morphine. Here, using different drugs administration paradigms, it is determined that the D4 R agonist PD168,077 prevents morphine-induced activation of the nigrostriatal dopamine pathway and morphological changes of substantia nigra pars compacta (SNc) dopamine neurons, leading to a restoration of dopamine levels and metabolism in the CPu. Results from receptor autoradiography indicate that D4 R activation modulates MOR function in the substantia nigra pars reticulata (SNr) and the striosomes of the CPu, suggesting that these regions are critically involved in the modulation of SNc dopamine neuronal function through a functional D4 R/MOR interaction. In addition, D4 R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. These results provide a novel role of D4 R agonist as a pharmacological strategy to prevent the adverse effects of morphine in the treatment of pain.

  5. Dopamine agonists in prevention of ovarian hyperstimulation syndrome.

    PubMed

    Kasum, Miro; Vrčić, Hrvoje; Stanić, Patrik; Ježek, Davor; Orešković, Slavko; Beketić-Orešković, Lidija; Pekez, Marijeta

    2014-01-01

    The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4-21 days), the dose of cabergoline (0.5 mg or 0.25 mg orally) and in the regimens used. At present, the best known effective regimen is 0.5 mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5 mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome.

  6. Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

    PubMed Central

    Bayliss, Jacqueline A.; Lemus, Moyra B.; Santos, Vanessa V.; Deo, Minh; Davies, Jeffrey S.; Kemp, Bruce E.; Elsworth, John D.

    2016-01-01

    Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson’s Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin’s neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD. PMID:27467571

  7. Preventing Breast Cancer: Making Progress

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... 000 women will have been diagnosed with invasive breast cancer, and nearly 41,000 women will die from ...

  8. Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion

    PubMed Central

    Wilson, Charles R. E.; Vezoli, Julien; Faraut, Maïlys C. M.; Leviel, Vincent; Knoblauch, Kenneth; Procyk, Emmanuel

    2016-01-01

    Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control—two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss. PMID:27824858

  9. Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

    PubMed Central

    Willuhn, Ingo; Burgeno, Lauren M.; Everitt, Barry J.; Phillips, Paul E. M.

    2012-01-01

    Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine. PMID:23184975

  10. Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use.

    PubMed

    Willuhn, Ingo; Burgeno, Lauren M; Everitt, Barry J; Phillips, Paul E M

    2012-12-11

    Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.

  11. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety.

    PubMed

    Zweifel, Larry S; Fadok, Jonathan P; Argilli, Emmanuela; Garelick, Michael G; Jones, Graham L; Dickerson, Tavis M K; Allen, James M; Mizumori, Sheri J Y; Bonci, Antonello; Palmiter, Richard D

    2011-05-01

    Generalized anxiety is thought to result, in part, from impairments in contingency awareness during conditioning to cues that predict aversive or fearful outcomes. Dopamine neurons of the ventral midbrain exhibit heterogeneous responses to aversive stimuli that are thought to provide a critical modulatory signal to facilitate orientation to environmental changes and assignment of motivational value to unexpected events. Here we describe a mouse model in which activation of dopamine neurons in response to an aversive stimulus is attenuated by conditional genetic inactivation of functional NMDA receptors on dopamine neurons. We discovered that altering the magnitude of excitatory responses by dopamine neurons in response to an aversive stimulus was associated with impaired conditioning to a cue that predicts an aversive outcome. Impaired conditioning by these mice was associated with the development of a persistent, generalized anxiety-like phenotype. These data are consistent with a role for dopamine in facilitating contingency awareness that is critical for the prevention of generalized anxiety.

  12. Progress toward a Prevention Perspective

    ERIC Educational Resources Information Center

    Stagner, Matthew W.; Lansing, Jiffy

    2009-01-01

    Matthew Stagner and Jiffy Lansing chart developments in the field of child maltreatment and propose a new framework for preventing child abuse and neglect. They begin by describing the concept of investment-prevention as it has been applied recently in fields such as health care and welfare. They then explain how the new framework applies to…

  13. Prevention | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Progress toward a prevention perspective.

    PubMed

    Stagner, Matthew W; Lansing, Jiffy

    2009-01-01

    Matthew Stagner and Jiffy Lansing chart developments in the field of child maltreatment and propose a new framework for preventing child abuse and neglect. They begin by describing the concept of investment-prevention as it has been applied recently in fields such as health care and welfare. They then explain how the new framework applies to maltreatment prevention, noting in particular how it differs from the traditional child protective services response to maltreatment. Whereas the traditional response aims to prevent a recurrence of maltreatment once it has already taken place, the new framework focuses on preventing maltreatment from occurring at all. Rather than identifying risk factors for maltreatment and addressing the problems and deficiencies of the primary caretaker, the new framework focuses on strengthening protective factors and building family and social networks to reinforce the ability of parents to care for their children. Whereas the orientation of the traditional child welfare service approach is legal and medical, the new framework has a more developmental and ecological orientation. It aims to build on the strengths children have at particular points of the life stage and enhance the social context of the child. Rather than putting families into the hands of unknown professionals who shuffle them from one program to another, including foster care, the investment-prevention model seeks to integrate professionals and paraprofessionals from the family's community into their everyday life, as well as to ensure an interconnected system of services. Finally, rather than seeking to minimize harm to the child, it aims to maximize potential--to strengthen the capacity of parents and communities to care for their children in ways that promote well-being. Researchers have struggled to define maltreatment, identify its causes, and assess its consequences and costs. In recent years, however, researchers have clarified the severe consequences of child

  15. Dopamine Transporter Imaging Assessment of Parkinson’s Disease Progression

    DTIC Science & Technology

    2000-08-01

    terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkison’s disease during a nine month...the r te of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation in...will directly evaluate in vivo the rate of ongoing dopaminergic ne ronal degeneration in early Parkinson’s disease , whether the rate of ongoing

  16. Dopamine Transporter Imaging Assessment of Parkinson’s Disease Progression

    DTIC Science & Technology

    2001-08-01

    terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkinson’s disease during a rime...dopa on the rate of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation...in early Parkinson’s disease , whether the rate of neuronal degeneration is affected by L-dopa, a potential neurotoxin, and whether the changes in

  17. Preventing effects of a novel anti-parkinsonian agent zonisamide on dopamine quinone formation.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Diaz-Corrales, Francisco J; Miyoshi, Ko; Ogawa, Norio; Murata, Miho

    2008-01-01

    The neurotoxicity of dopamine (DA) quinones as dopaminergic neuron-specific oxidative stress is considered to play a role in the pathogenesis and/or progression of Parkinson's disease (PD), since DA quinones conjugate with several key PD pathogenic molecules (e.g., tyrosine hydroxylase, alpha-synuclein and parkin) to form protein-bound quinone (quinoprotein) and consequently inhibit their functions. Zonisamide (ZNS) is used as an anti-epileptic agent but also improved the cardinal symptoms of PD in recent clinical trials in Japan. To evaluate the effects of ZNS on excess cytosolic free DA-induced quinone toxicity, we examined changes in DA quinone-related indices after ZNS treatment both in in vitro cell-free system and in cultured cells. Co-incubation of DA and ZNS in a cell-free system caused conversion of DA to stable melanin via formation of DA-semiquinone radicals and DA chrome. Long-term (5 days) treatment with ZNS decreased quinoprotein and increased DA/DOPA chromes in dopaminergic CATH.a cells. ZNS significantly inhibited quinoprotein formation induced by treatment with tetrahydrobiopterin and ketanserin that elevate cytosolic free DA in the cells. Our results suggest that the novel anti-parkinsonian agent ZNS possesses preventing effects against DA quinone formation induced by excess amount of cytosolic DA outside the synaptic vesicles.

  18. Intracellular Methamphetamine Prevents the Dopamine-induced Enhancement of Neuronal Firing*

    PubMed Central

    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D.; Lin, Landon M.; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-01-01

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na+ or Cl− ion. Although isosmotic substitution of extracellular Na+ ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl− ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons. PMID:24962577

  19. Intracellular methamphetamine prevents the dopamine-induced enhancement of neuronal firing.

    PubMed

    Saha, Kaustuv; Sambo, Danielle; Richardson, Ben D; Lin, Landon M; Butler, Brittany; Villarroel, Laura; Khoshbouei, Habibeh

    2014-08-08

    The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na(+) or Cl(-) ion. Although isosmotic substitution of extracellular Na(+) ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl(-) ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons.

  20. Fatigue-related impairments in oculomotor control are prevented by norepinephrine-dopamine reuptake inhibition

    PubMed Central

    Connell, Charlotte J. W.; Thompson, Benjamin; Turuwhenua, Jason; Srzich, Alexa; Gant, Nicholas

    2017-01-01

    Fatigue-induced reductions in saccade velocity have been reported following acute, prolonged exercise. Interestingly, the detrimental impact of fatigue on oculomotor control can be prevented by a moderate dose of caffeine. This effect may be related to central catecholamine upregulation via caffeine’s action as an adenosine antagonist. To test this hypothesis, we compared the protective effect of caffeine on oculomotor control post-exercise to that of a norepinephrine-dopamine reuptake inhibitor. Within a placebo-controlled crossover design, 12 cyclists consumed placebo, caffeine or a norepinephrine-dopamine reuptake inhibitor (bupropion) during 180 minutes of stationary cycling. Saccades, smooth pursuit and optokinetic nystagmus were measured using infrared oculography. Exercise fatigue was associated with an 8 ± 11% reduction in the peak velocity of prosaccades, and a 10 ± 11% decrement in antisaccade peak velocity. Optokinetic nystagmus quick phases decreased in velocity by 15 ± 17%. These differences were statistically significant (p < 0.05). Norepinephrine-dopamine reuptake inhibition and caffeine prevented fatigue-related decrements in eye movement velocity. Pursuit eye movements and visual attention were unaffected. These findings show that norepinephrine-dopamine reuptake inhibition protects oculomotor function during exercise fatigue. Caffeine’s fatigue-reversing effects on eye movements appear to be mediated, at least in part, via modulation of central catecholamines. PMID:28198465

  1. Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

    PubMed

    Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

    1997-07-30

    To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

  2. Uptake of taurine, GABA, 5-HT, and dopamine by blood platelets in progressive myoclonus epilepsy.

    PubMed

    Airaksinen, E M

    1979-10-01

    The uptakes of four neurotransmitters (taurine, GABA, 5-HT, and dopamine) by blood platelets from patients with degenerative-type progressive myoclonus epilepsy (PME) and from controls were studied using different incubation times and different concentrations. Only the uptakes of taurine differed significantly between patients and controls: patients' uptakes were 70% to 80% of control values at 10, 30, 60, and 120 min of incubation time. Km values were approximately the same, but Vmax values in PME patients were lower, showing quantitative but not qualitative differences in taurine uptake by platelets in PME. These results suggest that a defect or an inhibitory mechanism of some factor needed in the transport or binding of taurine (but not of GABA, 5-HT, and dopamine) is present in PME.

  3. Conditional Knockout of NMDA Receptors in Dopamine Neurons Prevents Nicotine-Conditioned Place Preference

    PubMed Central

    Phillip Wang, Lei; Li, Fei; Shen, Xiaoming; Tsien, Joe Z.

    2010-01-01

    Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction. PMID:20062537

  4. Conditional knockout of NMDA receptors in dopamine neurons prevents nicotine-conditioned place preference.

    PubMed

    Wang, Lei Phillip; Li, Fei; Shen, Xiaoming; Tsien, Joe Z

    2010-01-07

    Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.

  5. Bromocryptine prevents the decline in tuberoinfundibular neuronal release of dopamine after removal of chronic estrogen treatment

    SciTech Connect

    Gottschall, P.E.; Meites, J.

    1987-11-01

    Prolonged exposure to estradiol 17-..beta.. (E/sub 2/) in rats has been shown to decrease dopamine (DA) synthesis in and release from tuberoinfundibular dopaminergic (TIDA) neurons in Fischer 344 rats. The objective of the present study was to determine whether inhibition of the E/sub 2/-induced increase in anterior pituitary (AP) weight and prolactin (PRL) secretion by concomitant administration of the dopaminergic agonist, bromocryptine, could prevent the decrease in TIDA neuronal function produced by chronic E/sub 2/ administration. TIDA neuronal function was evaluated by in vitro superfusion and electrical stimulation of median eminence (ME) tissue after allowing for accumulation of (/sup 3/H) dopamine (DA). The effect of chronic E/sub 2/ and/or bromocryptine treatment on catecholamine content in tuberohypophyseal neurons in the neurointermediate lobe was also measured to determine whether increased pituitary size possibly damaged the tuberohypophyseal neurons.

  6. Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis

    PubMed Central

    Tadokoro, Shigenori; Okamura, Naoe; Sekine, Yoshimoto; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi

    2012-01-01

    Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia. PMID:21402722

  7. Hanford Site pollution prevention progress report

    SciTech Connect

    BETSCH, M.D.

    1999-10-05

    The Richland Operations Office (RL) and Office of River Protection (ORP) are pleased to issue the attached Pollution Prevention Progress Report. We have just met the most aggressive waste reduction and A recycling goals to date and are publishing this report to recognize A the site's progress, and to ensure it will sustain success beyond 1 Fiscal Year 2000. This report was designed to inform the been made by RL and ORP in Waste Minimization (WMin) and Pollution Prevention (P2). RL, ORP and their contractors are committed to protecting the environment, and we reiterate pollution prevention should continue to be at the forefront of the environmental cleanup and research efforts. As you read the attached report, we believe you will see a clear demonstration of RL and ORP's outstanding performance as it has been responsible and accountable to the nation, its employees, and the community in which we live and work. commitment that all employees have for environmental stewardship. The report provides useful information about the U.S. Department of Energy's (DOE'S) environmental policy and programs, and contains countless examples of waste minimization projects. This year was the first year our site received the White House Closing the Circle in the category of Affirmative Procurement. This Award recognizes our site for designing a comprehensive strategy for achieving 100 percent purchases of the U.S.Environmenta1 Protection Agency designated recycled items. DOE-Headquarters also acknowledged the site in 1999 for its public outreach efforts in communicating pollution prevention to Hanford Site employees and the community. Our site is truly a recognized leader in outreach as it has kept this title for two consecutive years. In previous years, we received the White House Closing the Circle Honorable Mention in Affirmative Procurement and several other National DOE Awards. Through partnership with the local community and stakeholders, the site and its contractors have a clear

  8. LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function

    PubMed Central

    Sloan, Max; Alegre-Abarrategui, Javier; Potgieter, Dawid; Kaufmann, Anna-Kristin; Exley, Richard; Deltheil, Thierry; Threlfell, Sarah; Connor-Robson, Natalie; Brimblecombe, Katherine; Wallings, Rebecca; Cioroch, Milena; Bannerman, David M.; Bolam, J. Paul; Magill, Peter J.; Cragg, Stephanie J.; Dodson, Paul D.; Wade-Martins, Richard

    2016-01-01

    Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18–21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics. PMID:26744332

  9. Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction.

    PubMed

    Pascoli, Vincent; Terrier, Jean; Hiver, Agnès; Lüscher, Christian

    2015-12-02

    The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.

  10. Nifedipine prevents iron accumulation and reverses iron-overload-induced dopamine neuron degeneration in the substantia nigra of rats.

    PubMed

    Ma, ZeGang; Zhou, Yu; Xie, JunXia

    2012-11-01

    The mechanisms of iron accumulation in substantia nigra (SN) of Parkinson's diseases remain unclear. The objective of this study was to investigate effects of nifedipine on iron-overload-induced iron accumulation and neurodegeneration in SN of rats. By high performance liquid chromatography-electrochemical detection, tyrosine hydroxylase (TH) immunohistochemistry, and iron content array, we first quantified iron content and the number of dopamine neurons in SN of experimental rats treated with iron dextran. We further assessed effects of treatment with nifedipine. Our results showed that nifedipine treatment prevents iron dextran-induced dopamine depletion in the striatum. Consistently, we found that nifedipine restores the number of TH-positive neurons reduced by iron dextran overload and prevents increase of iron content in the SN. These results suggested that nifedipine may suppress iron toxicity in dopamine neurons and prevent neurodegeneration.

  11. Concise Review: Using Stem Cells to Prevent the Progression of Myopia-A Concept.

    PubMed

    Janowski, Miroslaw; Bulte, Jeff W M; Handa, James T; Rini, David; Walczak, Piotr

    2015-07-01

    The prevalence of myopia has increased in modern society due to the educational load of children. This condition is growing rapidly, especially in Asian countries where it has already reached a pandemic level. Typically, the younger the child's age at the onset of myopia, the more rapidly the condition will progress and the greater the likelihood that it will develop the known sight-threatening complications of high myopia. This rise in incidence of severe myopia has contributed to an increased frequency of eye diseases in adulthood, which often complicate therapeutic procedures. Currently, no treatment is available to prevent myopia progression. Stem cell therapy can potentially address two components of myopia. Regardless of the exact etiology, myopia is always associated with scleral weakness. In this context, a strategy aimed at scleral reinforcement by transplanting connective tissue-supportive mesenchymal stem cells is an attractive approach that could yield effective and universal therapy. Sunlight exposure appears to have a protective effect against myopia. It is postulated that this effect is mediated via local ocular production of dopamine. With a variety of dopamine-producing cells already available for the treatment of Parkinson's disease, stem cells engineered for dopamine production could be used for the treatment of myopia. In this review, we further explore these concepts and present evidence from the literature to support the use of stem cell therapy for the treatment of myopia. © 2015 AlphaMed Press.

  12. Concise Review: Using Stem Cells to Prevent the Progression of Myopia – A Concept

    PubMed Central

    Janowski, Miroslaw; Bulte, Jeff W.M.; Handa, James T.; Rini, David; Walczak, Piotr

    2016-01-01

    The prevalence of myopia has increased in modern society due to the educational load of children. This condition is growing rapidly, especially in Asian countries where it has already reached a pandemic level. Typically, the younger the child’s age at the onset of myopia, the more rapidly the condition will progress and the greater the likelihood that it will develop the known sight-threatening complications of high myopia. This rise in incidence of severe myopia has contributed to an increased frequency of eye diseases in adulthood, which often complicate therapeutic procedures. Currently, no treatment is available to prevent myopia progression. Stem cell therapy can potentially address two components of myopia. Regardless of the exact etiology, myopia is always associated with scleral weakness. In this context, a strategy aimed at scleral reinforcement by transplanting connective tissue-supportive mesenchymal stem cells (MSCs) is an attractive approach that could yield effective and universal therapy. Sunlight exposure appears to have a protective effect against myopia. It is postulated that this effect is mediated via local ocular production of dopamine. With a variety of dopamine-producing cells already available for the treatment of Parkinson’s disease, stem cells engineered for dopamine production could be utilized for the treatment of myopia. In this review, we further explore these concepts and present evidence from the literature to support the use of stem cell therapy for the treatment of myopia. PMID:25752937

  13. Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history.

    PubMed

    Chen, Hengxi; Fu, Jing; Huang, Wei

    2016-07-25

    Hyperprolactinemia is the presence of abnormally high circulating levels of prolactin. Idopathic hyperprolactinemia is the term used when no cause of prolactin hypersecretion can be identified and it is causally related to the development of miscarriage in pregnant women, especially women who have a history of recurrent miscarriage. A possible mechanism is that high levels of prolactin affect the function of the ovaries, resulting in a luteal phase defect and miscarriage. A dopamine agonist is a compound with high efficacy in lowering prolactin levels and restoring gonadal function. To assess the effectiveness and safety of different types of dopamine agonists in preventing future miscarriage given to women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2016) and reference lists of retrieved studies. Randomized controlled trials (RCTs) in all languages examining the effect of dopamine agonists on preventing future miscarriage. Women who had idiopathic hyperprolactinemia with a history of recurrent miscarriages were eligible for inclusion in this review. Comparisons planned included: dopamine agonists alone versus placebo/no treatment; and dopamine agonists combined with other therapy versus other therapy alone. Two review authors independently assessed a single trial for inclusion, evaluated trial quality and extracted data. Data were checked for accuracy. One study (recruiting 48 women with idiopathic hyperprolactinemia) met our inclusion criteria; 46 women (42 pregnancies - 4/46 women did not conceive during the study period) were included in the analysis. The study compared the use of a dopamine agonist (bromocriptine, 2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus a no-treatment control. The study was judged as being at a high risk of bias. It was not possible to carry out meta-analysis due to insufficient data.The study

  14. Outcomes of assisted reproduction treatment after dopamine agonist -cabergoline- for prevention of ovarian hyper stimulation syndrome

    PubMed Central

    Movahedi, Shohreh; Safdarian, Leili; Agahoseini, Marzieh; Aleyasin, Ashraf; Khodaverdi, Sepideh; Asadollah, Sara; Kord Valeshabad, Ali; Fallahi, Parvin; Rezaeeian, Zahra

    2016-01-01

    Background: Release of vascular endothelial growth factor (VEGF) by ovaries in response to HCG administration is one of the main mechanisms of ovarian hyper stimulation syndrome. Since Dopamine/dopamine receptor2 (Dp-r2) pathway activity -mediated by VEGF/ Vascular endothelial growth factor receptor 2 (VEGFR- 2) signaling-, is associated with angiogenic events, dopamine agonists were used for the management of severe forms of OHSS. In order to assess the effects of Cabergoline on angiogenesis in the human endometrium, and subsequently its impacts on the implantation rate this study was conducted. Methods: This historical cohort study was conducted based on existing data of 115 patients (20-40 years) whom underwent assisted reproductive treatment (ART) and with a high probability for developing OHSS between March 2007 and September 2008. Forty five cases received Cabergoline were compared to 70 control subjects. The statistical methods used were: Unpaired t-test for continuous variables and the chi-square test (or Fisher’s exact test if required) for categorical variables. Results: None of the patients (treatment or control group) developed OHSS. The etiologies of infertility and administration of GnRH agonist or antagonist protocols were similar in two groups (p>0.2). Number of transferred embryos and zygote intra-fallopian transfer (ZIFT) did not differ between the two groups (p≥0.06). Implantation rate in treatment (3.1%) and control (6.6%) subjects was similar (p=0.4). No significant difference was observed in fertilization rate, chemical, clinical and ongoing pregnancies between the two groups (p>0.5). Conclusion: Cabergoline can be safely administered in ART protocols to prevent OHSS, without compromising ART outcomes. PMID:27493915

  15. Tofacitinib prevents radiographic progression in rheumatoid arthritis.

    PubMed

    Kim, Joon Wan; Choi, In Ah; Lee, Eun Young; Song, Yeong Wook; Lee, Eun Bong

    2013-08-01

    Tofacitinib, a novel Janus kinase inhibitor, may prevent structural damage in rheumatoid arthritis (RA). In this cohort study, we compared radiographic progression of hand joints between 21 RA patients who took tofacitinb for 18 months in a phase IIb and its extension study and 42 patients who took conventional disease modifying antirheumatic drugs (DMARDs), using simple erosion narrowing score. For tofacitinib group, changes before and after the treatment were also compared. The changes of erosion and sum scores were significantly less in tofacitinib than DMARDs group (for erosion, -0.60 ± 1.83 vs 0.51 ± 1.77, P = 0.038; for sum, -0.50 ± 1.72 vs 1.57 ± 4.13, P = 0.012). Joint space narrowing score (JSN) was also less in tofacitinib group (0.095 ± 0.58 vs 1.06 ± 2.60, P = 0.055). In tofacitinib group, yearly rates of both erosion and JSN were significantly decreased after administration of tofacitinib (For erosion, 0.62 ± 0.93 to -0.14 ± 0.48, P = 0.009; for JSN, 0.47 ± 0.64 to 0.03 ± 0.40, P = 0.032), as was change of sum score (1.09 ± 1.27 to -0.10 ± 0.63, P < 0.001). In conclusion, tofacitinib may prevent structural damage caused by RA.

  16. Dopamine-Induced Changes in Serum Erythropoietin and Creatinine Clearance Reflect Risk Factors for Progression of IgA Nephropathy.

    PubMed

    Sulikowska, Beata; Johnson, Richard J; Wiechecka-Korenkiewicz, Joanna; Korenkiewicz, Jadwiga; Marszalek, Andrzej; Odrowaz-Sypniewska, Grazyna; Manitius, Jacek

    2015-08-01

    The infusion of low-dose dopamine is normally associated with an increase in creatinine clearance, thereby allowing one to assess renal functional reserve. Increased renal blood flow is also associated with a reduction in erythropoietin (EPO) levels. We evaluated the use of dopamine infusion in subjects with IgA nephropathy to determine if these functional changes correlate with risk factors for progression and compared this to the renal biopsy findings. Changes in creatinine clearance and EPO levels were determined in 46 non-nephrotic IgA patients with relative preserved renal function after the infusion of low dose dopamine. Control subjects (n = 15) were evaluated using similar protocols. Subjects with IgA nephropathy could be separated into those who showed a fall in EPO levels (n = 24) and those who showed no change or a rise in EPO levels (n = 22). Subjects showing the expected fall in EPO demonstrated a higher increase in creatinine clearance, similar to that observed in control subjects. Most importantly, subjects who showed a fall in EPO had less proteinuria, less N-acetyl-β-D-glucosaminidase excretion, lower serum uric acid, blood pressure, and less features of metabolic syndrome despite similar inflammation and fibrosis on biopsy as compared to the others. A decrease in EPO in response to dopamine is associated with a clinical phenotype that is less likely to develop progressive renal disease. These studies suggest that a fall in EPO in response to dopamine likely reflects preserved tubulointerstitial function that cannot be assessed by renal biopsy alone.

  17. Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat.

    PubMed

    Meng, Tao; Zheng, Zhi-Hong; Liu, Ting-Ting; Lin, Ling

    2012-05-01

    Both dopamine (DA) and melatonin (MLT) are abundant neuromodulators located in vertebrate retina. The retinal DA deficiency and variations in MLT levels have been linked to Parkinson's disease (PD). No studies have investigated the ipsilateral and contralateral DA and MLT in retina and their relationships in 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats. We established PD rat model by unilateral injection of 6-OHDA into the right substantia nigra and the right medial forebrain bundle. Eye tissue was collected and the levels of MLT and DA were measured twice daily at 10:00 and 22:00. The concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic (DOPAC) and homovanillic acid (HVA), as well as MLT were determined by HPLC. The results show that DA levels in the eye contralateral to the side of a unilateral intracerebral 6-OHDA lesion significantly decreased (P < 0.001). Both the ratios of DOPAC/DA and HVA/DA were increased in comparison with the vehicle groups after 3 weeks post-lesion. The concentrations of MLT at 10:00 and 22:00 in both eyes were distinctly increased compared with the vehicle groups (P < 0.05). The change of DA and its metabolites, as well as MLT appeared to correlate well with the rotation behavior of rats. These findings suggest that rats receive a unilateral intracerebral injection of 6-OHDA that mainly causes the contralateral eye destruction of DA-containing neurons. Increased retinal MLT level probably is associated with the progression of PD.

  18. Prevention Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

    PubMed

    Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

    2017-07-27

    Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  20. Progress in Neuroprotective Strategies for Preventing Epilepsy

    PubMed Central

    Acharya, Munjal M.; Hattiangady, Bharathi; Shetty, Ashok K.

    2008-01-01

    Neuroprotection is increasingly considered as a promising therapy for preventing and treating temporal lobe epilepsy (TLE). The development of chronic TLE, also termed as epileptogenesis, is a dynamic process. An initial precipitating injury (IPI) such as the status epilepticus (SE) leads to neurodegeneration, abnormal reorganization of the brain circuitry and a significant loss of functional inhibition. All of these changes likely contribute to the development of chronic epilepsy, characterized by spontaneous recurrent motor seizures (SRMS) and learning and memory deficits. The purpose of this review is to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating chronic TLE. Although the administration of certain conventional and new generation antiepileptic drugs is effective for primary neuroprotection such as reduced neurodegeneration after acute seizures or the SE, their competence for preventing the development of chronic epilepsy after an IPI is either unknown or not promising. On the other hand, alternative strategies such as the ketogenic diet therapy, administration of distinct neurotrophic factors, hormones or antioxidants seem useful for preventing and treating chronic TLE. However, long term studies on the efficacy of these approaches introduced at different time-points after the SE or an IPI are lacking. Additionally, grafting of fetal hippocampal cells at early time-points after an IPI holds considerable promise for preventing TLE, though issues regarding availability of donor cells, ethical concerns, timing of grafting after SE, and durability of graft-mediated seizure suppression need to be resolved for further advances with this approach. Overall, from the studies performed so far, there is consensus that neuroprotective strategies need to be employed as quickly as possible after the onset of the SE or an IPI for

  1. Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia.

    PubMed

    Gil-Navarro, S; Lomeña, F; Cot, A; Lladó, A; Montagut, N; Castellví, M; Bosch, B; Rami, L; Antonell, A; Balasa, M; Pavia, J; Iranzo, A; Molinuevo, J L; Sánchez-Valle, R

    2013-11-01

    Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aβ42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I

  2. Getting Personal: Progress and Pitfalls in HIV Prevention among Latinas

    ERIC Educational Resources Information Center

    Amaro, Hortensia; Raj, Anita; Reed, Elizabeth; Ulibarri, Monica

    2011-01-01

    This article first presents the political, personal, and epidemiological context of Hortensia Amaro's 1988 publication in "Psychology of Women Quarterly" ("PWQ"), "Considerations for Prevention of HIV Infection Among Hispanic Women" (Amaro, 1988). Second, it provides a brief summary of progress in HIV prevention with Latinas. The third section…

  3. Getting Personal: Progress and Pitfalls in HIV Prevention among Latinas

    ERIC Educational Resources Information Center

    Amaro, Hortensia; Raj, Anita; Reed, Elizabeth; Ulibarri, Monica

    2011-01-01

    This article first presents the political, personal, and epidemiological context of Hortensia Amaro's 1988 publication in "Psychology of Women Quarterly" ("PWQ"), "Considerations for Prevention of HIV Infection Among Hispanic Women" (Amaro, 1988). Second, it provides a brief summary of progress in HIV prevention with Latinas. The third section…

  4. Conjugation of Hyaluronic Acid onto Surfaces via the Interfacial Polymerization of Dopamine to Prevent Protein Adsorption.

    PubMed

    Huang, Renliang; Liu, Xia; Ye, Huijun; Su, Rongxin; Qi, Wei; Wang, Libing; He, Zhimin

    2015-11-10

    A versatile, convenient, and cost-effective method that can be used for grafting antifouling materials onto different surfaces is highly desirable in many applications. Here, we report the one-step fabrication of antifouling surfaces via the polymerization of dopamine and the simultaneous deposition of anionic hyaluronic acid (HA) on Au substrates. The water contact angle of the Au surfaces decreased from 84.9° to 24.8° after the attachment of a highly uniform polydopamine (PDA)/HA hybrid film. The results of surface plasmon resonance analysis showed that the Au-PDA/HA surfaces adsorbed proteins from solutions of bovine serum albumin, lysozyme, β-lactoglobulin, fibrinogen, and soybean milk in ultralow or low amounts (4.8-31.7 ng/cm(2)). The hydrophilicity and good antifouling performance of the PDA/HA surfaces is attributable to the HA chains that probably attached onto their upper surface via hydrogen bonding between PDA and HA. At the same time, the electrostatic repulsion between PDA and HA probably prevents the aggregation of PDA, resulting in the formation of a highly uniform PDA/HA hybrid film with the HA chains (with a stretched structure) on the upper surface. We also developed a simple method for removing this PDA/HA film and recycling the Au substrates by using an aqueous solution of NaOH as the hydrolyzing agent. The Au surface remained undamaged, and a PDA/HA film could be redeposited on the surface, with the surface exhibiting good antifouling performance even after 10 such cycles. Finally, it was found that this grafting method is applicable to other substrates, including epoxy resins, polystyrene, glass, and steel, owing to the strong adhesion of PDA with these substrates.

  5. Positive association between--1021TT genotype of dopamine beta hydroxylase gene and progressive behavior of injection heroin users.

    PubMed

    Xie, Xiaohu; Xu, Limin; Liu, Huifen; Chen, Weisheng; Zhuang, Dingding; Zhang, Jianbing; Duan, Shiwei; Zhou, Wenhua

    2013-04-29

    By balancing the ratios of dopamine and norepinephrine, dopamine beta hydroxylase (DBH) plays an important role in brain reward circuit that is involved with behavioral effects of heroin addiction. DBH -1021C/T (rs1611115) is a functional variant with strong correlation with plasma DBH activity and several nerval and psychic disorders. In the present study, we have collected 333 male cases with heroin addiction and 200 male healthy controls to explore the role of -1021C/T in heroin addiction. There is no evidence of association between -1021C/T and heroin addiction on both genotype and allele levels (P>0.05). In the injection subgroup of cases, -1021TT carriers have longer heroin addiction time (P<0.001) and higher dosage of self-administered heroin (P=0.045) than carriers with -1021CC or -1021CT, suggesting that patients with TT genotype are likely to have more progressive style of heroin users with injection route. In conclusion, our results support -1021TT genotype may be implicated with a more progressive nature of heroin addiction, although DBH -1021C/T is unlikely to be involved in the risk of heroin addiction.

  6. Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness?

    PubMed

    Wienecke, Miriam; Werth, Esther; Poryazova, Rositsa; Baumann-Vogel, Heide; Bassetti, Claudio L; Weller, Michael; Waldvogel, Daniel; Storch, Alexander; Baumann, Christian R

    2012-12-01

    Sleep-wake disturbances are frequent in patients with Parkinson's disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep-wake disturbances in Parkinson's disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson's disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson's disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin-deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson's disease. Poorer sleep quality is linked to dopamine deficiency and other disease-related factors. Despite hypocretin cell loss in Parkinson's disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

  7. [Can progression of myopia be prevented? A literature review].

    PubMed

    Jensen, H

    1992-08-03

    There is no simple explanation as to when or how myopia commences, nor is there any simple method of preventing the progression of myopia. Non-surgical methods have been attempted: sight training, exercise, drugs to induce cycloplegia and to reduce intraocular pressure, as well as contact lenses and bifocal glasses; none of these have been able to prevent progression. Promising results have been disappointing when these treatments are repeated on larger groups of patients without investigator bias. Surgical procedures for the prevention of progression are not carried out in Denmark at present. New methods of reinforcing the scleral wall also in low grade myopia have been reported from Moscow. Compounds are being injected and transplants are being inserted behind the eye. It is exciting to see whether these results can be reproduced, if trial of this type of treatment is permitted in Denmark.

  8. Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study.

    PubMed

    Alfaro-Rodriguez, Alfonso; Alonso-Spilsbury, María; Arch-Tirado, Emilio; Gonzalez-Pina, Rigoberto; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

    2013-09-27

    Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 μM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 μM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 μM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.

  9. PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia.

    PubMed

    Beyaert, Michael G R; Daya, Ritesh P; Dyck, Bailey A; Johnson, Rodney L; Mishra, Ram K

    2013-03-01

    Allosteric modulators are emerging as new therapeutics for the treatment of psychiatric illnesses, such as schizophrenia. Conventional antipsychotic drugs are typically dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric site, and block excessive dopamine neurotransmission in the brain. However, they are unable to treat all symptoms of schizophrenia and often cause adverse motor and metabolic side effects. The binding profile of allosteric modulators differs, as they interact with their receptor at a novel binding site and their activity is determined by physiological signaling. In collaboration, our laboratories have synthesized and evaluated over 185 compounds for their allosteric modulatory activity at the dopamine D2 receptor. Of these compounds, PAOPA is among the most potent allosteric modulators, and has been shown to be effective in treating the MK-801 induced preclinical animal model of schizophrenia. The objective of this study was to evaluate PAOPA's ability to prevent and reverse behavioral abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia. Amphetamine sensitized rats were given PAOPA during sensitization and following sensitization to determine whether PAOPA is able to prevent and reverse behavioral abnormalities. Furthermore, changes in post-mortem dopamine levels were measured by high performance liquid chromatography in various brain regions. The results presented demonstrate that PAOPA is able to prevent and reverse behavioral and biochemical abnormalities in an amphetamine-sensitized animal model of schizophrenia. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  10. The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.

    PubMed

    Terleckyj, I; Sonsalla, P K

    1994-04-01

    The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

  11. Prevention of dementia: lessons from SYST-EUR and PROGRESS.

    PubMed

    Hanon, Olivier; Forette, Françoise

    2004-11-15

    Hypertension is one of the principal risk factors for cerebrovascular diseases, closely correlated also with cognitive decline and dementia. Data from recent therapeutic trials (SYST-EUR, PROGRESS) open the way toward the prevention of dementia (vascular or Alzheimer's type) by antihypertensive treatments. The results of these two studies suggest different mechanisms of action of antihypertensive drugs in the prevention of cognitive decline. The use of angiotensin converting enzyme (ACE) inhibitors, with or without diuretics, resulted in decrease incidence of stroke-related dementia, but dementia without stroke was not reduced. With the dihydropyridine calcium antagonists, a reduction in both Alzheimer's type and vascular dementia was demonstrated.

  12. Hanford site pollution prevention plan progress report, 1993

    SciTech Connect

    Kirkendall, J.R.

    1996-08-26

    This report tracks progress made during 1995 against the goals stated in DOE/RL-92-62, Executive Summary, Hanford Site Pollution Prevention Plan. The Executive Summary of the plan was submitted to the Washington State Department of Ecology (Ecology) in September 1992. The plan, Executive Summary, and the progress reports are elements of a pollution prevention planning program that is required by WAC 173-307,`Plans,` for all hazardous substance users and/or all hazardous waste generators regulated by Ecology. These regulations implement RCW 70.95C, `Waste Reduction,` an act relating to hazardous waste reduction. The act encourages voluntary efforts to redesign industrial processes to help reduce or eliminate hazardous substances and hazardous waste byproducts, and to maximize the in- process reuse or reclamation of valuable spent material.

  13. Annual report of waste generation and pollution prevention progress, 1994

    SciTech Connect

    1996-09-01

    This Report summarizes the waste generation and pollution prevention activities of the major operational sites in the Department of Energy (DOE). We are witnessing progress in waste reduction from routine operations that are the focus of Department-wide reduction goals set by the Secretary on May 3,1996. The goals require that by the end of 1999, we reduce, recycle, reuse, and otherwise avoid waste generation to achieve a 50 percent reduction over 1993 levels. This Report provides the first measure of our progress in waste reduction and recycling against our 1993 waste generation baseline. While we see progress in reducing waste from our normal operations, we must begin to focus attention on waste generated by cleanup and facilities stabilization activities that are the major functions of the Office of Environmental Management. Reducing the generation of waste is one of the seven principles that I have established for the Office of Environmental Management Ten Year Plan. As part of our vision to complete a major portion of the environmental cleanup at DOE sites over the next ten years, we must utilize the potential of the pollution prevention program to reduce the cost of our cleanup program. We have included the Secretarial goals as part of the performance measures for the Ten Year Plan, and we are committed to implementing pollution prevention ideas. Through the efforts of both Federal and contractor employees, our pollution prevention program has reduced waste and the cost of our operations. I applaud their efforts and look forward to reporting further waste reduction progress in the next annual update of this Report.

  14. Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity.

    PubMed

    Odaka, Haruki; Numakawa, Tadahiro; Adachi, Naoki; Ooshima, Yoshiko; Nakajima, Shingo; Katanuma, Yusuke; Inoue, Takafumi; Kunugi, Hiroshi

    2014-01-01

    Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H₂O₂ exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H₂O₂ was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H₂O₂, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca²⁺ channel demonstrated a survival effect against H₂O₂. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H₂O₂.

  15. The dopamine D(2) partial agonist and antagonist terguride decreases heroin self-administration on fixed- and progressive-ratio schedules.

    PubMed

    Zhang, Dengke; Wang, Xuyi; Xiang, Xiaojun; Chen, Hongxian; Zhang, Jian; Su, Qiaorong; Hao, Wei

    2010-12-01

    Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D(2) receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Hanford Site Pollution Prevention Plan Progress report, 1993

    SciTech Connect

    Not Available

    1994-08-01

    This report tracks progress against the goals stated in the Hanford Site 5-year Pollution Prevention Plan. The executive summary of the plan was submitted to the Washington State Department of Ecology (Ecology) in September 1992. The plan, executive summary, and the progress reports are elements of a pollution prevention planning program that is required by Washington Administrative Code (WAC) 173-307 for all hazardous substance users and/or all hazardous waste generators regulated by Ecology. These regulations implement Chapter 70.95C, Revised Code of Washington, an act relating to hazardous waste reduction. The act encourages voluntary efforts to redesign industrial processes to help reduce or eliminate hazardous substances and hazardous waste byproducts, and to maximize the inprocess reuse or reclamation of valuable spent material. Although the Hanford Site is exempt, it is voluntarily complying with this state regulatory-mandated program. This is the first year the Hanford Site is submitting a progress report. It covers calendar year 1993 plus the last quarter of 1992. What is reported, in accordance with WAC 173-307, are reductions in hazardous substance use and hazardous waste generated. A system of Process Waste Assessments (PWA) was chosen to meet the requirements of the program. The PWAs were organized by a physical facility or company organization. Each waste-generating facility/organization performed PWAs to identify, screen, and analyze their own reduction options. Each completed PWA identified any number of reduction opportunities, that are listed individually in the plan and summarized by category in the executive summary. These opportunities were to be implemented or evaluated further over the duration of the 5-year plan. The basis of this progress report is to track action taken on these PWA reduction opportunities in relationship to achieving the goals stated in the Pollution Prevention Plan.

  17. Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death under Oxidative Stress via Reducing Excitotoxicity

    PubMed Central

    Odaka, Haruki; Numakawa, Tadahiro; Adachi, Naoki; Ooshima, Yoshiko; Nakajima, Shingo; Katanuma, Yusuke; Inoue, Takafumi; Kunugi, Hiroshi

    2014-01-01

    Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H2O2 exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H2O2 was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H2O2, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca2+ channel demonstrated a survival effect against H2O2. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H2O2. PMID:24914776

  18. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter.

    PubMed

    Anneken, John H; Angoa-Pérez, Mariana; Kuhn, Donald M

    2015-04-01

    Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release

  19. Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

    SciTech Connect

    Gallagher, G.; Brown, A.; Szabo, S.

    1987-03-01

    Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.

  20. Prevention of atherosclerosis progression in asymptomatic healthy elderly.

    PubMed

    Lees, Robert S

    2007-11-01

    This review focuses on the role of lipid-lowering, blood pressure-lowering, antithrombotic drugs and diet and their place in the prevention and treatment of atherosclerosis in middle-aged and elderly men and woman. The major emphasis is on noninvasive assessment of the extent of atherosclerotic plaque and the importance of following plaque progression or regression by use of noninvasive ultrasound. With these data, we can demonstrate to both patients and physicians the value, at any age, of treating hypertension and abnormal blood lipids.

  1. N-acetylcysteine versus Dopamine to Prevent Acute Kidney Injury after Cardiac Surgery in Patients with Preexisting Moderate Renal Insufficiency

    PubMed Central

    Savluk, Omer Faruk; Guzelmeric, Fusun; Yavuz, Yasemin; Cevirme, Deniz; Gurcu, Emre; Ogus, Halide; Orki, Tulay; Kocak, Tuncer

    2017-01-01

    Objective Acute kidney injury after cardiac surgery is associated with mortality and morbidity. Therefore, strategies to prevent acute kidney injury are very important. The aim of this placebo-controlled randomized double-blind study was to compare the prophylactic efficacy of N-Acetylcysteine and dopamine administration in patients with pre-existing moderate renal insufficiency who were undergoing cardiopulmonary bypass. Methods This study included 135 patients with pre-existing moderate renal insufficiency who were scheduled for coronary artery bypass grafting surgery. Serum creatinine and GFR were recorded preoperatively and on the first and second postoperative days. Results On the first and second postoperative days, the drugs used showed statistically significant differences among the creatinine groups (P<0.001). According to Tukey’s HSD, on the first and second PO, the creatinine of Group N, D and P were significantly different (P<0.001). On the first and second PO, the used drugs showed statistically significant differences among the effects of eGFR (P<0.001). According to Tukey’s HSD on the first postoperative day, the average eGFR score of Group N compared to D and P were significantly difference (P<0.001). On the second postoperative day, the eGFR of Group N and D showed no difference (P=0.37), but P showed a difference (P<0.001). Conclusion We found that the prophylactic use of intravenous N-Acetylcysteine had a protective effect on renal function, whereas the application of renal dose dopamine did not have a protective effect in patients with pre-existing moderate renal failure.

  2. Research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity

    PubMed Central

    Zhang, Jing; Cui, Xiaohai; Yan, Yan; Li, Min; Yang, Ya; Wang, Jiansheng; Zhang, Jia

    2016-01-01

    Anthracyclines, including doxorubicin, epirubicin, daunorubicin and aclarubicin, are widely used as chemotherapeutic agents in the treatment of hematologic and solid tumor, including acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcomas and ovarian cancer. In the cancer treatment, anthracyclines also can be combined with other chemotherapies and molecular-targeted drugs. The combination of anthracyclines with other therapies is usually the first-line treatment. Anthracyclines are effective and potent agents with a broad antitumor spectrum, but may cause adverse reactions, including hair loss, myelotoxicity, as well as cardiotoxicity. We used hematopoietic stimulating factors to control the myelotoxicity, such as G-CSF, EPO and TPO. However, the cardiotoxicity is the most serious side effect of anthracyclines. Clinical research and practical observations indicated that the cardiotoxicity of anthracyclines is commonly progressive and irreversible. Especially to those patients who have the first time use of anthracyclines, the damage is common. Therefore, early detection and prevention of anthracyclines induced cardiotoxicity are particularly important and has already aroused more attention in clinic. By literature review, we reviewed the research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity. PMID:27508008

  3. Refractory epilepsy: a progressive, intractable but preventable condition?

    PubMed

    Kwan, Patrick; Brodie, Martin J

    2002-03-01

    Intractable seizures are just one manifestation of 'refractory epilepsy', which can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behaviour and a restricted lifestyle. The biological basis of 'refractoriness' is likely to be multifactorial, and may include the severity of the syndrome and/or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Some of these deleterious changes may be a consequence of recurrent seizures. We hypothesize that 'refractory epilepsy' may be prevented by interrupting this self-perpetuating progression. There is increasing evidence that these patients can be identified early in the clinical course and, thus, be targeted early for effective therapeutic intervention. Failure of two first-line AEDs due to lack of efficacy or poor tolerability should prompt consideration of epilepsy surgery in a patient with a resectable brain abnormality. For the majority not suitable for 'curative' surgery, AEDs should be combined with the aim of achieving 'synergism'. This strategy has the potential to improve outcome by preventing the insidious progression to intractable 'refractoriness' and a downward spiraling quality of life. Copyright 2002 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.

  4. Hanford Site Pollution Prevention Plan progress report, 1994. Revision 1

    SciTech Connect

    1995-09-01

    This report tracks progress made during 1994 against the goals stated in DOE/RL-92-62, Executive Summary, Hanford Site Pollution Prevention Plan. The Executive Summary of the plan was submitted to the Washington State Department of Ecology (Ecology) in September 1992. The plan, Executive Summary, and the progress reports are elements of a pollution prevention planning program that is required by WAC 173-307, ``Plans,`` for all hazardous substance users and/or all hazardous waste generators regulated by Ecology. These regulations implement RCW 70.95C, ``Waste Reduction,`` an act relating to hazardous waste reduction. The act encourages voluntary efforts to redesign industrial processes to help reduce or eliminate hazardous substances and hazardous waste byproducts, and to maximize the in-process reuse or reclamation of valuable spent material. The Hanford Site is voluntarily complying with this state regulatory-mandated program. All treatment, storage, or disposal (TSD) facilities are exempt from participating; the Hanford Site is classified as a TSD.

  5. A single dopamine pathway underlies progressive locomotor deficits in a Drosophila model of Parkinson disease.

    PubMed

    Riemensperger, Thomas; Issa, Abdul-Raouf; Pech, Ulrike; Coulom, Hélène; Nguyễn, Mỹ-Vân; Cassar, Marlène; Jacquet, Mélanie; Fiala, André; Birman, Serge

    2013-11-27

    Expression of the human Parkinson-disease-associated protein α-synuclein in all Drosophila neurons induces progressive locomotor deficits. Here, we identify a group of 15 dopaminergic neurons per hemisphere in the anterior medial region of the brain whose disruption correlates with climbing impairments in this model. These neurons selectively innervate the horizontal β and β' lobes of the mushroom bodies, and their connections to the Kenyon cells are markedly reduced when they express α-synuclein. Using selective mushroom body drivers, we show that blocking or overstimulating neuronal activity in the β' lobe, but not the β or γ lobes, significantly inhibits negative geotaxis behavior. This suggests that modulation of the mushroom body β' lobes by this dopaminergic pathway is specifically required for an efficient control of startle-induced locomotion in flies.

  6. Myopia onset and progression: can it be prevented?

    PubMed

    Russo, Andrea; Semeraro, Francesco; Romano, Mario R; Mastropasqua, Rodolfo; Dell'Omo, Roberto; Costagliola, Ciro

    2014-06-01

    Myopia is the commonest ocular abnormality and the high and growing prevalence of myopia, especially but not only in Asian populations, as well as its progressive nature in children, has contributed to a recent surge in interest. Such worldwide growing prevalence seems to be associated with increasing educational pressures, combined with life-style changes, which have reduced the time that children spend outdoors. Highly nearsighted people are at greater risk for several vision-threatening problems such as retinal detachments, choroidal neovascularization, cataracts and glaucoma, thus the potential benefits of interventions that can limit or prevent myopia progression would be of remarkable social impact. Our understanding of the regulatory processes that lead an eye to refractive errors is undoubtedly incomplete but has grown enormously in the last decades thanks to the animal studies, observational clinical studies, and randomized clinical trials recently published. In this review we assess the effects of several types of life-style and interventions, including outdoor activities, eye drops, undercorrection of myopia, multifocal spectacles, contact lenses, and refractive surgery on the onset and progression of nearsightedness.

  7. Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect

    PubMed Central

    Claussen, Catherine M; Witte, Lindsey J; Dafny, Nachum

    2015-01-01

    Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. PMID:27186140

  8. Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord.

    PubMed

    Brewer, Kori L; Baran, Christine A; Whitfield, Brian R; Jensen, A Marley; Clemens, Stefan

    2014-01-01

    Dopamine (DA) modulates spinal reflexes, including nociceptive reflexes, in part via the D3 receptor subtype. We have previously shown that mice lacking the functional D3 receptor (D3KO) exhibit decreased paw withdrawal latencies from painful thermal stimuli. Altering the DA system in the CNS, including D1 and D3 receptor systems, reduces the ability of opioids to provide analgesia. Here, we tested if the increased pain sensitivity in D3KO might result from a modified μ-opioid receptor (MOR) function at the spinal cord level. As D1 and D3 receptor subtypes have competing cellular effects and can form heterodimers, we tested if the changes in MOR function may be mediated in D3KO through the functionally intact D1 receptor system. We assessed thermal paw withdrawal latencies in D3KO and wild type (WT) mice before and after systemic treatment with morphine, determined MOR and phosphorylated MOR (p-MOR) protein expression levels in lumbar spinal cords, and tested the functional effects of DA and MOR receptor agonists in the isolated spinal cord. In vivo, a single morphine administration (2 mg/kg) increased withdrawal latencies in WT but not D3KO, and these differential effects were mimicked in vitro, where morphine modulated spinal reflex amplitudes (SRAs) in WT but not D3KO. Total MOR protein expression levels were similar between WT and D3KO, but the ratio of pMOR/total MOR was higher in D3KO. Blocking D3 receptors in the isolated WT cord precluded morphine's inhibitory effects observed under control conditions. Lastly, we observed an increase in D1 receptor protein expression in the lumbar spinal cord of D3KO. Our data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state. We propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway.

  9. Adenovirus Capsid-Based Anti-Cocaine Vaccine Prevents Cocaine from Binding to the Nonhuman Primate CNS Dopamine Transporter

    PubMed Central

    Maoz, Anat; Hicks, Martin J; Vallabhjosula, Shankar; Synan, Michael; Kothari, Paresh J; Dyke, Jonathan P; Ballon, Douglas J; Kaminsky, Stephen M; De, Bishnu P; Rosenberg, Jonathan B; Martinez, Diana; Koob, George F; Janda, Kim D; Crystal, Ronald G

    2013-01-01

    Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [11C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62±4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 × 105, the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective ‘high' reported in humans. PMID:23660705

  10. Oxidative stress, progressive damage in the substantia nigra and plasma dopamine oxidation, in rats chronically exposed to ozone.

    PubMed

    Santiago-López, D; Bautista-Martínez, J A; Reyes-Hernandez, C I; Aguilar-Martínez, M; Rivas-Arancibia, S

    2010-09-01

    The purpose of our work was to determine the effects of oxidative stress on the neurodegeneration process in the substantia nigra, and to evaluate dopamine-oxidation metabolites in the plasma using a cyclic voltammetry (CV) technique. We have also studied the correlation between the increases in oxidized dopamine-species levels with the severity of lipid-peroxidation in the plasma. Sixty-four male Wistar rats were divided into four experimental groups and received air (Group I, control) or ozone (0.25 ppm) daily by inhalation for 4h for 15 (Group II), 30 (Group III), and 60 (Group IV) days. The brains were processed for immunohistochemical location of dopamine and p53 in the substantia nigra. Plasma collected from these animals was assayed for oxidized dopamine products using CV and lipid-peroxidation levels were measured. Our results indicate that chronic exposure to low O(3) doses causes that the number of dopaminergic neurons decreased, and p53-immunoreactive cells increases until 30 days; which was a function of the time of exposure to ozone. Oxidative stress produces a significant increase in the levels of the dopamine quinones (DAQs) that correlated well (r=0.962) with lipid peroxides in the plasma during the study period. These results suggest that DAQ could be a reliable, peripheral oxidative indicator of nigral dopaminergic damage in the brain. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  11. Age-related behavioural phenotype and cellular characterisation of mice with progressive ablation of D1 dopamine receptor-expressing cells.

    PubMed

    Babovic, Daniela; Jiang, Luning; Gantois, Ilse; Lawrence, Andrew J; Ferreri, Vincenzo; Schütz, Günter; Waddington, John L; Drago, John

    2010-01-05

    In this study we characterize the behavioural and cellular phenotype of mutant (MUT) mice with progressive loss of D1 dopamine receptor (Drd1a)-expressing cells. Adult [14-19 weeks] MUT mice showed intact working memory in the spontaneous alternation test but evidenced anxiety-like behaviour in the elevated plus maze and the light-dark test. The ethogram of mature adult MUT [average age 22 weeks] was compared with that of young adult MUT mice [average age 12 weeks]. While MUT mice evidenced hyperactivity over initial exploration at both time points, the topography of hyperactivity shifted. Moreover, initial hyperactivity was sustained over habituation at 12 weeks, but not at 22 weeks. Thus, by 22 weeks MUT mice evidenced shifts in, and mitigation of, these early phenotypic effects. However, orofacial behaviours of chewing and sifting were reduced similarly at 12 and 22 weeks. These data support the hypothesis that aspects of the mutant phenotype change with time. Quantitative autoradiography at 20 weeks revealed loss of D1-like dopamine receptor binding in the entire basal ganglia, with upregulated D2-like binding. There appear to be topographically specific interactions between normal maturational processes and compensatory mechanisms evoked subsequent to targeted ablation of D1 dopamine receptor-expressing cells. Understanding the mechanistic bases of mitigation vs persistence of individual phenotypes in relation to neural adaptation consequent to cell loss may lead to novel therapeutic strategies for basal ganglia disorders.

  12. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    PubMed

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-09-18

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  13. The dopamine D3 receptor partial agonist CJB090 and antagonist PG01037 decrease progressive ratio responding for methamphetamine in rats with extended-access

    PubMed Central

    Orio, Laura; Wee, Sunmee; Newman, Amy H.; Pulvirenti, Luigi; Koob, George F.

    2010-01-01

    Previous work suggests a role for dopamine D3-like receptors in psychostimulant reinforcement. The development of new compounds acting selectively at dopamine D3 receptors has opened new possibilities to explore the role of these receptors in animal models of psychostimulant dependence. Here we investigated whether the dopamine D3 partial agonist CJB090 (1–10 mg/kg, i.v) and the D3 antagonist PG01037 (8–32 mg/kg, s.c.,) modified methamphetamine (0.05 mg/kg/injection) intravenous self-administration under fixed- (FR) and progressive- (PR) ratio schedules in rats allowed limited (short access, ShA; 1h sessions 3 days/week) or extended access (long access, LgA; 6h sessions 6 days/week). Under a FR1 schedule, the highest dose of the D3 partial agonist CJB090 selectively reduced methamphetamine self-administration in LgA but not in ShA rats, whereas the full D3 antagonist PG01037 produced no effect in either group. Under a PR schedule of reinforcement, the D3 partial agonist CJB090 reduced the maximum number of responses performed (“breakpoint”) for methamphetamine in LgA rats at the doses of 5 and 10 mg/kg and also it produced a significant reduction in the ShA group at the highest dose. However, the D3 full antagonist PG01037 only reduced PR methamphetamine self-administration in LgA rats at the highest dose of 32 mg/kg with no effect in the ShA group. The results suggest that rats might be more sensitive to pharmacological modulation of dopamine D3 receptors following extended access to methamphetamine self-administration, opening the possibility that D3 receptors play a role in excessive methamphetamine intake. PMID:20456290

  14. Non-thermal plasma prevents progression of endometriosis in mice.

    PubMed

    Ishida, Chiharu; Mori, Masahiko; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Hori, Masaru; Iwase, Akira; Kikkawa, Fumitaka; Toyokuni, Shinya

    2016-10-01

    Endometriosis is observed in ∼10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2'-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

  15. Fucoidan Prevents the Progression of Osteoarthritis in Rats.

    PubMed

    Lee, Don-Gil; Park, Sang-Yong; Chung, Won-Seok; Park, Jae-Hee; Hwang, Eunson; Mavlonov, Gafurjon Tom; Kim, In-Ho; Kim, Ki-Young; Yi, Tae-Hoo

    2015-09-01

    This study investigated the effects of fucoidan (extract from Hizikia fusiforme) on symptoms and inflammatory cytokine activation in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA). Forty male SD rats were divided into five groups, including normal, negative control (MIA), positive control (Lyprinol), and two experimental groups treated with 50 or 100 mg/kg fucoidan. Weight-bearing assessments were done after MIA injection into the right knee to induce OA. After 14 days of treatment, microcomputed tomographic (micro-CT) images were made of rat knee joints, and then animals were sacrificed for joint histology and inflammatory cytokine level assessments. MIA injection successfully induced OA by causing 40% weight-bearing imbalance, severe bone loss and cartilage degeneration, and markedly increased cytokine levels. However, fucoidan groups showed over 45% of imbalance and no articular cartilage surface lesions or change in subchondral trabecular bones in Micro-CT images. Histological analysis revealed that cartilage morphology and cell counts were also normal in the 100 mg/kg fucoidan group. In addition, the 100 mg/kg fucoidan groups exhibited lower serum tumor necrosis factor alpha (TNF-α) (30%), interleukin 1 beta (IL-1β) (48%), and matrix metalloproteinase-1 (MMP-1) (65%) compared to the MIA groups. These results suggest that administration of fucoidan prevents the progression of OA in a MIA-induced OA rat model.

  16. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter

    PubMed Central

    Anneken, John H.; Angoa-Pérez, Mariana; Kuhn, Donald M.

    2016-01-01

    Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. PMID:25626880

  17. D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug.

    PubMed

    Pierre, P J; Vezina, P

    1998-07-01

    Prior exposure to amphetamine leads to sensitized locomotor responding to subsequent injections and an enhanced predisposition to self-administer low doses of the drug. Because D1 dopamine (DA) receptors have been shown to play an important role in the development of sensitized locomotor responding to amphetamine, the present experiment assessed their contribution to the development of facilitated amphetamine self-administration produced by prior exposure to the drug. During a pre-exposure phase, rats were administered two injections on each of 10 consecutive days. The first injection (saline, 1 ml/kg, i.p., or the D1 DA receptor antagonist SCH23390, 0.04 mg/kg, s.c.) preceded the second (saline or amphetamine, 1.5 mg/kg, i.p.) by 30 min. Starting 10 days after the last injection, animals were given the opportunity to lever press for a low dose of amphetamine (10 microg/kg per infusion) in a two-lever (active versus inactive) continuous reinforcement operant task, in each of seven daily sessions. Consistent with previous reports, prior exposure to amphetamine resulted in an increase in active versus inactive lever pressing. Blocking D1 DA receptors with SCH23390 prior to each of the amphetamine pre-exposure injections prevented the development of this enhanced self-administration of amphetamine. When animals were grouped according to their locomotor response to a novel environment (assessed prior to the experiment), it was found, again in agreement with previous reports, that enhanced drug self-administration (as indicated by increased active versus inactive lever pressing as well as shorter latencies to emit the first active lever press, shorter inter-response times and more time-out responses on this lever) was observed only in amphetamine pre-exposed rats that had shown a locomotor response to novelty above the median of the subject sample (high responders). Preceding the amphetamine pre-exposure injections with SCH23390 blocked the development of enhanced drug

  18. Dopamine and binge eating behaviors

    PubMed Central

    Bello, Nicholas T.; Hajnal, Andras

    2010-01-01

    Central dopaminergic mechanisms are involved in the motivational aspects of eating and food choices. This review focuses on human and animal data examining the importance of dopamine on binge eating behaviors. Early works examining dopamine metabolites in the cerebrospinal fluid and plasma of bulimic individuals suggested decreased dopamine turnover during the active phase of the illness. While neuroimaging studies of dopamine mechanisms in bulimia nervosa (BN) and binge eating disorder (BED) are limited, genetic studies in humans have implicated an increased frequency of dopamine transporter and associated D2 receptor polymorphisms with binge pathology. Recent examinations of rodent models of dietary-induced binge eating (DIBE) have investigated plausible dopamine mechanisms involved in sustaining binge eating behaviors. In DIBE models, highly palatable foods (fats, sugars and their combination), as well as restricted access conditions appear to promote ingestive responses and result in sustained dopamine stimulation within the nucleus accumbens. Taken together with studies examining the comorbidity of illicit drug use and eating disorders, the data reviewed here support a role for dopamine in perpetuating the compulsive feeding patterns of BN and BED. As such, we propose that sustained stimulation of the dopamine systems by bingeing promoted by preexisting conditions (e.g., genetic traits, dietary restraint, stress, etc.) results in progressive impairments of dopamine signaling. To disrupt this vicious cycle, novel research-based treatment options aiming at the neural substrates of compulsive eating patterns are necessary. PMID:20417658

  19. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine.

    PubMed

    Chase, T N

    1998-05-01

    Normal motor function is dependent on the highly regulated synthesis and release of the transmitter dopamine by neurons projecting from the substantia nigra to the corpus striatum. Parkinson's disease involves the progressive degeneration of these neurons. Its core symptoms are a direct consequence of a striatal insufficiency of intrasynaptic dopamine. Levodopa, the standard of care for the treatment of PD, acts after its conversion to dopamine by restoring striatal dopaminergic transmission. However, there are significant differences between the normally functioning dopamine system and the restoration of function provided by standard levodopa treatment. Increasing clinical and preclinical evidence suggests that the intermittent stimulation of dopamine receptors resulting from current therapeutic regimens contributes to the response complications that ultimately affect most parkinsonian patients. It now appears that chronic nonphysiologic stimulation of dopaminergic receptors on striatal GABAergic neurons activates characteristic signaling pathways, leading to a potentiation of the synaptic efficacy of adjacent glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype. As a result, function of these GABAergic efferent neurons changes in ways that favor the appearance of motor complications. Conceivably, use of dopaminomimetic replacement strategies that provide more continuous dopamine receptor stimulation will act to prevent or alleviate these disabling complications. A number of promising approaches to achieving this goal are now under development.

  20. Drug Education and Prevention: Has Progress Been Made?

    ERIC Educational Resources Information Center

    Coggans, Niall

    2006-01-01

    Ten years after publication of the UK Government's strategy for drug misuse in 1995, Tackling Drugs Together, the impact of drug education and prevention programmes remains less than desired. The 1995 strategy envisaged a new emphasis on education and prevention and there have been developments since then in drug education, especially with…

  1. Annual report of waste generation and pollution prevention progress 1999

    SciTech Connect

    2000-09-01

    This Annual Report summarizes and highlights waste generation, waste reduction, pollution prevention accomplishments, and cost avoidance for 44 U.S. Department of Energy reporting sites for Calendar Year 1999. This section summarizes Calendar Year 1999 Complex-wide waste generation and pollution prevention accomplishments.

  2. Drug Education and Prevention: Has Progress Been Made?

    ERIC Educational Resources Information Center

    Coggans, Niall

    2006-01-01

    Ten years after publication of the UK Government's strategy for drug misuse in 1995, Tackling Drugs Together, the impact of drug education and prevention programmes remains less than desired. The 1995 strategy envisaged a new emphasis on education and prevention and there have been developments since then in drug education, especially with…

  3. HPV Immunization - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Chemical Exposures - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Smoking Cessation - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Secondhand Smoke - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. HPV Immunization - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Smoking Cessation - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Diet - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression

    PubMed Central

    Shukla, Ashish; Curtis, Anne B

    2014-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia and a major global public health problem due to its associated morbidity, including stroke and heart failure, diminished quality of life, and increased mortality. AF often presents initially in a paroxysmal form and may progress to a more sustained form over time. Evidence from randomized controlled trials suggests that there may be no mortality benefit to using a rhythm control approach in comparison with rate control of AF. Nevertheless, sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and consequently they remain an additional target for therapy. The present review evaluates the clinical correlates of arrhythmia progression and risk stratification techniques available to assess probability of AF progression. Further, currently available management options for arrhythmia control in AF are evaluated and their therapeutic effect and efficacy on disease progression are explored. PMID:24379678

  11. Secondhand Smoke - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Tobacco Use - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease

    PubMed Central

    Yao, Zhi; Duchen, Michael R.; Wood, Nicholas W.; Abramov, Andrey Y.

    2012-01-01

    Background Parkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis of neuronal vulnerability to dopamine in Parkinson's disease is not well understood. Methodology We investigated the mechanism of dopamine induced cell death in transgenic PINK1 knockout mouse neurons. We show that dopamine results in mitochondrial depolarisation caused by mitochondrial permeability transition pore (mPTP) opening. Dopamine-induced mPTP opening is dependent on a complex of reactive oxygen species production and calcium signalling. Dopamine-induced mPTP opening, and dopamine-induced cell death, could be prevented by inhibition of reactive oxygen species production, by provision of respiratory chain substrates, and by alteration in calcium signalling. Conclusions These data demonstrate the mechanism of dopamine toxicity in PINK1 deficient neurons, and suggest potential therapeutic strategies for neuroprotection in Parkinson's disease. PMID:22662171

  14. Targeting vasculogenesis to prevent progression in multiple myeloma.

    PubMed

    Moschetta, M; Mishima, Y; Kawano, Y; Manier, S; Paiva, B; Palomera, L; Aljawai, Y; Calcinotto, A; Unitt, C; Sahin, I; Sacco, A; Glavey, S; Shi, J; Reagan, M R; Prosper, F; Bellone, M; Chesi, M; Bergsagel, L P; Vacca, A; Roccaro, A M; Ghobrial, I M

    2016-05-01

    The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.

  15. [Prognosis and progression of cognitive impairment. Preventive measures].

    PubMed

    López Mongil, Rosa; López Trigo, José Antonio

    2016-06-01

    Because of the substantial increase in population ageing, age-related processes, such as dementia and Alzheimer disease (AD), are becoming highly prevalent. The course of this disease, including preprodromic phases, lasts at least 20 years. The presence of comorbidities, especially those of vascular origin, can trigger and aggravate disease progression. On the other hand, cognitive reserve, the absence or control of comorbid factors and healthy lifestyles can protect or modify -in the sense of slow down- disease progression. Knowledge of the phases of AD and their functional impact on affected individuals helps to identify the average prognosis and, in particular, to establish and predict care plans based on the individual's needs.

  16. Annual report of waste generation and pollution prevention progress 2000 [USDOE] [9th edition

    SciTech Connect

    2001-06-01

    This ninth edition of the Annual Report of Waste Generation and Pollution Prevention Progress highlights waste reduction, pollution prevention accomplishments, and cost savings/avoidance for the U.S. Department of Energy (DOE) Pollution Prevention Program for Fiscal Year 2000. This edition marks the first time that progress toward meeting the 2005 Pollution Prevention Goals, issued by the Secretary of Energy in November 1999, is being reported. In addition, the Annual Report has a new format, and now contains information on a fiscal year basis, which is consistent with other DOE reports.

  17. "MARK I" MEASUREMENT METHODOLOGY FOR POLLUTION PREVENTION PROGRESS OCCURRING AS A RESULT OF PRODUCT DECISIONS

    EPA Science Inventory

    A methodology for assessing progress in pollution prevention resulting from product redesign, reformulation or replacement is described. The method compares the pollution generated by the original product with that from the modified or replacement product, taking into account, if...

  18. Joint Group on Pollution Prevention: Partnering for Progress

    NASA Technical Reports Server (NTRS)

    Hill, R.

    2001-01-01

    This viewgraph presentation outlines the Joint Group on Pollution Prevention (JG-PP) partnership. Details are given on what groups comprise JG-PP, the proven methodology for what JG-PP can accomplish, the common problems, joint solutions, and shared efforts, and some of the JG-PP projects.

  19. Volunteers to Prevent Emotional Problems in Children. Summary Progress Report.

    ERIC Educational Resources Information Center

    Thomson, Ruth

    The Counseling Service of Addison County, a community mental health clinic, began in 1966 as a four-year project under a National Institutes of Mental Health grant to determine whether emotional problems could be prevented by the early assignment of college student volunteers (from Middlebury College) to underachievers in the early grades of…

  20. Smart Coating for Corrosion Indication and Prevention: Recent Progress

    NASA Technical Reports Server (NTRS)

    Li, Wenyan; Hintze, Paul; Calle, Luz M.; Buhrow, Jerry; Curran, Jerry; Muehlberg, A. J.; Gelling, V. J.; Webster, D. C.; Croll, S. G.; Contu, F.; Taylor, S. R.

    2009-01-01

    The authors are developing a smart coating system based on pH-triggered release microcapsules. These microcapsules can be incorporated into various coating systems for corrosion detection, protection and self-repair of mechanical coating damage. This paper will present the results from progress made to date in the controlled release properties of these microcapsules as well as in their corrosion indication and corrosion inhibition function.

  1. Annual report of waste generation and pollution prevention progress 1995

    SciTech Connect

    1997-02-01

    This fourth Annual Report presents and analyzes 1995 DOE complex-wide waste generation and pollution prevention activities at 40 reporting sites in 25 States, and trends DOE waste generation from 1991 through 1995. DOE has established a 50% reduction goal (relative to the 1993 baseline) for routine operations radioactive and hazardous waste generation, due by December 31, 1999. Routine operations waste generation decreased 37% from 1994 to 1995, and 43% overall from 1993--1995.

  2. HIV, Tat and dopamine transmission.

    PubMed

    Gaskill, Peter J; Miller, Douglas R; Gamble-George, Joyonna; Yano, Hideaki; Khoshbouei, Habibeh

    2017-09-01

    Human Immunodeficiency Virus (HIV) is a progressive infection that targets the immune system, affecting more than 37 million people around the world. While combinatorial antiretroviral therapy (cART) has lowered mortality rates and improved quality of life in infected individuals, the prevalence of HIV associated neurocognitive disorders is increasing and HIV associated cognitive decline remains prevalent. Recent research has suggested that HIV accessory proteins may be involved in this decline, and several studies have indicated that the HIV protein transactivator of transcription (Tat) can disrupt normal neuronal and glial function. Specifically, data indicate that Tat may directly impact dopaminergic neurotransmission, by modulating the function of the dopamine transporter and specifically damaging dopamine-rich regions of the CNS. HIV infection of the CNS has long been associated with dopaminergic dysfunction, but the mechanisms remain undefined. The specific effect(s) of Tat on dopaminergic neurotransmission may be, at least partially, a mechanism by which HIV infection directly or indirectly induces dopaminergic dysfunction. Therefore, precisely defining the specific effects of Tat on the dopaminergic system will help to elucidate the mechanisms by which HIV infection of the CNS induces neuropsychiatric, neurocognitive and neurological disorders that involve dopaminergic neurotransmission. Further, this will provide a discussion of the experiments needed to further these investigations, and may help to identify or develop new therapeutic approaches for the prevention or treatment of these disorders in HIV-infected individuals. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Recent Progress in Cancer-Related Lymphedema Treatment and Prevention

    PubMed Central

    Shaitelman, Simona F.; Cromwell, Kate D.; Rasmussen, John C.; Stout, Nicole L.; Armer, Jane M.; Lasinski, Bonnie B.; Cormier, Janice N.

    2016-01-01

    This article provides an overview of the recent developments in the diagnosis, treatment, and prevention of cancer-related lymphedema. Lymphedema incidence by tumor site is evaluated. Measurement techniques and trends in patient education and treatment are also summarized to include current trends in therapeutic and surgical treatment options as well as longer-term management. Finally, an overview of the policies related to insurance coverage and reimbursement will give the clinician an overview of important trends in the diagnosis, treatment, and management of cancer-related lymphedema. PMID:25410402

  4. Annual report of waste generation and pollution prevention progress 1998

    SciTech Connect

    1999-09-01

    This seventh Annual Report presents and analyzes DOE Complex-wide waste generation and pollution prevention activities at 45 reporting sites from 1993 through 1998. This section summarizes Calendar Year 1998 Complex-wide waste generation and pollution prevention accomplishments. More detailed information follows this section in the body of the Report. In May 1996, the Secretary of Energy established a 50 percent Complex-Wide Waste Reduction Goal (relative to the 1993 baseline) for routine operations radioactive, mixed, and hazardous waste generation, to be achieved by December31, 1999. DOE has achieved its Complex-Wide Waste Reduction Goals for routine operations based upon a comparison of 1998 waste generation to the 1993 baseline. Excluding sanitary waste, routine operations waste generation decreased 67 percent overall from 1993 to 1998. However, for the first time since 1994, the total amount of materials recycled by the Complex decreased from 109,600 metric tons in 1997 to 92,800 metric tons in 1998. This decrease is attributed to the fact that in 1997, several large ''one-time only'' recycling projects were conducted throughout the Complex. In order to demonstrate commitment to DOE's Complex-wide recycling goal, it is important for sites to identify all potential large-scale recycling/reuse opportunities.

  5. A Perspective on Progress and Gaps in HIV Prevention Science

    PubMed Central

    Mesquita, Pedro M.M.; Herold, Betsy C.

    2012-01-01

    Abstract In the past few years, the transdisciplinary field of HIV prevention has reached several milestones. Topically applied tenofovir gel provided significant protection from sexual transmission of HIV in a large-scale clinical trial and oral Truvada (emtricitabine/tenofovir disoproxil fumarate) was recently approved for preexposure prophylaxis (PrEP) following two successful clinical trials in men and women. These achievements are tempered by the disappointing results of other clinical trials, which highlight the complexities of prevention research. In this perspective, we discuss scientific and developmental gaps for topical chemoprophylaxis of the sexual transmission of HIV, which depends on the complex interactions between the pharmacokinetics and pharmacodynamics of drugs, formulation and delivery systems, anatomic site of transmission, and host mucosal immune defenses. Despite the considerable time and resources devoted to unraveling the initial steps in sexual transmission of HIV, current knowledge is based on animal models and human explanted tissue, which may not fully recapitulate what happens clinically. Understanding these events, including the role that sex hormones, semen, and mucosal secretions play in transmission, and the interplay between innate immunity, the mucosal environment, and drug efficacy is paramount. This drives some of the most pressing questions in the field. PMID:22966871

  6. Diastolic heart failure: progress, treatment challenges, and prevention.

    PubMed

    Wood, Philip; Piran, Sanaz; Liu, Peter P

    2011-01-01

    Diastolic heart failure (DHF) is an important entity, the significance of which is increasingly recognized. This report examines the available evidence regarding the role, significance, and mechanisms of DHF. Epidemiologic studies have documented the rising burden of DHF, and experimental data are revealing the unique mechanisms distinguishing it from systolic heart failure. Despite controversies on the definition of DHF, or heart failure with preserved ejection fraction, standardized clinical criteria with supplementary imaging and structural data have identified DHF as a distinct pathophysiological entity. The mechanisms underlying DHF include abnormal matrix dynamics, altered myocyte cytoskeleton, and impaired active relaxation. The commonly held belief that survival of patients with DHF is better than that of patients with systolic heart failure has been challenged by updated data. The heterogeneous etiologies or risk factors for the condition include aging, diabetes, hypertension, and ischemia, making a common diagnostic or treatment pathway difficult. Novel therapeutic targets that address the pathophysiology of this disease are under consideration, although there are no proven therapies for DHF to date. Exacerbating factors include volume and sodium indiscretion, arrhythmias, ischemia, and comorbidities. Strategies to ameliorate or to obviate these precipitating factors are most effective in preventing DHF and its exacerbations. Meanwhile, prevention of DHF through appropriate and aggressive risk factor identification and management must remain the cornerstone of clinical intervention. Copyright © 2011. Published by Elsevier Inc.

  7. Progress towards the prevention and treatment of norovirus infections.

    PubMed

    Arias, Armando; Emmott, Edward; Vashist, Surender; Goodfellow, Ian

    2013-11-01

    Noroviruses are now recognized as the major cause of acute gastroenteritis in the developed world, yet our ability to prevent and control infection is limited. Recent work has highlighted that, while typically an acute infection in the population, immunocompromised patients often experience long-term infections that may last many years. This cohort of patients and those regularly exposed to infectious material, for example, care workers and others, would benefit greatly from the development of a vaccine or antiviral therapy. While a licensed vaccine or antiviral has yet to be developed, work over the past 10 years in this area has intensified and trials with a vaccine candidate have proven promising. Numerous antiviral targets and small molecule inhibitors that have efficacy in cell culture have now been identified; however, further studies in this area are required in order to make these suitable for clinical use.

  8. Progress towards the prevention and treatment of norovirus infections

    PubMed Central

    Arias, Armando; Emmott, Edward; Vashist, Surender; Goodfellow, Ian

    2014-01-01

    Noroviruses are now recognized as the major cause of acute gastroenteritis in the developed world, yet our ability to prevent and control infection is limited. Recent work has highlighted that, while typically an acute infection in the population, immunocompromised patients often experience long-term infections that may last many years. This cohort of patients and those regularly exposed to infectious material, for example, care workers and others, would benefit greatly from the development of a vaccine or antiviral therapy. While a licensed vaccine or antiviral has yet to be developed, work over the past 10 years in this area has intensified and trials with a vaccine candidate have proven promising. Numerous antiviral targets and small molecule inhibitors that have efficacy in cell culture have now been identified; however, further studies in this area are required in order to make these suitable for clinical use. PMID:24199805

  9. Rh immunization in Manitoba: progress in prevention and management.

    PubMed Central

    Bowman, J. M.; Pollock, J.

    1983-01-01

    For two decades the perinatal mortality caused by erythroblastosis has been decreasing in Manitoba. The improved management of Rh-immunized pregnancies has lowered the death rate among affected infants from 10.8% to 3.4%, while the prevention of Rh immunization has reduced its incidence from 9.1 to 2.2 per 1000 total births. In its first 6 years and 8 months Manitoba's antenatal prophylaxis program, in which immunoglobulin is administered to Rh-negative women at 28 weeks' gestation, reduced the incidence of Rh immunization during pregnancy by 93%. In combination with post-abortion and postpartum prophylaxis the antenatal treatment has provided a protection rate of 98.6% among primigravidas at risk. Further improvements are expected. PMID:6409390

  10. [Cardiovascular prevention: current progress and the long road to travel].

    PubMed

    Marrugat, Jaume; Sala, Joan; Elosua, Roberto; Ramos, Rafael; Baena-Díez, José Miguel

    2010-06-01

    This article describes the limitations of the currently available screening modalities used for determining cardiovascular risk in the general population. In addition, it contains an analysis of the potential ways in which the predictive and classificatory abilities of the cardiovascular risk charts used in primary care can be improved to enable them to function more effectively. Also included are discussions of existing opportunities for improving current strategies for screening and cardiovascular prevention, of the value of measuring new biomarkers in individual patients, including genetic predisposition to coronary heart disease, and of some of the clinical measures used in practice, such as the ankle-brachial index and the carotid intima-media thickness. In addition, the most important subgroups of individuals at a high cardiovascular risk, as judged by their size and the number of cardiovascular events experienced at 10 years, are described. Finally, there is a brief review of the potential role that image modalities currently being developed could play in particular subgroups of asymptomatic individuals with an elevated disease risk.

  11. Annual report of waste generation and pollution prevention progress 1997

    SciTech Connect

    1998-09-01

    This sixth Annual Report presents and analyzes DOE Complex-wide waste generation and pollution prevention activities at 36 reporting sites from 1993 through 1997. In May 1996, the Secretary of Energy established a 50 percent Complex-Wide Waste Reduction Goal (relative to the 1993 baseline) for routine operations radioactive and hazardous waste generation, to be achieved by December 31, 1999. Excluding sanitary waste, routine operations waste generation increased three percent from 1996 to 1997, and decreased 61 percent overall from 1993 to 1997. DOE has achieved its Complex-Wide Waste Reduction Goals for routine operations based upon a comparison of 1997 waste generation to the 1993 baseline. However, it is important to note that increases in low-level radioactive and low-level mixed waste generation could reverse this achievement. From 1996 to 1997, low-level radioactive waste generation increased 10 percent, and low-level mixed waste generation increased slightly. It is critical that DOE sites continue to reduce routine operations waste generation for all waste types, to ensure that DOE`s Complex-Wide Waste Reduction Goals are achieved by December 31, 1999.

  12. Apolipoprotein J/Clusterin Prevents a Progressive Glomerulopathy of Aging

    PubMed Central

    Rosenberg, Mark E.; Girton, Richard; Finkel, David; Chmielewski, David; Barrie III, Arthur; Witte, David P.; Zhu, Guang; Bissler, John J.; Harmony, Judith A. K.; Aronow, Bruce J.

    2002-01-01

    Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal. PMID:11865066

  13. A Systematic Process to Prioritize Prevention Activities: Sustaining Progress Toward the Reduction of Military Injuries

    DTIC Science & Technology

    2010-01-01

    avoids overtraining and utilizes agility- ike training has been found to reduce physical training– elated injuries while meeting desired physical fıtness...M F A P ( S v d v C t 2 P A Systematic Process to Prioritize Prevention Activities Sustaining Progress Toward the Reduction of Military Injuries ...Schaefer, MD, MPH, Galen Barbour, MD, Kenneth S. Yew, MD, Bruce H. Jones, MD, MPH Background: To sustain progress toward injury reduction and other

  14. Ketogenic Diet Prevents Epileptogenesis and Disease Progression in Adult Mice and Rats

    PubMed Central

    Lusardi, Theresa A.; Akula, Kiran K.; Coffman, Shayla Q.; Ruskin, David; Masino, Susan A.; Boison, Detlev

    2015-01-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  15. Progress in the Development of Effective Vaccines to Prevent Selected Gram Positive Bacterial Infections

    PubMed Central

    Bronze, Michael S.; Dale, James B.

    2010-01-01

    Infections due to virulent gram positive bacteria, such as Staphylococcus aureus, group B streptococci and group A streptococci remain significant causes of morbidity and mortality despite progress in antimicrobial therapy. Despite significant advances in the understanding of the pathogenesis of infection due to these organisms, there are only limited strategies to prevent infection. In this paper, we review efforts to develop safe and effective vaccines that would prevent infections due to these 3 pathogens. PMID:20697258

  16. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson's disease.

    PubMed

    Chung, Young C; Baek, Jeong Y; Kim, Sang R; Ko, Hyuk W; Bok, Eugene; Shin, Won-Ho; Won, So-Yoon; Jin, Byung K

    2017-03-03

    The effects of capsaicin (CAP), a transient receptor potential vanilloid subtype 1 (TRPV1) agonist, were determined on nigrostriatal dopamine (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). The results showed that TRPV1 activation by CAP rescued nigrostriatal DA neurons, enhanced striatal DA functions and improved behavioral recovery in MPTP-treated mice. CAP neuroprotection was associated with reduced expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and reactive oxygen species/reactive nitrogen species from activated microglia-derived NADPH oxidase, inducible nitric oxide synthase or reactive astrocyte-derived myeloidperoxidase. These beneficial effects of CAP were reversed by treatment with the TRPV1 antagonists capsazepine and iodo-resiniferatoxin, indicating TRPV1 involvement. This study demonstrates that TRPV1 activation by CAP protects nigrostriatal DA neurons via inhibition of glial activation-mediated oxidative stress and neuroinflammation in the MPTP mouse model of PD. These results suggest that CAP and its analogs may be beneficial therapeutic agents for the treatment of PD and other neurodegenerative disorders that are associated with neuroinflammation and glial activation-derived oxidative damage.

  17. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson's disease

    PubMed Central

    Chung, Young C; Baek, Jeong Y; Kim, Sang R; Ko, Hyuk W; Bok, Eugene; Shin, Won-Ho; Won, So-Yoon; Jin, Byung K

    2017-01-01

    The effects of capsaicin (CAP), a transient receptor potential vanilloid subtype 1 (TRPV1) agonist, were determined on nigrostriatal dopamine (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). The results showed that TRPV1 activation by CAP rescued nigrostriatal DA neurons, enhanced striatal DA functions and improved behavioral recovery in MPTP-treated mice. CAP neuroprotection was associated with reduced expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and reactive oxygen species/reactive nitrogen species from activated microglia-derived NADPH oxidase, inducible nitric oxide synthase or reactive astrocyte-derived myeloidperoxidase. These beneficial effects of CAP were reversed by treatment with the TRPV1 antagonists capsazepine and iodo-resiniferatoxin, indicating TRPV1 involvement. This study demonstrates that TRPV1 activation by CAP protects nigrostriatal DA neurons via inhibition of glial activation-mediated oxidative stress and neuroinflammation in the MPTP mouse model of PD. These results suggest that CAP and its analogs may be beneficial therapeutic agents for the treatment of PD and other neurodegenerative disorders that are associated with neuroinflammation and glial activation-derived oxidative damage. PMID:28255166

  18. The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial†

    PubMed Central

    Busso, Cristiano; Fernández-Sánchez, Manuel; García-Velasco, Juan Antonio; Landeras, José; Ballesteros, Augustín; Muñoz, Elkin; González, Sandra; Simón, Carlos; Arce, Joan-Carles; Pellicer, Antonio

    2010-01-01

    BACKGROUND Ovarian hyperstimulation syndrome (OHSS) seems to be induced by the ovarian release of vascular endothelial growth factor (VEGF), which increases vascular permeability. Dopamine agonists inhibit VEGF receptor phosphorylation and thereby decrease vascular permeability. METHODS A randomized, double-blind, placebo-controlled, multicentre study assessing three oral doses (50, 100, 200 µg/day) of the non-ergot derived dopamine agonist quinagolide started on the day of human chorionic gonadotrophin (hCG) and continued for 17–21 days without dose-titration in comparison to placebo in preventing moderate/severe early OHSS (onset ≤9 days after hCG administration) in 182 IVF patients with ≥20 but less than 30 follicles ≥10 mm. RESULTS The incidence of moderate/severe early OHSS was 23% (12/53) in the placebo group and 12% (6/51), 13% (7/52) and 4% (1/26) in the quinagolide 50, 100 and 200 µg/day groups, respectively. The moderate/severe early OHSS rate was significantly lower with all quinagolide groups combined compared with placebo [P = 0.019; OR = 0.28 (0.09–0.81)]. The incidence of ultrasound evidence of ascites among patients with no clinical pregnancy was significantly reduced from 31% (8/26) with placebo to 11% (8/70) with all quinagolide groups combined [P = 0.033; OR = 0.29 (0.10–0.88)], although there was no difference for those with clinical pregnancy. Quinagolide did not have a detrimental effect on pregnancy or live birth rates. The incidence of gastrointestinal and central nervous system adverse events increased with increasing doses of quinagolide. CONCLUSIONS Quinagolide appears to prevent moderate/severe early OHSS while not affecting treatment outcome. The effect is more marked in patients who did not achieve a clinical pregnancy. Quinagolide administered in high doses without dose-titration is associated with poor tolerability. ClinicalTrials.gov Identifier: NCT00329693. PMID:20139430

  19. [The use of subatmospheric pressure to prevent burn wound progression: first experiences in burn wound treatment].

    PubMed

    Haslik, W; Kamolz, L-P; Andel, H; Meissl, G; Frey, M

    2004-05-01

    Thermal injury applied to living tissue results in zones of injury. Cell death is complete in the zone of coagulation. Beneath this area, there is the zone of lesser injury, where most of the cells are initially viable. If this zone of stasis is not reversed, the burn wound will progress. One of the major aspects to prevent progression is to reduce the edema formation and to preserve microcirculation. We present our first experiences to prevent the progression by use of topical negative pressure. Within the last months, all patients with bilateral partial thickness hand burns were included into this treatment protocol. Within one patient, one hand was treated with the V.A.C. (KCI, Austria), the contra lateral one by use of Flammazine (Smith and Nephew, Germany). Our first observations and data indicate, that both important factors (edema and microcirculation) could be influenced positively by use of the V.A.C.

  20. Differential patterns of dopamine transporter loss in the basal ganglia of progressive supranuclear palsy and Parkinson's disease: analysis with [(123)I]IPT single photon emission computed tomography.

    PubMed

    Im, Joo-Hyuk; Chung, Sun J; Kim, Jae-Seung; Lee, Myoung C

    2006-05-15

    We evaluated the patterns of dopamine transporter loss in the striatum of ten controls, twenty patients with Parkinson's disease (PD), and nine with progressive supranuclear palsy (PSP) using (123)I-IPT single photon emission tomography (SPECT). Four ROIs in the striatum correspond to the head of caudate nucleus (ROI 1), a transitional region between head of caudate and putamen (ROI 2), anterior putamen (ROI 3), and posterior putamen (ROI 4). A striatal ratio of specific to nondisplaceable uptake (V3'') was calculated normalizing the activity of the ROIs to that of occipital cortex. V3'' values were significantly reduced in all ROIs of PD and PSP patients, compared with controls (p=0.001). V3'' value in ROI 2 was significantly lower in PSP group, compared with PD group (p=0.02). The percent reductions of striatal uptake in ROI 1, ROI 2, ROI 3 and ROI 4 were 56%, 53%, 64% and 78% in PD patients, whereas 75%, 72%, 75% and 77% in PSP patients, respectively. The reduction patterns of uptake were significantly different between PD and PSP groups (p=0.001). In PD patients, the percent reductions of (123)I-IPT uptake were significantly greater in ROI 3 and 4 compared with ROI 1 or 2, whereas those were similar in all ROIs of PSP patients. In addition, PD patients showed a significantly higher posterior putamen/caudate ratio of reduced (123)I-IPT uptake than the anterior putamen/caudate ratio (p=0.005). Our results implicate that (123)I-IPT SPECT is a relatively simple and reliable technique that may be useful in differentiating PD from PSP.

  1. Accelerating Progress in Eating Disorders Prevention: A Call for Policy Translation Research and Training.

    PubMed

    Austin, S Bryn

    2016-01-01

    The public health burden of eating disorders is well documented, and over the past several decades, researchers have made important advances in the prevention of eating disorders and related problems with body image. Despite these advances, however, several critical limitations to the approaches developed to date leave the field far from achieving the large-scale impact that is needed. This commentary provides a brief review of what achievements in prevention have been made and identifies the gaps that limit the potential for greater impact on population health. A plan is then offered with specific action steps to accelerate progress in high-impact prevention, most compellingly by promoting a shift in priorities to policy translation research and training for scholars through the adoption of a triggers-to-action framework. Finally, the commentary provides an example of the application of the triggers-to-action framework as practiced at the Strategic Training Initiative for the Prevention of Eating Disorders, a program based at the Harvard T. H. Chan School of Public Health and Boston Children's Hospital. Much has been achieved in the nearly 30 years of research carried out for the prevention of eating disorders and body image problems, but several critical limitations undermine the field's potential for meaningful impact. Through a shift in the field's priorities to policy translation research and training with an emphasis on macro-environmental influences, the pace of progress in prevention can be accelerated and the potential for large-scale impact substantially improved.

  2. Do dopamine agonists prevent or reduce the severity of ovarian hyperstimulation syndrome in women undergoing assisted reproduction? A systematic review and meta-analysis.

    PubMed

    Baumgarten, Miriam; Polanski, Lukasz; Campbell, Bruce; Raine-Fenning, Nick

    2013-09-01

    Controlled ovarian stimulation is an integral part of assisted reproduction treatment. This can result in ovarian hyperstimulation syndrome (OHSS), which is associated with significant morbidity and potentially mortality. Recent approaches to ovarian stimulation have led to a reduction in the prevalence of OHSS but it still occurs. Dopamine agonists (DAs) have been used with some success during the ovarian stimulation phase when there are early signs of OHSS but there is no consensus on when to start and stop treatment or on the dose and specific agonist to use. EMBRASE, MEDLINE and Cochrane were searched using the following terms: ovarian hyperstimulation syndrome, controlled ovarian hyperstimulation, DAs, cabergoline, quinagolide, bromocriptide, pergolide, talipexole, ropinirole and pranipexole. The search yielded 20 publications. In total 1646 woman were included and 914 received a DA. In the treated group 86 (9.41%) developed OHSS, compared with 157 (21.45%) in the non-treated group. Nine studies were suitable for meta-analysis. This showed a benefit to the use of DAs (RR 0.51 [0.33, 0.78], Chi² = 16.07). The use of DAs appears to be effective for the prevention of OHSS. DAs are useful but less effective for the treatment of OHSS. No conclusions can be made regarding the most effective drug, the optimal dose or the most appropriate drug regimen.

  3. Prevention studies in Alzheimer's disease: progress towards the development of new therapeutics.

    PubMed

    Coley, Nicola; Gallini, Adeline; Andrieu, Sandrine

    2015-07-01

    Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches.

  4. Parkinson's disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process.

    PubMed

    Willis, Gregory L

    2008-01-01

    For more than 50 years, Parkinson's disease (PD) has been conceptualized as a product of nigro-striatal dopamine (NSD) system degeneration. In spite of a growing body of evidence depicting the mammalian brain as an interrelated complexity of circuitous systems, dopamine (DA) deficiency of the NSD is still regarded as the main problem, with DA replacement being the purpose of therapeutic intervention. For at least 191 years circadian involvement in various aspects of PD, including depression and insomnia, has been recognized as an integral part of the symptom matrix of PD and yet attempts to elucidate the involvement of this system is uncharted territory. The present review attempts a major reorganization of mammalian brain into a coordinated complex involving the NSD and the retinal hypothalamic tract (RHT) as the primary systems involved in the retino-diencephalic/mesencephalic-pineal (RDMP) axis. Secondary systems including the lateral hypothalamus (LH), the area postraema (AP) and the subthalamic nucleus (STN) also form an integral part of this system as they have been shown to be either intimately related to the primary systems of the RDMP axis or have been shown to be significantly involved in the expression and treatment of PD. A large volume of evidence suggests that the RDMP axis is activated during the course of PD and during therapeutic intervention. Four types of neurotoxicity associated with melatonin are identified and the susceptibility of various parts of the RDMP axis to undergo neuropathological change, the tendency for melatonin to induce PD-like behavioural toxicity, and the relationship of this to PD symptomotology are described. This includes adverse effects of melatonin on motor function, hypotension, the adjuvant use of benzodiazepines, depression, insomnia, body weight regulation and various biochemical effects of melatonin administration: all problems currently facing the proposal to introduce melatonin as an adjuvant. It is suggested

  5. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

    PubMed Central

    Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Holmes Morton, D.; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.

    2014-01-01

    Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine ‘transportopathy’ to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5–34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having ‘juvenile parkinsonism’. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more

  6. Efficacy of nighttime brace in preventing progression of idiopathic scoliosis of less than 25°.

    PubMed

    Lateur, G; Grobost, P; Gerbelot, J; Eid, A; Griffet, J; Courvoisier, A

    2017-04-01

    The objective of the present study was to assess, at skeletal maturity, the efficacy of non-operative treatment by isolated nighttime brace in the prevention of progression of progressive idiopathic scoliosis of less than 25°. Isolated nighttime brace treatment is effective in the prevention of progression of mild progressive idiopathic scoliosis (Cobb<25°). A single-center retrospective study included 142 patients managed by nighttime brace for progressive idiopathic scoliosis with Cobb angle<25°, with assessment at skeletal maturity. Mean Cobb angle at start of treatment was 15.5° (range, 10-25°). Mean values for Cobb angle and sagittal parameters before treatment and at skeletal maturity were compared on Student t-test. Change in Cobb angle over time was also analyzed. Mean Cobb angle at skeletal maturity was 16.3°, showing significant increase over baseline (15.5°; P=0.04), although the difference was less than the uncertainty of measurement (±6°). In baseline Risser 0 or 1, mean change in Cobb angle at skeletal maturity (16.2°) was not significant (P=0.1). Cobb angle diminished in 26 cases (18%), increased in 24 (17%) and was unchanged in 92 (65%). The present study confirmed the efficacy of non-operative treatment by nighttime brace in mild progressive idiopathic scoliosis (<25°) in a large majority of cases. A nighttime brace thus seems to be an effective option for the treatment of adolescent scoliosis, ensuring a safe curve of around 20°. Level IV, retrospective study. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model.

    PubMed

    Bateman, Randall J; Benzinger, Tammie L; Berry, Scott; Clifford, David B; Duggan, Cynthia; Fagan, Anne M; Fanning, Kathleen; Farlow, Martin R; Hassenstab, Jason; McDade, Eric M; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P; Santacruz, Anna; Schneider, Lon S; Wang, Guoqiao; Xiong, Chengjie

    2017-01-01

    The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  8. Candidiasis: a fungal infection--current challenges and progress in prevention and treatment.

    PubMed

    Hani, Umme; Shivakumar, Hosakote G; Vaghela, Rudra; Osmani, Riyaz Ali M; Shrivastava, Atul

    2015-01-01

    Despite therapeutic advances candidiasis remains a common fungal infection most frequently caused by C. albicans and may occur as vulvovaginal candidiasis or thrush, a mucocutaneous candidiasis. Candidiasis frequently occurs in newborns, in immune-deficient people like AIDS patients, and in people being treated with broad spectrum antibiotics. It is mainly due to C. albicans while other species such as C. tropicalis, C. glabrata, C. parapsilosis and C. krusei are increasingly isolated. OTC antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis. Present review summarizes the diagnosis, current status and challenges in the treatment and prevention of candidiasis with prime focus on host defense against candidiasis, advancements in diagnosis, probiotics role and recent progress in the development of vaccines against candidiasis.

  9. Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice.

    PubMed

    de Theije, Caroline G M; van den Elsen, Lieke W J; Willemsen, Linette E M; Milosevic, Vanja; Korte-Bouws, Gerdien A H; Lopes da Silva, Sofia; Broersen, Laus M; Korte, S Mechiel; Olivier, Berend; Garssen, Johan; Kraneveld, Aletta D

    2015-03-01

    Allergy is suggested to exacerbate impaired behaviour in children with neurodevelopmental disorders. We have previously shown that food allergy impaired social behaviour in mice. Dietary fatty acid composition may affect both the immune and nervous system. The aim of this study was to assess the effect of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) on food allergy-induced impaired social behaviour and associated deficits in prefrontal dopamine (DA) in mice. Mice were fed either control or n-3 LCPUFA-enriched diet before and during sensitization with whey. Social behaviour, acute allergic skin response and serum immunoglobulins were assessed. Monoamine levels were measured in brain and intestine and fatty acid content in brain. N-3 LCPUFA prevented impaired social behaviour of allergic mice. Moreover, n-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation into the brain and restored reduced levels of prefrontal DA and its metabolites 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine and homovanillic acid in allergic mice. In addition to these brain effects, n-3 LCPUFA supplementation reduced the allergic skin response and restored decreased intestinal levels of serotonin metabolite 5-hydroxyindoleacetic acid in allergic mice. N-3 LCPUFA may have beneficial effects on food allergy-induced deficits in social behaviour, either indirectly by reducing the allergic response and restoring intestinal 5-HT signalling, or directly by DHA incorporation into neuronal membranes, affecting the DA system. Therefore, it is of interest to further investigate the relevance of food allergy-enhanced impairments in social behaviour in humans and the potential benefits of dietary n-3 LCPUFA supplementation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

    PubMed

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Rakesh; Shukla, Shubha

    2016-12-14

    Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in

  11. Helicobacter pylori Eradication Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

    PubMed Central

    Lee, Chung-Wei; Rickman, Barry; Rogers, Arlin B.; Ge, Zhongming; Wang, Timothy C.; Fox, James G.

    2009-01-01

    Helicobacter pylori infection results in chronic gastritis, which may progress to gastric cancer. In this study, we investigated the efficacy of H. pylori eradication in preventing the progression of gastritis to gastric cancer in H. pylori–infected transgenic INS-GAS mice. H. pylori infection induced severe dysplasia and gastric cancer classified as high-grade and low-grade gastrointestinal intraepithelial neoplasia (GIN) in INS-GAS mice at 28 weeks postinfection (WPI). H. pylori eradication therapy using omeprazole, metronidazole, and clarithromycin was administered p.o. at 8, 12, or 22 WPI. Compared with untreated infected mice, H. pylori eradication at 8, 12, and 22 WPI significantly reduced the severity of dysplasia (P < 0.01). Moreover, H. pylori eradication at 8 WPI completely prevented the development of GIN (P < 0.001). Although not as effective as early antimicrobial treatment, prevention of progression to high-grade GIN was achieved by H. pylori eradication at 12 and 22 WPI (P < 0.05). Consistent with reduced gastric pathology, H. pylori eradication at all time points significantly down-regulated gastric Interferon-γ, tumor necrosis factor-α, inducible nitric oxide synthase, and Reg 1 mRNA levels (P < 0.05) and reduced epithelial proliferation in the corpus (P < 0.01) compared with untreated infected mice. We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics are given at an early point of infection, but that eradication therapy given at a later time point delayed the development of severe dysplastic lesions. PMID:18441088

  12. Use of subatmospheric pressure to prevent progression of partial-thickness burns in a swine model.

    PubMed

    Morykwas, M J; David, L R; Schneider, A M; Whang, C; Jennings, D A; Canty, C; Parker, D; White, W L; Argenta, L C

    1999-01-01

    The poorly understood, complex series of events that follows thermal injury frequently results in progressive loss of tissue. The concept of reversing this distinctive series of events has focused on the zone of stasis. Tissues in the zone of stasis that surround burn injuries usually die over a period of 48 to 72 hours postinjury, resulting in a more severe injury. Application of a controlled subatmospheric pressure (125 mm Hg) in an artificially closed space to partial-thickness burns in pigs significantly decreased the maximum depth of cellular death under the burn when the pressure was applied within 12 hours after burn creation (depth of control burns = 0.885 +/- 0.115 mm; subatmospheric pressure treated burns (0-hour delay) = 0.095 +/- 0.025 mm). A decrease in the depth of cell death was noted when subatmospheric pressure was applied for as little as 6 hours. In summary, the application of the negative pressure to partial-thickness burn injuries prevented progression of the wound to a deeper injury in this experimental pig model. A 12-hour working window exists between injury and treatment with reduced pressure, with an application time of as little as 6 hours for successful prevention of injury progression. This technique may represent a new, inexpensive, 'low tech' method for the treatment of partial-thickness burn injuries.

  13. Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

    PubMed Central

    Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Moaddel, Ruin; Xiao, Cheng

    2016-01-01

    , menthol alone exerts several neurobiological changes. We are among the first to show that menthol, by itself, increases the number of nicotinic acetylcholine receptors (nAChRs) in the mouse brain. It does so at a dose that matches nicotine in its ability to increase nAChR number. At this same dose, menthol also alters midbrain dopamine neuron function and prevents nicotine reward-related behavior. Together, our data show that menthol is more than an “inert” flavor additive and is able to change the function of midbrain dopamine neurons that are part of the mesolimbic reward pathway. PMID:26961950

  14. Practical Approaches to Evaluating Progress and Outcomes in Community-Wide Teen Pregnancy Prevention Initiatives.

    PubMed

    Tevendale, Heather D; Condron, D Susanne; Garraza, Lucas Godoy; House, L Duane; Romero, Lisa M; Brooks, Megan A M; Walrath, Christine

    2017-03-01

    This paper presents an overview of the key evaluation components for a set of community-wide teen pregnancy prevention initiatives. We first describe the performance measures selected to assess progress toward meeting short-term objectives on the reach and quality of implementation of evidence-based teen pregnancy prevention interventions and adolescent reproductive health services. Next, we describe an evaluation that will compare teen birth rates in intervention communities relative to synthetic control communities. Synthetic controls are developed via a data-driven technique that constructs control communities by combining information from a pool of communities that are similar to the intervention community. Finally, we share lessons learned thus far in the evaluation of the project, with a focus on those lessons that may be valuable for local communities evaluating efforts to reduce teen pregnancy. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  15. Calcification of tissue heart valve substitutes: progress toward understanding and prevention.

    PubMed

    Schoen, Frederick J; Levy, Robert J

    2005-03-01

    Calcification plays a major role in the failure of bioprosthetic and other tissue heart valve substitutes. Tissue valve calcification is initiated primarily within residual cells that have been devitalized, usually by glutaraldehyde pretreatment. The mechanism involves reaction of calcium-containing extracellular fluid with membrane-associated phosphorus to yield calcium phosphate mineral deposits. Calcification is accelerated by young recipient age, valve factors such as glutaraldehyde fixation, and increased mechanical stress. Recent studies have suggested that pathologic calcification is regulated by inductive and inhibitory factors, similar to the physiologic mineralization of bone. The most promising preventive strategies have included binding of calcification inhibitors to glutaraldehyde fixed tissue, removal or modification of calcifiable components, modification of glutaraldehyde fixation, and use of tissue cross linking agents other than glutaraldehyde. This review summarizes current concepts in the pathophysiology of tissue valve calcification, including emerging concepts of endogenous regulation, progress toward prevention of calcification, and issues related to calcification of the aortic wall of stentless bioprosthetic valves.

  16. Prevention and health promotion: decades of progress, new challenges, and an emerging agenda.

    PubMed

    Smith, Timothy W; Orleans, C Tracy; Jenkins, C David

    2004-03-01

    Daily habits (e.g., smoking, diet, and exercise) and their immediate consequences (e.g., obesity) confer risk for most of the major health problems in industrialized nations. Hence, determinants of these behaviors and their modifications have been central topics in health psychology. Considerable scientific and applied progress has been made, but the field faces important challenges and opportunities in the future. These challenges and opportunities include changes in demographics and patterns of health, the need for a more comprehensive model of the domain of health behavior and prevention, the need to integrate behavioral and psychosocial risk and resilience, the incorporation of new technologies, and addressing a variety of professional and economic barriers to the implementation of prevention in health care.

  17. Cataract progression after prophylactic laser peripheral iridotomy: potential implications for the prevention of glaucoma blindness.

    PubMed

    Lim, Laurence S; Husain, Rahat; Gazzard, Gus; Seah, Steve K L; Aung, Tin

    2005-08-01

    To evaluate changes in lens opacity in the first year after prophylactic laser peripheral iridotomy (LPI) performed in fellow eyes of subjects with acute primary angle closure (APAC). Prospective observational case series. Sixty Asian subjects with unilateral APAC. All fellow eyes underwent prophylactic LPI within the first week of presentation, followed by 1 week of topical steroids. The degree of lens opacity was graded at the slit-lamp examination using the Lens Opacity Classification System III (LOCS III) with standard color photographs as the reference for grading of lens opacity. This was performed 2 weeks, 4 months, and 12 months after LPI. Progression in lens opacity was defined as an increase in LOCS III grade by 2 or more units in any lens region. Lens Opacity Classification Sytem III grades in nuclear, cortical, and posterior subcapsular (PSC) regions. Most patients were Chinese (85%) and female (63.3%), with an average age of 61.5 +/- 10.6 years. The mean baseline LOCS grades in the nuclear, cortical, and PSC regions were 3.58 +/- 0.74, 0.57 +/- 1.08, and 0.23 +/- 0.72, respectively. With 12 months of follow-up, 14 of the 60 eyes (23.3%; 95% confidence interval, 16.9-29.7%) showed significant progression in any lens region. Progression in the nuclear, cortical, and PSC regions was documented in 5%, 6.7%, and 16.7% of cases, respectively. By use of logistic regression, the following factors were not found to be significant for cataract progression in any lens region: age, race, gender, history of hypertension or diabetes, presence of peripheral anterior synechiae or angle width at baseline, and total laser energy delivered. In fellow eyes of APAC, prophylactic LPI is complicated by significant cataract progression, mainly in the posterior subcapsular region. These findings may have implications for the role of prophylactic LPI in the prevention of angle-closure blindness.

  18. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    PubMed Central

    2009-01-01

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

  19. Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy.

    PubMed

    You, Hanning; Gao, Ting; Cooper, Timothy K; Morris, Sidney M; Awad, Alaa S

    2015-09-01

    Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN-which is more clinically relevant-is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid-reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2(Akita) mice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury.

  20. Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy

    PubMed Central

    You, Hanning; Gao, Ting; Cooper, Timothy K.; Morris, Sidney M.

    2015-01-01

    Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN–which is more clinically relevant–is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2Akita mice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid-reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2Akita mice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury. PMID:26041444

  1. Repeated Treatments with Ingenol Mebutate Prevents Progression of UV-Induced Photodamage in Hairless Mice

    PubMed Central

    Thaysen-Petersen, Daniel; Bay, Christiane; Hald, Andreas; Skak, Kresten; Zibert, John Robert; Paasch, Uwe; Wulf, Hans Christian; Haedersdal, Merete

    2016-01-01

    Background and Aim Ingenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR). Methods Hairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0–12). LSR (0–24) were assessed once daily (Days 1–7) after each IngMeb treatment. Results IngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1–5: UVR+IngMeb+CP 3.6–5.5 vs. UVR+IngMeb 2.6–4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001). Conclusion Repeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors. PMID:27636884

  2. Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression.

    PubMed

    Torii, Hidemasa; Kurihara, Toshihide; Seko, Yuko; Negishi, Kazuno; Ohnuma, Kazuhiko; Inaba, Takaaki; Kawashima, Motoko; Jiang, Xiaoyan; Kondo, Shinichiro; Miyauchi, Maki; Miwa, Yukihiro; Katada, Yusaku; Mori, Kiwako; Kato, Keiichi; Tsubota, Kinya; Goto, Hiroshi; Oda, Mayumi; Hatori, Megumi; Tsubota, Kazuo

    2017-02-01

    Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression.

  3. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice

    PubMed Central

    2014-01-01

    Background Intraneuronal inclusions of TAR DNA-binding protein 43 (TDP-43) have been found in the majority of Amyotrophic Lateral Sclerosis (ALS) patients. Mutations in the gene encoding TDP-43 cause familial ALS. Transgenic mice expressing mutant TDP-43 with one such mutation (TDP-43 (A315T)) under control of the murine prion promoter develop motor symptoms, but their use is currently hampered by sudden death. We aimed to understand and overcome the cause of sudden death in TDP-43 (A315T) mice. Since intestinal obstruction was suspected to be the cause, intestinal motility of TDP-43 (A315T) mice was studied in an ex-vivo pellet propulsion assay. The effect on the enteric and motor phenotype was assessed, both in animals on normal chow or on a jellified fiber deprived diet, aimed at preventing intestinal obstruction. Results The frequency of the propulsive motor complexes was significantly reduced in the colon of TDP-43 (A315T) compared to non transgenic (NTG) mice. Immunohistochemistry revealed significant enlargement in size and reduction in number of the nitric oxide synthase (NOS) neurons in the myenteric plexus of TDP-43 (A315T) mice. Prevention of intestinal obstruction by jellified food abolished sudden death, allowing the motor phenotype to develop and slowly progress with a more pronounced degeneration of upper and lower motor axons. A downregulation of endogenous TDP-43 mRNA and protein levels was observed prior to neurodegeneration. Conclusion TDP-43 (A315T) mice suffer from intestinal dysmotility due to degeneration of NOS neurons in the myenteric plexus. Feeding the mice jellified food prevents sudden death and allows the motor phenotype to progress. PMID:24938805

  4. ATM prevents DSB formation by coordinating SSB repair and cell cycle progression.

    PubMed

    Khoronenkova, Svetlana V; Dianov, Grigory L

    2015-03-31

    DNA single-strand breaks (SSBs) arise as a consequence of spontaneous DNA instability and are also formed as DNA repair intermediates. Their repair is critical because they otherwise terminate gene transcription and generate toxic DNA double-strand breaks (DSBs) on replication. To prevent the formation of DSBs, SSB repair must be completed before DNA replication. To accomplish this, cells should be able to detect unrepaired SSBs, and then delay cell cycle progression to allow more time for repair; however, to date there is no evidence supporting the coordination of SSB repair and replication in human cells. Here we report that ataxia-telangiectasia mutated kinase (ATM) plays a major role in restricting the replication of SSB-containing DNA and thus prevents DSB formation. We show that ATM is activated by SSBs and coordinates their repair with DNA replication. SSB-mediated ATM activation is followed by a G1 cell cycle delay that allows more time for repair and thus prevents the replication of damaged DNA and DSB accrual. These findings establish an unanticipated role for ATM in the signaling of DNA SSBs and provide important insight into the molecular defects leading to genetic instability in patients with ataxia-telangiectasia.

  5. A systematic process to prioritize prevention activities sustaining progress toward the reduction of military injuries.

    PubMed

    Canham-Chervak, Michelle; Hooper, Tomoko I; Brennan, Fred H; Craig, Stephen C; Girasek, Deborah C; Schaefer, Richard A; Barbour, Galen; Yew, Kenneth S; Jones, Bruce H

    2010-01-01

    To sustain progress toward injury reduction and other health promotion goals, public health organizations need a systematic approach based on data and an evaluation of existing scientific evidence on prevention. This paper describes a process and criteria developed to systematically and objectively define prevention program and policy priorities. Military medical surveillance data were obtained and summarized, and a working group of epidemiology and injury experts was formed. After reviewing the available data, the working group used predefined criteria to score leading military unintentional injury causes on five main criteria that assessed factors contributing to program and policy success: (1) importance of the problem, (2) effectiveness of existing prevention strategies, (3) feasibility of establishing programs and policies, (4) timeliness of implementation and results, and (5) potential for evaluation. Injury problems were ranked by total median score. Causes with the highest total median scores were physical training (34 points), military parachuting (32 points), privately-owned vehicle crashes (31 points), sports (29 points), falls (27 points), and military vehicle crashes (27 points). Using a data-driven, criteria-based process, three injury causes (physical training, military parachuting, and privately owned-vehicle crashes) with the greatest potential for successful program and policy implementation were identified. Such information is useful for public health practitioners and policymakers who must prioritize among health problems that are competing for limited resources. The process and criteria could be adapted to systematically assess and prioritize health issues affecting other communities. Published by Elsevier Inc.

  6. Reducing Available Soluble β-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice

    PubMed Central

    Gregory, Julia L.; Prada, Claudia M.; Fine, Sara J.; Garcia-Alloza, Monica; Betensky, Rebecca A.; Arbel-Ornath, Michal; Greenberg, Steven M.; Bacskai, Brian J.; Frosch, Matthew P.

    2012-01-01

    Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment, and is commonly associated with Alzheimer disease (AD). CAA progression, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain is poorly understood. We manipulated Aβ levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding “peripheral sink” protein gelsolin, and direct inhibition of its formation via administration of LY-411575, a small molecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58 ± 0.15% and 0.52 ± 0.09% to 0.11 ± 0.18% (p = 0.04) and −0.17 ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. CAA progression was also halted when gelsolin was combined with LY-411575 (−0.004 ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ, but without evidence of substantial amyloid clearance from vessels. PMID:23095848

  7. Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract.

    PubMed

    Mathew, Milan C; Ervin, Ann-Margret; Tao, Jeremiah; Davis, Richard M

    2012-06-13

    Age-related cataract is a major cause of visual impairment in the elderly. Oxidative stress has been implicated in its formation and progression. Antioxidant vitamin supplementation has been investigated in this context. To assess the effectiveness of antioxidant vitamin supplementation in preventing and slowing the progression of age-related cataract. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 2), MEDLINE (January 1950 to March 2012), EMBASE (January 1980 to March 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to March 2012), Open Grey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 2 March 2012. We also checked the reference lists of included studies and ongoing trials and contacted investigators to identify eligible randomized trials. We included only randomized controlled trials in which supplementation with one or more antioxidant vitamins (beta-carotene, vitamin C and vitamin E) in any form, dosage or combination for at least one year was compared to another antioxidant vitamin or to placebo. Two authors extracted data and assessed trial quality independently. We pooled results for the primary outcomes, i.e., incidence of cataract and incidence of cataract extraction. We did not pool results of the secondary outcomes - progression of cataract and loss of visual acuity, because of differences in definitions of outcomes and data presentation. We pooled results by type of cataract when data were available. We did not perform a sensitivity analysis. Nine trials involving 117

  8. Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract

    PubMed Central

    Mathew, Milan C; Ervin, Ann-Margret; Tao, Jeremiah; Davis, Richard M

    2013-01-01

    Background Age-related cataract is a major cause of visual impairment in the elderly. Oxidative stress has been implicated in its formation and progression. Antioxidant vitamin supplementation has been investigated in this context. Objectives To assess the effectiveness of antioxidant vitamin supplementation in preventing and slowing the progression of age-related cataract. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 2), MEDLINE (January 1950 to March 2012), EMBASE (January 1980 to March 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to March 2012), Open Grey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 2 March 2012. We also checked the reference lists of included studies and ongoing trials and contacted investigators to identify eligible randomized trials. Selection criteria We included only randomized controlled trials in which supplementation with one or more antioxidant vitamins (beta-carotene, vitamin C and vitamin E) in any form, dosage or combination for at least one year was compared to another antioxidant vitamin or to placebo. Data collection and analysis Two authors extracted data and assessed trial quality independently. We pooled results for the primary outcomes, i.e., incidence of cataract and incidence of cataract extraction. We did not pool results of the secondary outcomes - progression of cataract and loss of visual acuity, because of differences in definitions of outcomes and data presentation. We pooled results by type of cataract when data

  9. Cerium nitrate treatment prevents progressive tissue necrosis in the zone of stasis following burn.

    PubMed

    Eski, Muhitdin; Ozer, Firat; Firat, Cemal; Alhan, Doğan; Arslan, Nuri; Senturk, Tolga; Işik, Selcuk

    2012-03-01

    Cerium nitrate (CN) was used as a topical antiseptic agent for the treatment of burn wounds and found to reduce the number of anticipated death in burn. This decreased burn related mortality cannot be explained by the control of wound infection alone. In the studies performed to elucidate the unexplained effects of CN treatment, it was shown that CN treatment reduced the alarm cytokine levels, decreased leukocyte activation, reduced macromolecular leakage and finally burn edema formation. We hypothesized that CN treatment prevents the conversion of the zone of stasis to progressive tissue necrosis by decreasing leukocyte activation and reducing macromolecular leakage and burn edema. This was investigated on a well-described burn comb model in the rats. Fifty-four rats were randomly divided into control and CN treatment groups. Each rat in CN treatment group received 0.04 M CN bathing 30 min after burn whereas rats in control group received 0.09% saline bathing. Viability of zone of stasis is assessed with (99 m)Tc-sestamibi scintigraphy. Nine rats in each group were scintigraphically evaluated at the 3rd and 7th day after burn and remaining 9 rats had macroscopic and histological examination at the 21st day after burn to confirm the scintigraphic results. In CN treatment groups, the scintigraphic uptake ratios were higher both at post burn day 3rd and 7th when compared to that of control groups. This was statistically significant (p≤0.05). In the CN treatment group, the results of the average percentage of the re-epithelialization in the zone of stasis were higher than that of control groups. The difference between the groups was also statistically significant (p≤0.05). These results were accepted that CN treatment prevents progressive tissue necrosis in the zone of stasis. This study further elucidates the unexplained effects of CN treatment on burn. Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

  10. Home modification and prevention of frailty progression in older adults: a Japanese prospective cohort study.

    PubMed

    Mitoku, Kazuko; Shimanouchi, Setsu

    2014-08-01

    The aim of this study was to determine whether home modification was associated with subsequent progression of frailty and mortality in older adults. We conducted a prospective cohort study in 574 adults 65 and older who required a low or moderate level of care. Of these, 34% modified their homes-most frequently a corridor-and the most common type of modification was the installation of handrails. The mortality was significantly lower among older adults with home modifications than in those without home modifications at 2 years (adjusted hazard ratio [HR] = 0.52; 95% confidence interval [CI] [0.32, 0.87]), 3 years (HR = 0.57, 95% CI [0.54, 0.81]), and 4.7 years (HR = 0.65, 95% CI [0.65, 0.91]). These findings suggest that home modification may prevent the progression of frailty (i.e., need for low/moderate level of care increasing to the need for high level of care) in older adults.

  11. Rosuvastatin Treatment Prevents Progressive Kidney Inflammation and Fibrosis in Stroke-Prone Rats

    PubMed Central

    Gianella, Anita; Nobili, Elena; Abbate, Mauro; Zoja, Carla; Gelosa, Paolo; Mussoni, Luciana; Bellosta, Stefano; Canavesi, Monica; Rottoli, Daniela; Guerrini, Uliano; Brioschi, Maura; Banfi, Cristina; Tremoli, Elena; Remuzzi, Giuseppe; Sironi, Luigi

    2007-01-01

    Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of α-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis. PMID:17392157

  12. Prevention of postoperative progression of pulmonary metastases in osteosarcoma by antiangiogenic therapy using endostatin.

    PubMed

    Kaya, Mitsunori; Wada, Takuro; Nagoya, Satoshi; Yamashita, Toshihiko

    2007-11-01

    We have previously offered data suggesting a positive linkage of postoperative up-regulation of systemic angiogenic activity and postoperative progression of pulmonary metastasis in osteosarcoma. The finding that the significant down-regulation of endostatin was critical in angiogenic elevation after primary tumor removal suggests that endostatin is a candidate for antiangiogenic therapy for osteosarcoma. In the current study, we evaluated the effect of antiangiogenic therapy using endostatin on postoperative progression of pulmonary metastasis from osteosarcoma. Mouse osteosarcoma cell line LM 8 cells were inoculated in subcutaneous layer of nude mice. Two weeks after tumor inoculation, the primary tumor was removed surgically, and antiangiogenic therapy using adenovirus encoding endostatin expression vector (Ad5CMV-mEnd) was performed. Two weeks after the antiangiogenic treatment, pulmonary metastasis was evaluated by counting the number of metastatic nodules. The evaluation of systemic angiogenic activity was performed using Matrigel plug assay. Two weeks after the viral injection, mice were sacrificed, and the macroscopic pulmonary metastases were counted. Notably, the number of pulmonary metastases was smaller in the mice injected with Ad5CMV-mEnd than in controls, accompanied by significant suppression of systemic angiogenic activity. In addition, the sizes of the pulmonary metastases of the mice injected with Ad5CMV-mEnd were smaller than in the control group. Our results indicate that antiangiogenic therapy using endostatin has the potential to prevent postoperative progression of pulmonary metastasis from osteosarcoma. Although this therapeutic strategy cannot provide a cure for osteosarcoma, it should enable osteosarcoma patients to coexist with dormant pulmonary metastasis and lead to improvement of their prognosis.

  13. Oral health information systems--towards measuring progress in oral health promotion and disease prevention.

    PubMed Central

    Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas; Ogawa, Hiroshi

    2005-01-01

    This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has been designed by WHO and used by countries worldwide for the surveillance of oral disease and health. Global, regional and national oral health databanks have highlighted the changing patterns of oral disease which primarily reflect changing risk profiles and the implementation of oral health programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers and the general public. WHO has developed global and regional oral health databanks for surveillance, and international projects have designed oral health indicators for use in oral health information systems for assessing the quality of oral health care and surveillance systems. Modern oral health information systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease and in health promotion may assist countries to implement effective public health programmes to the benefit of the poor and disadvantaged population groups worldwide. PMID:16211160

  14. Darbepoetin-α prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure

    PubMed Central

    Rastogi, Sharad; Imai, Makoto; Sharov, Victor G.; Mishra, Sudhish; Sabbah, Hani N.

    2008-01-01

    In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-α (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) ∼25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 μg/kg, n = 7) or to no therapy (HF, n = 7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1α, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1α and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia. PMID:18952719

  15. Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta.

    PubMed Central

    Lacey, M G; Mercuri, N B; North, R A

    1987-01-01

    1. Intracellular recordings were made from neurones in the substantia nigra zona compacta in slices of rat mesencephalon in vitro. The majority of neurones fired action potentials spontaneously at 0.2-5.6 Hz. Dopamine, applied either by superfusion or from the tip of a pressurized pipette, prevented spontaneous action potential firing and hyperpolarized the membrane. 2. When the membrane potential was held negative to the threshold for action potential firing, the hyperpolarization evoked by dopamine was accompanied by a fall in input resistance. Under voltage clamp, dopamine produced an outward membrane current associated with an increase in membrane conductance. The effects of superfused dopamine on firing rate, membrane potential and membrane current were concentration dependent in the range 1-100 microM. 3. The reversal potential for the hyperpolarizations and the outward currents produced by dopamine was -109.7 +/- 1.7 mV (n = 12) when the potassium concentration was 2.5 mM and -74.0 +/- 5.0 mV (n = 4) when the potassium concentration was 10.5 mM. The change in reversal potentials in these and intermediate potassium concentrations was described by the Nernst equation. 4. The outward current induced by dopamine was reversibly reduced by barium (100-300 microM) and by high concentrations of tetraethylammonium (greater than or equal to 10 mM). Calcium-free solutions with cobalt (0.5-2 mM) did not reduce the current in response to dopamine during the first 5 min of their application. Currents and hyperpolarizations caused by dopamine were unaffected by tetrodotoxin (1 microM). 5. The hyperpolarization produced by dopamine was mimicked by the D2 receptor agonist quinpirole (LY 171555, 0.1-3 microM) and was blocked by the D2 receptor agonists domperidone and (-)-sulpiride. Agonists and antagonists at D1 receptors had no effect. 6. (-)-Sulpiride (30 nM-30 microM) produced a progressive shift to the right in the concentration-response curve to either dopamine or

  16. Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss.

    PubMed

    Garcia, Bonnie G; Neely, M Diana; Deutch, Ariel Y

    2010-10-01

    Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion-induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease.

  17. TCF7L2 Polymorphisms and Progression to Diabetes in the Diabetes Prevention Program

    PubMed Central

    Florez, Jose C.; Jablonski, Kathleen A.; Bayley, Nick; Pollin, Toni I.; de Bakker, Paul I.W.; Shuldiner, Alan R.; Knowler, William C.; Nathan, David M.; Altshuler, David

    2006-01-01

    Background Common polymorphisms of the transcription factor 7–like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. Methods We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year. Results Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P = 0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. Conclusions Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992.) PMID:16855264

  18. Mesenchymal stem cells (MSC) prevented the progression of renovascular hypertension, improved renal function and architecture.

    PubMed

    Oliveira-Sales, Elizabeth B; Maquigussa, Edgar; Semedo, Patricia; Pereira, Luciana G; Ferreira, Vanessa M; Câmara, Niels O; Bergamaschi, Cassia T; Campos, Ruy R; Boim, Mirian A

    2013-01-01

    Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×10(5) cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.

  19. Mesenchymal Stem Cells (MSC) Prevented the Progression of Renovascular Hypertension, Improved Renal Function and Architecture

    PubMed Central

    Oliveira-Sales, Elizabeth B.; Maquigussa, Edgar; Semedo, Patricia; Pereira, Luciana G.; Ferreira, Vanessa M.; Câmara, Niels O.; Bergamaschi, Cassia T.; Campos, Ruy R.; Boim, Mirian A.

    2013-01-01

    Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×105 cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future. PMID:24223811

  20. Progress towards hepatitis B prevention through vaccination in the Western Pacific, 1990-2014.

    PubMed

    Wiesen, Eric; Diorditsa, Sergey; Li, Xi

    2016-05-27

    Hepatitis B infections are responsible for more than 300 thousand deaths per year in the Western Pacific Region. Because of this high burden, the countries and areas of the Region established a goal of reducing hepatitis B chronic infection prevalence among children to less than 1% by 2017. This study was conducted to measure the progress in hepatitis B prevention and assess the status of achievement of the 2017 Regional hepatitis B control goal. A literature review was conducted to identify studies of hepatitis B prevalence in the countries and areas of the region, both before and after vaccine introduction. A mathematical model was applied to assess infections and deaths prevented by hepatitis B vaccination and hepatitis B prevalence in countries without recent empirical data. The majority of countries and areas (22 out of 36) were estimated to have over 8% prevalence of chronic hepatitis B infection among persons born before vaccine introduction. After introduction of hepatitis B vaccine, most countries and areas (24 out of 36) had chronic infection prevalence of less than 1% among children born after vaccine introduction. It was estimated that in the past 25 years immunization programmes in the Western Pacific Region have averted 7,167,128 deaths that would have occurred in the lifetime of children born between 1990 and 2014 if hepatitis B vaccination programmes had not been established. Regional prevalence among children born in 2012 was estimated to be 0.93%, meaning that the Regional hepatitis B control goal was achieved. While additional efforts are needed to further reduce hepatitis B transmission in the region, this study demonstrates the great success of the hepatitis B vaccination efforts in the Western Pacific Region.

  1. Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats

    PubMed Central

    Achterberg, E J Marijke; van Kerkhof, Linda W M; Servadio, Michela; van Swieten, Maaike M H; Houwing, Danielle J; Aalderink, Mandy; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-01-01

    Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression. PMID:26174597

  2. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson's disease.

    PubMed

    Hernandez-Chan, Nancy G; Bannon, Michael J; Orozco-Barrios, Carlos E; Escobedo, Lourdes; Zamudio, Sergio; De la Cruz, Fidel; Gongora-Alfaro, Jose L; Armendáriz-Borunda, Juan; Reyes-Corona, David; Espadas-Alvarez, Armando J; Flores-Martínez, Yazmin M; Ayala-Davila, Jose; Hernandez-Gutierrez, Maria E; Pavón, Lenin; García-Villegas, Refugio; Nadella, Rasajna; Martinez-Fong, Daniel

    2015-07-22

    The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson's disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion recovers from parkinsonism. The plasmids phDAT-BDNF-flag and phDAT-EGFP, coding for enhanced green fluorescent protein, were transfected using neurotensin (NTS)-polyplex, which enables delivery of genes into the dopaminergic neurons via neurotensin-receptor type 1 (NTSR1) internalization. Two weeks after transfections, RT-PCR and immunofluorescence techniques showed that the residual dopaminergic neurons retain NTSR1 expression and susceptibility to be transfected by the NTS-polyplex. phDAT-BDNF-flag transfection did not increase dopaminergic neurons, but caused 7-fold increase in dopamine fibers within the SN and 5-fold increase in innervation and dopamine levels in the striatum. These neurotrophic effects were accompanied by a significant improvement in motor behavior. NTS-polyplex-mediated BDNF overexpression in dopaminergic neurons has proven to be effective to remit hemiparkinsonism in the rat. This BDNF gene therapy might be helpful in the early stage of Parkinson's disease.

  3. Are Substance Use Prevention Programs More Effective in Schools Making Adequate Yearly Progress? A Study of Project ALERT

    ERIC Educational Resources Information Center

    Clark, Heddy Kovach; Ringwalt, Chris L.; Shamblen, Stephen R.; Hanley, Sean M.; Flewelling, Robert L.

    2011-01-01

    This exploratory study sought to determine if a popular school-based drug prevention program might be effective in schools that are making adequate yearly progress (AYP). Thirty-four schools with grades 6 through 8 in 11 states were randomly assigned either to receive Project ALERT (n = 17) or to a control group (n = 17); of these, 10 intervention…

  4. [Progress of research on genetic engineering antibody and its application in prevention and control of parasitic diseases].

    PubMed

    Yao, Yuan; Yu, Chuan-xin

    2013-08-01

    Antibody has extensive application prospects in the biomedical field. The inherent disadvantages of traditional polyclonal antibody and monoclonal antibody limit their application values. The humanized and fragmented antibody remodeling has given a rise to a series of genetic engineered antibody variant. This paper reviews the progress of research on genetic engineering antibody and its application in prevention and control of parasitic diseases.

  5. Are Substance Use Prevention Programs More Effective in Schools Making Adequate Yearly Progress? A Study of Project ALERT

    ERIC Educational Resources Information Center

    Clark, Heddy Kovach; Ringwalt, Chris L.; Shamblen, Stephen R.; Hanley, Sean M.; Flewelling, Robert L.

    2011-01-01

    This exploratory study sought to determine if a popular school-based drug prevention program might be effective in schools that are making adequate yearly progress (AYP). Thirty-four schools with grades 6 through 8 in 11 states were randomly assigned either to receive Project ALERT (n = 17) or to a control group (n = 17); of these, 10 intervention…

  6. The small molecule AUTEN-99 (autophagy enhancer-99) prevents the progression of neurodegenerative symptoms

    PubMed Central

    Kovács, Tibor; Billes, Viktor; Komlós, Marcell; Hotzi, Bernadette; Manzéger, Anna; Tarnóci, Anna; Papp, Diána; Szikszai, Fanni; Szinyákovics, Janka; Rácz, Ákos; Noszál, Béla; Veszelka, Szilvia; Walter, Fruzsina R.; Deli, Mária A.; Hackler, Laszlo; Alfoldi, Robert; Huzian, Orsolya; Puskas, Laszlo G.; Liliom, Hanna; Tárnok, Krisztián; Schlett, Katalin; Borsy, Adrienn; Welker, Ervin; Kovács, Attila L.; Pádár, Zsolt; Erdős, Attila; Legradi, Adam; Bjelik, Annamaria; Gulya, Károly; Gulyás, Balázs; Vellai, Tibor

    2017-01-01

    Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation. Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson’s and Huntington’s diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging. PMID:28205624

  7. Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program

    PubMed Central

    Dabelea, D.; Ma, Y.; Knowler, W. C.; Marcovina, S.; Saudek, C. D.; Arakaki, R.; White, N. H.; Kahn, S. E.; Orchard, T. J.; Goldberg, R.; Palmer, J.; Hamman, R. F.

    2014-01-01

    Aims To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program. Methods A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes. Results The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA1c, estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56–1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%). Conclusions These data suggest that ‘diabetes autoimmunity’, as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes. PMID:24646311

  8. Measuring the progress of capacity building in the Alberta Policy Coalition for Cancer Prevention.

    PubMed

    Raine, Kim D; Sosa Hernandez, Cristabel; Nykiforuk, Candace I J; Reed, Shandy; Montemurro, Genevieve; Lytvyak, Ellina; MacLellan-Wright, Mary-Frances

    2014-07-01

    The Alberta Policy Coalition for Cancer Prevention (APCCP) represents practitioners, policy makers, researchers, and community organizations working together to coordinate efforts and advocate for policy change to reduce chronic diseases. The aim of this research was to capture changes in the APCCP's capacity to advance its goals over the course of its operation. We adapted the Public Health Agency of Canada's validated Community Capacity-Building Tool to capture policy work. All members of the APCCP were invited to complete the tool in 2010 and 2011. Responses were analyzed using descriptive statistics and t tests. Qualitative comments were analyzed using thematic content analysis. A group process for reaching consensus provided context to the survey responses and contributed to a participatory analysis. Significant improvement was observed in eight out of nine capacity domains. Lessons learned highlight the importance of balancing volume and diversity of intersectoral representation to ensure effective participation, as well as aligning professional and economic resources. Defining involvement and roles within a coalition can be a challenging activity contingent on the interests of each sector represented. The participatory analysis enabled the group to reflect on progress made and future directions for policy advocacy. © 2013 Society for Public Health Education.

  9. Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program.

    PubMed

    Dabelea, D; Ma, Y; Knowler, W C; Marcovina, S; Saudek, C D; Arakaki, R; White, N H; Kahn, S E; Orchard, T J; Goldberg, R; Palmer, J; Hamman, R F

    2014-09-01

    To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program. A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes. The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA(1c), estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56-1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%). These data suggest that 'diabetes autoimmunity', as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

  10. Progress in Definition, Prevention and Treatment of Fungal Infections in Cystic Fibrosis.

    PubMed

    Schwarz, Carsten; Hartl, Dominik; Eickmeier, Olaf; Hector, Andreas; Benden, Christian; Durieu, Isabelle; Sole, Amparo; Gartner, Silvia; Milla, Carlos E; Barry, Peter James

    2017-07-31

    Cystic fibrosis (CF) is a chronic lethal multi-system condition; however, most of the morbidity and mortality is dependent on the status of the respiratory system. Progressive respiratory decline is mediated by chronic infection and inflammation, punctuated by important acute events known as pulmonary exacerbations which can lead to accelerated decline. The main bacterial species causing infections include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Achromobacter xylosoxidans. In addition to bacteria, fungi are detected in a significant number of patients. The impact of fungal colonization of the airways is still not completely elucidated, but an increasing body of evidence suggests an important role for moulds and yeasts. Although fungal infections are rare, fungi can cause severe pneumonia requiring appropriate targeted treatment. The most common fungi in respiratory samples of patients with CF are Aspergillus fumigatus, Aspergillus terreus and Scedosporium species for filamentous fungi, and yeasts such as Candida albicans and Candida glabrata. Therapeutic strategies depend on the detected fungus and the underlying clinical status of the patient. The antifungal therapy can range from a simple monotherapy up to a combination of three different drugs. Treatment course may be indicated in some patients for two weeks and in others for up to six months, and in rare cases even longer. New antifungal drugs have been developed and are being tested in clinical studies offering the hope of therapeutic alternatives to existing drugs. Identifying relevant risk factors and diagnostic criteria for fungal colonization and infection is crucial to enabling an adequate prevention, diagnosis and treatment.

  11. Perinatal HIV and its prevention: progress toward an HIV-free generation.

    PubMed

    Fowler, Mary Glenn; Gable, Alicia R; Lampe, Margaret A; Etima, Monica; Owor, Maxensia

    2010-12-01

    This article reviews the epidemiology of perinatal (HIV)-1 in the United States in the past 2 decades and the international HIV epidemic among pregnant women and their infants. Since the peak of 1700 reported cases of pediatric AIDS in 1992, there has been dramatic progress in decreasing perinatal HIV transmission in the United States with fewer than 50 new cases of AIDS annually (>96% reduction) and fewer than 300 annual perinatal HIV transmissions in 2005. This success has been due to use of combination antiretrovirals given to mothers during pregnancy and labor/delivery, obstetric interventions that reduce the risk of transmission, provision of zidovudine (ZDV) prophylaxis for 6 weeks to HIV-exposed newborns and use of formula. Internationally, the burden of mother-to-child HIV transmission remains heavy with 2.1 million children less than 15 years of age estimated to be living with HIV and 430,000 new HIV infections in infants occurring each year, with most cases occurring in Africa. Current international efforts are directed at scaling up successful prevention of mother-to-child transmission interventions and new research directed at making breastfeeding safer using antiretroviral prophylaxis to either mothers or their infants.

  12. Dopamine and baclofen inhibit the hyperpolarization-activated cation current in rat ventral tegmental neurones.

    PubMed Central

    Jiang, Z G; Pessia, M; North, R A

    1993-01-01

    1. Whole-cell patch-clamp recordings were made from dopamine-containing ventral tegmental area neurones in slices of rat midbrain. An inward current (Ih) was activated by hyperpolarization from -60 mV. 2. Dopamine (30 microM) reduced the amplitude of Ih by 10-30% at potentials from -70 to -120 mV. The effect was concentration dependent, mimicked by the D2 agonist quinpirole, and prevented by the D2 antagonist (-)-sulpiride. Baclofen (0.3-3 microM) also inhibited Ih; this action was antagonized by 2-hydroxysaclofen but not by (-)-sulpiride. The decrease in Ih resulted from a reduction in the maximal current with no change in the voltage dependence. 3. The action of dopamine was unaffected by cadmium (200 microM), forskolin (10 microM), the adenylyl cyclase inhibitor 2',3'-dideoxyadenosine (100 microM), or by intracellular solution containing cyclic AMP (2 mM). 4. Ih was progressively reduced during the first 5-10 min of recording with electrodes containing guanosine 5'-O-(3-thiotriphosphate); after this time, dopamine had no further effect. 5. It is concluded that agonists acting at D2 receptors and GABAB receptors reduce Ih in ventral tegmental neurones. PMID:8392580

  13. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  14. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program.

    PubMed

    Mather, Kieren J; Funahashi, Tohru; Matsuzawa, Yuji; Edelstein, Sharon; Bray, George A; Kahn, Steven E; Crandall, Jill; Marcovina, Santica; Goldstein, Barry; Goldberg, Ronald

    2008-04-01

    To determine whether baseline adiponectin levels or intervention-associated change in adiponectin levels were independently associated with progression to diabetes in the Diabetes Prevention Program (DPP). Cox proportional hazards analysis was used to evaluate the contribution of adiponectin and treatment-related change in adiponectin to risk of progression to diabetes. Baseline adiponectin was a strong independent predictor of incident diabetes in all treatment groups (hazard ratio per approximately 3 microg/ml higher level; 0.61 in the lifestyle, 0.76 in the metformin, and the 0.79 in placebo groups; all P < 0.001, P = 0.13 comparing groups). Baseline differences in adiponectin between sexes and race/ethnicity groups were not reflected in differences in diabetes risk. DPP interventions increased adiponectin levels ([means +/- SE] 0.83 +/- 0.05 microg/ml in the lifestyle group, 0.23 +/- 0.05 microg/ml in the metformin group, and 0.10 +/- 0.05 microg/ml in the placebo group; P < 0.001 for increases versus baseline, P < 0.01 comparing groups). These increases were associated with reductions in diabetes incidence independent of baseline adiponectin levels in the lifestyle and placebo groups but not in the metformin subjects (hazard ratio 0.72 in the lifestyle group (P < 0.001), 0.92 in the metformin group (P = 0.18), and 0.89 in the placebo group; P = 0.02 per approximately 1 microg/ml increase, P = 0.02 comparing groups). In the lifestyle group, adjusting for change in weight reduced, but did not remove, the effect of increased adiponectin. Adiponectin is a powerful marker of diabetes risk in subjects at high risk for diabetes, even after adjustment for weight. An increase in adiponectin in the lifestyle and placebo groups was associated with a reduction in diabetes risk. However, these changes in adiponectin were comparatively small and less strongly related to diabetes outcome than baseline adiponectin levels.

  15. Spirafolide from bay leaf (Laurus nobilis) prevents dopamine-induced apoptosis by decreasing reactive oxygen species production in human neuroblastoma SH-SY5Y cells.

    PubMed

    Ham, Ahrom; Kim, Bora; Koo, Uk; Nam, Kung-Woo; Lee, Sung-Jin; Kim, Kyeong Ho; Shin, Jongheon; Mar, Woongchon

    2010-12-01

    Reactive oxygen species (ROS) are important mediators in many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. This study tested the neuroprotective effects of spirafolide, a compound purified from the leaves of Laurus nobilis L. (Lauraceae), against dopamine (DA)-induced apoptosis in human neuroblastoma SH-SY5Y cells. Following a 24-h exposure of cells to DA (final conc., 0.6 mM), we observed a marked increase in apoptosis, increased generation of ROS and decreased cell viability. Pretreatment of the cells for 24 h with spirafolide (0.4, 2, and 10 μM) before exposure to DA notably increased cell survival (p < 0.01) and lowered intracellular ROS levels (p < 0.01). These results indicate that spirafolide has neuroprotective effects against DA toxicity. These effects may contribute to the treatment of neurodegenerative diseases.

  16. 22-Oxacalcitriol Prevents Progression of Peritoneal Fibrosis in a Mouse Model

    PubMed Central

    Hirose, Misaki; Nishino, Tomoya; Obata, Yoko; Nakazawa, Masayuki; Nakazawa, Yuka; Furusu, Akira; Abe, Katsushige; Miyazaki, Masanobu; Koji, Takehiko; Kohno, Shigeru

    2013-01-01

    ♦ Objective: Vitamin D plays an important role in calcium homeostasis and is used to treat secondary hyperparathyroidism among dialysis patients. The biologic activity of vitamin D and its analogs is mediated by vitamin D receptor (VDR), which is distributed widely throughout the body. Recent papers have revealed that low vitamin D levels are correlated with severe fibrosis in chronic diseases, including cystic fibrosis and hepatitis. The aim of the present study was to evaluate the protective effects of vitamin D against the progression of peritoneal fibrosis. ♦ Methods: Peritoneal fibrosis was induced by injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. An analog of vitamin D, 22-oxacalcitriol (OCT), was administered subcutaneously daily from initiation of the CG injections. The peritoneal tissue was excised at 3 weeks. Changes in morphology were assessed by hematoxylin and eosin staining. Expression of VDR, alpha smooth muscle actin (as a marker of myofibroblasts), type III collagen, transforming growth factor β(TGF-β), phosphorylated Smad2/3, F4/80 (as a marker of macrophages), and monocyte chemoattractant protein-1 (MCP-1) was examined by immunohistochemistry. Southwestern histochemistry was used to detect activated nuclear factor κB (NF-κB). ♦ Results: In the CG-injected mice, immunohistochemical analysis revealed expression of VDR in mesothelial cells, myofibroblasts, and macrophages in the thickened submesothelial zone. Treatment with OCT significantly prevented peritoneal fibrosis and reduced the accumulation of type III collagen in CG-treated mice. Among the markers of fibrosis, the numbers of myofibroblasts, cells positive for TGF-β, and cells positive for phosphorylated Smad2/3 were significantly decreased in the OCT-treated group compared with the vehicle-treated group. Furthermore, OCT suppressed inflammatory mediators of fibrosis, as shown by the reduced numbers of activated NF

  17. Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs.

    PubMed

    Bhatia, Ayesha; O'Brien, Kathryn; Chen, Mei; Wong, Alex; Garner, Warren; Woodley, David T; Li, Wei

    2016-01-01

    Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5-treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing.

  18. Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs

    PubMed Central

    Bhatia, Ayesha; O’Brien, Kathryn; Chen, Mei; Wong, Alex; Garner, Warren; Woodley, David T.; Li, Wei

    2016-01-01

    Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5–treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing. PMID:27382602

  19. Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking.

    PubMed

    Roberto, Christina A; Swinburn, Boyd; Hawkes, Corinna; Huang, Terry T-K; Costa, Sergio A; Ashe, Marice; Zwicker, Lindsey; Cawley, John H; Brownell, Kelly D

    2015-06-13

    Despite isolated areas of improvement, no country to date has reversed its obesity epidemic. Governments, together with a broad range of stakeholders, need to act urgently to decrease the prevalence of obesity. In this Series paper, we review several regulatory and non-regulatory actions taken around the world to address obesity and discuss some of the reasons for the scarce and fitful progress. Additionally, we preview the papers in this Lancet Series, which each identify high-priority actions on key obesity issues and challenge some of the entrenched dichotomies that dominate the thinking about obesity and its solutions. Although obesity is acknowledged as a complex issue, many debates about its causes and solutions are centred around overly simple dichotomies that present seemingly competing perspectives. Examples of such dichotomies explored in this Series include personal versus collective responsibilities for actions, supply versus demand-type explanations for consumption of unhealthy food, government regulation versus industry self-regulation, top-down versus bottom-up drivers for change, treatment versus prevention priorities, and a focus on undernutrition versus overnutrition. We also explore the dichotomy of individual versus environmental drivers of obesity and conclude that people bear some personal responsibility for their health, but environmental factors can readily support or undermine the ability of people to act in their own self-interest. We propose a reframing of obesity that emphasises the reciprocal nature of the interaction between the environment and the individual. Today's food environments exploit people's biological, psychological, social, and economic vulnerabilities, making it easier for them to eat unhealthy foods. This reinforces preferences and demands for foods of poor nutritional quality, furthering the unhealthy food environments. Regulatory actions from governments and increased efforts from industry and civil society will be

  20. Perinatal hepatitis B prevention program in Shandong Province, China. Evaluation and progress.

    PubMed

    Zhang, Li; Ko, Stephen; Lv, Jingjing; Ji, Feng; Yan, Bingyu; Xu, Fujie; Xu, Aiqiang

    2014-01-01

    Post-exposure prophylaxis with hepatitis B vaccine (HepB) alone is highly effective in preventing perinatal hepatitis B virus (HBV) transmission and the World Health Organization recommends administering HepB to all infants within 24 h after delivery. Maternal screening for HBsAg and administration of hepatitis B immune globulin (HBIG) in addition to HepB for infants born to HBsAg-positive pregnant women can increase the effectiveness of post-exposure prophylaxis for perinatal HBV transmission. In Shangdong Province, China which has a high prevalence of chronic HBV infection, HepB birth dose and HBIG were integrated into the routine childhood immunization program in 2002 and July 2011 respectively. We assessed progress toward implementation of these measures. Hospital-based reporting demonstrated an increase in maternal screening from 70.7% to 96.9% from 2004-2012; HepB birth dose coverage (within 24 h) remained high (96.3-97.1%) during this period. For infants with known HBsAg-positive mothers, the coverage of HBIG increased from 85.0% (before July 2011) to 92.1% (after July 2011). However, HBIG coverage in western areas of Shandong Province remained at 81.1% among infants with known HBsAg-positive mothers. Preterm/low-birth-weight and illness after birth were the most commonly reported reasons for delay in the first dose of HepB to >24 h of birth. Additional education on the safety and immune protection from HepB and HBIG might help to correct delays in administering the HepB birth dose and low HBIG coverage in the western areas of the Shandong Province.

  1. The Protective Effects of Ivabradine in Preventing Progression from Viral Myocarditis to Dilated Cardiomyopathy

    PubMed Central

    Yue-Chun, Li; Guang-Yi, Chen; Li-Sha, Ge; Chao, Xing; Xinqiao, Tian; Cong, Lin; Xiao-Ya, Dai; Xiangjun, Yang

    2016-01-01

    To study the beneficial effects of ivabradine in dilated cardiomyopathy (DCM) mice, which evolved from coxsackievirus B3-induced chronic viral myocarditis. Four-to-five-week-old male balb/c mice were inoculated intraperitoneally with coxsackievirus B3 (Strain Nancy) on days 1, 14, and 28. The day of the first virus inoculation was defined as day 1. Thirty-five days later, the surviving chronic viral myocarditis mice were divided randomly into two groups, a treatment group and an untreated group. Ivabradine was administered by gavage for 30 consecutive days in the treatment group, and the untreated group was administered normal saline. Masson’s trichrome stain was used to evaluate the fibrosis degree in myocardial tissue. The expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), collagen I, collagen III and p38-MAPK signaling pathway proteins were detected by Western blot. Electrocardiogram was used to investigate the heart rate and rhythm. The thickness of the ventricular septum and left ventricular posterior wall, left ventricular end diastolic dimension, left ventricular end systolic dimension, left ventricular ejection fractions and fractional shortening were studied by echocardiography. Compared with the untreated chronic viral myocarditis mice, ivabradine significantly increased the survival rate, attenuated the myocardial lesions and fibrosis, improved the impairment of the left ventricular function, diminished the heart dimension, decreased the production of collagen I and collagen III, reduced the expression of the proinflammatory cytokines TNF-α, IL-1β, and IL-6, and lowered the production of phospho-p38 MAPK. The findings indicate the therapeutic effect of ivabradine in preventing the progression from viral myocarditis to DCM in mice with chronic viral myocarditis induced by coxsackievirus B3, is associated with inhibition of the p38 MAPK pathway, downregulated inflammatory responses and decreased

  2. Methamphetamine Regulation of Firing Activity of Dopamine Neurons

    PubMed Central

    Lin, Min; Sambo, Danielle

    2016-01-01

    Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca2+ homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca2+-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane. SIGNIFICANCE STATEMENT Methamphetamine (METH) competes with dopamine uptake, increases dopamine efflux via the dopamine transporter, and affects the excitability of

  3. Dopamine Modulates Cell Cycle in the Lateral Ganglionic Eminence

    PubMed Central

    Ohtani, Nobuyo; Goto, Tomohide; Waeber, Christian; Bhide, Pradeep G.

    2005-01-01

    Dopamine is a neuromodulator the functions of which in the regulation of complex behaviors such as mood, motivation, and attention are well known. Dopamine appears in the brain early in the embryonic period when none of those behaviors is robust, raising the possibility that dopamine may influence brain development. The effects of dopamine on specific developmental processes such as neurogenesis are not fully characterized. The neostriatum is a dopamine-rich region of the developing and mature brain. If dopamine influenced neurogenesis, the effects would likely be pronounced in the neostriatum. Therefore, we examined whether dopamine influenced neostriatal neurogenesis by influencing the cell cycle of progenitor cells in the lateral ganglionic eminence (LGE), the neuroepithelial precursor of the neostriatum. We show that dopamine arrives in the LGE via the nigrostriatal pathway early in the embryonic period and that neostriatal neurogenesis progresses in a dopamine-rich milieu. Dopamine D1-like receptor activation reduces entry of progenitor cells from the G1-to S-phase of the cell cycle, whereas D2-like receptor activation produces the opposite effects by promoting G1- to S-phase entry. D1-like effects are prominent in the ventricular zone, and D2-like effects are prominent in the subventricular zone. The overall effects of dopamine on the cell cycle are D1-like effects, most likely because of the preponderance of D1-like binding sites in the embryonic neostriatum. These data reveal a novel developmental role for dopamine and underscore the relevance of dopaminergic signaling in brain development. PMID:12684471

  4. Oral adsorbents for preventing or delaying the progression of chronic kidney disease.

    PubMed

    Wu, Hong Mei; Sun, Hong Juan; Wang, Feng; Yang, Ming; Dong, Bi Rong; Liu, Guan J

    2014-10-15

    Chronic kidney disease (CKD) is a worldwide public health problem which is at high increased risk of cardiovascular disease (CVD) and renal failure. Deterioration of kidney function causes an increase in circulating toxins, which, in turn promotes the progression of CKD. Oral adsorbents with capacity to adsorb and remove substances including uraemic toxins from the intestine could be effective in minimising kidney injury. To investigate the benefits and harms of oral adsorbents for preventing or delaying the progression of CKD. We searched the Cochrane Renal Group's Specialised Register (to 22 September 2014) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The following four Chinese medical databases were also searched: China Biological Medicine Database (1979 to May 2012); Chinese Science and Technique Journals Database (to May 2012); China National Infrastructure (to May 2012); Wan Fang database (to May 2012). Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral adsorbents for preventing or delaying the progression of CKD. Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (incidence of end-stage kidney disease (ESKD), mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI). Adverse events were expressed as risk differences (RD). Fifteen studies (1590 patients) conducted in Japan, China, and the USA were identified. The risk of bias of the included studies was moderate or high and the sample sizes were small.Three studies compared oral AST-120 plus routine treatment with placebo plus routine treatment; however data on our outcome measures of interest were not reported in two studies. These studies did not assess or did not provide data for our primary outcomes of

  5. Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity

    PubMed Central

    Covarrubias, Alejandra A.; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I.

    2014-01-01

    Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP+), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility. PMID:25402186

  6. Presence and function of dopamine transporter (DAT) in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    PubMed

    Urra, Javier A; Villaroel-Espíndola, Franz; Covarrubias, Alejandra A; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I

    2014-01-01

    Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP(+)), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  7. Curcumin delivery from poly(acrylic acid-co-methyl methacrylate) hollow microparticles prevents dopamine-induced toxicity in rat brain synaptosomes.

    PubMed

    Yoncheva, Krassimira; Kondeva-Burdina, Magdalena; Tzankova, Virginia; Petrov, Petar; Laouani, Mohamed; Halacheva, Silvia S

    2015-01-01

    The potential of poly(methyl methacrylate-co-acrylic acid) (PMMA-AA) copolymers to form hollow particles and their further formulation as curcumin delivery system have been explored. The particles were functionalized by crosslinking the acrylic acid groups via bis-amide formation with either cystamine (CYS) or 3,3'-dithiodipropionic acid dihydrazide (DTP) which simultaneously incorporated reversibility due to the presence of disulfide bonds within the crosslinker. Optical micrographs showed the formation of spherical hollow microparticles with a size ranging from 1 to 7 μm. Curcumin was loaded by incubation of its ethanol solution with aqueous dispersions of the cross-linked particles and subsequent evaporation of the ethanol. Higher loading was observed in the microparticles with higher content of hydrophobic PMMA units indicating its influence upon the loading of hydrophobic molecules such as curcumin. The in vitro release studies in a phosphate buffer showed no initial burst effect and sustained release of curcumin that correlated with the swelling of the particles under these conditions. The capacity of encapsulated and free curcumin to protect rat brain synaptosomes against dopamine-induced neurotoxicity was examined. The encapsulated curcumin showed greater protective effects in rat brain synaptosomes as measured by synaptosomal viability and increased intracellular levels of glutathione. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Detection of cell surface dopamine receptors.

    PubMed

    Xiao, Jiping; Bergson, Clare

    2013-01-01

    Dopamine receptors are a class of metabotropic G protein-coupled receptors. Plasma membrane expression is a key determinant of receptor signaling, and one that is regulated both by extra and intracellular cues. Abnormal dopamine receptor signaling is implicated in several neuropsychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder, as well as drug abuse. Here, we describe in detail the application of two complementary applications of protein biotinylation and enzyme-linked immunoabsorbent assay (ELISA) for detecting and quantifying levels of dopamine receptors expressed on the cell surface. In the biotinylation method, cell surface receptors are labeled with Sulfo-NHS-biotin. The charge on the sulfonyl facilitates water solubility of the reactive biotin compound and prevents its diffusion across the plasma membrane. In the ELISA method, surface labeling is achieved with antibodies specific to extracellular epitopes on the receptors, and by fixing the cells without detergent such that the plasma membrane remains intact.

  9. Detection of Cell Surface Dopamine Receptors

    PubMed Central

    Xiao, Jiping; Bergson, Clare

    2014-01-01

    Dopamine receptors are a class of metabotropic G protein-coupled receptors. Plasma membrane expression is a key determinant of receptor signaling, and one that is regulated both by extra and intracellular cues. Abnormal dopamine receptor signaling is implicated in several neuropsychiatric disorders, including schizophrenia and attention deficit hyperactivity disorder, as well as drug abuse. Here, we describe in detail the application of two complementary applications of protein biotinylation and enzyme-linked immunoabsorbant assay (ELISA) for detecting and quantifying levels of dopamine receptors expressed on the cell surface. In the biotinylation method, cell surface receptors are labeled with Sulfo-NHS-biotin. The charge on the sulfonyl facilitates water solubility of the reactive biotin compound and prevents its diffusion across the plasma membrane. In the ELISA method, cells surface labeling is achieved with antibodies specific to extracellular epitopes on the receptors, and by fixing the cells without detergent such that the plasma membrane remains intact. PMID:23296774

  10. Weight and Physical Activity - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. UV Exposure and Sun-Protective Behavior - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Tobacco Policy/Regulatory Factors - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function

    PubMed Central

    Horvath, Tamas L.; Erion, Derek M.; Elsworth, John D.; Roth, Robert H.; Shulman, Gerald I.; Andrews, Zane B.

    2012-01-01

    Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson’s disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice, however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson’s disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. PMID:21406233

  14. GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function.

    PubMed

    Horvath, Tamas L; Erion, Derek M; Elsworth, John D; Roth, Robert H; Shulman, Gerald I; Andrews, Zane B

    2011-07-01

    Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson's disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice; however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting that the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson's disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. The Role of Dopamine and Glutamate Modulation in Huntington Disease

    PubMed Central

    Mittal, Sumeer K.; Eddy, Clare

    2013-01-01

    Background: Huntington disease (HD) is an inherited neuropsychiatric condition with progressive neurodegenerative changes, mainly affecting the striatum. Pathological processes within the striatum are likely to lead to alterations in dopamine and glutamate activity in frontostriatal circuitry, resulting in characteristic motor, behavioural and cognitive symptoms. Methods: We conducted a systematic literature search in order to identify and review randomised, double-blinded, placebo-controlled trials of anti-dopaminergic and anti-glutamatergic therapy in HD. Results: Ten studies satisfied our selection criteria. These studies investigated a range of agents which act to antagonise dopamine (tetrabenazine, typical and atypical antipsychotics) or glutamate (amantadine, riluzole) transmission. Discussion: Although most agents showed efficacy in terms of amelioration of chorea, the available evidence did not allow us to identify a universally effective treatment. One difficulty associated with analysing the available evidence was a high prevalence of side effects, which prevented the full therapeutic potential of the medications from being adequately investigated. A further limitation is that many studies evaluated treatment effectiveness only in relation to patients' motor symptoms, even though behavioural and cognitive changes may negatively impact patients' quality of life. There is a clear need for further higher-level evidence addressing the effects of dopaminergic and glutamatergic agents on global functioning in HD. PMID:22713410

  16. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes.

    PubMed

    Jorde, Rolf; Sollid, Stina T; Svartberg, Johan; Schirmer, Henrik; Joakimsen, Ragnar M; Njølstad, Inger; Fuskevåg, Ole M; Figenschau, Yngve; Hutchinson, Moira Y S

    2016-04-01

    Vitamin D deficiency is associated with insulin resistance and risk of future diabetes. The objective of the study was to test whether supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes mellitus (T2DM). This was a randomized controlled trial performed in 2008 through 2015. The study was conducted at the clinical research unit at a teaching hospital. Five hundred eleven subjects (mean age 62 y, 314 males) with prediabetes diagnosed with an oral glucose tolerance test as part of the Tromsø Study 2007–2008 were included. A total of 256 were randomized to vitamin D and 255 to placebo. Twenty-nine subjects in the vitamin D and 24 in the placebo group withdrew because of adverse events. Interventions included vitamin D (cholecalciferol) 20 000 IU/wk vs placebo for 5 years. Annual oral glucose tolerance tests were performed. Progression to T2DM was the main outcome measure. Secondary outcomes were change in glucose levels, insulin resistance, serum lipids, and blood pressure. The mean baseline serum 25-hydroxyvitamin D level was 60 nmol/L (24 ng/mL). One hundred three in the vitamin D and 112 in the placebo group developed T2DM (hazard risk 0.90; 95% confidence interval 0.69–1.18, Cox regression, P = .45, intention to treat analysis). No consistent significant effects on the other outcomes were seen. Subgroup analyses in subjects with low baseline 25-hydroxyvitamin D yielded similar results. No serious side effects related to the intervention were recorded. In subjects without vitamin D deficiency, vitamin D supplementation is unlikely to prevent progression from prediabetes to diabetes. Very large studies with inclusion of vitamin D-deficient subjects will probably be needed to show such a putative effect. This study tested if supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes (T2DM).

  17. CDC's research portfolio in older adult fall prevention: a review of progress, 1985-2005, and future research directions.

    PubMed

    Sleet, David A; Moffett, Daphne B; Stevens, Judy

    2008-01-01

    Falls are a leading cause of mortality and morbidity among adults age 65 and older. Population models predict steep increases in the 65 and older population bands in the next 10-15 years and in turn, public health is bracing for increased fall rates and the strain they place on health care systems and society. To assess progress in fall prevention, the Centers for Disease Control and Prevention conducted a research portfolio review to examine the quality, relevance, outcomes and successes of the CDC fall prevention program and its impact on public health. A peer review panel was charged with reviewing 20 years of funded research and conducting a SWOT (strengths, weaknesses, opportunities, and threats) analysis for extramural and intramural research activities. Information was collected from grantees (via a survey instrument), staff were interviewed, and progress reports and products were reviewed and analyzed. CDC has invested over $24,900,000 in fall-related research and programs over 20 years. The portfolio has had positive impacts on research, policies and programs, increasing the public health injury prevention workforce, and delivering effective fall prevention programs. Public health agencies, practitioners, and policy makers recognize that while there are some evidence-based older adult fall prevention interventions available, many remain unused or are infeasible to implement. Specific recommendations across the public health model, include: additional research in gathering robust epidemiologic data on trends and patterns of fall-related injuries at all levels; researching risk factors by setting or sub-population; developing and testing innovative interventions; and engaging in translation and dissemination research on best practices to increase uptake and adoption of fall prevention strategies. CDC has responded to a number of suggestions from the portfolio review including: funding translation research of a proven Tai Chi fall intervention; beginning to

  18. Prevention of sexual transmission of HIV: real results, science progressing, societies remaining behind.

    PubMed

    Laga, Marie; Piot, Peter

    2012-06-19

    HIV spread has reached a turning point following decades of increasing and sustained incidence. An effective vaccine has not been developed, but critical breakthroughs with prevention based on antiretroviral treatment are promising. The new prevention technologies will have to be combined with condoms and incorporated into the mixes of combination prevention approaches that are tailored to the local epidemic and context. To address the implementation gap, more political will and leadership will be needed to overcome the socio-cultural, legal or religious barriers to prevention. We have learned that the generation of demand for HIV prevention is not easy, as for health promotion in general. Despite optimism about treatment as prevention, many western countries are facing an increase in new HIV cases, and HIV is no longer a collective concern. If we manage to find common ground on combination prevention, customize approaches to people's needs and exercise technical and political leadership, our decade may see the beginning of the end of the epidemic.

  19. Mitigating preventable chronic disease: Progress report of the Cleveland Clinic's Lifestyle 180 program

    PubMed Central

    2011-01-01

    Background Poor lifestyle choices are key in development and progression of preventable chronic diseases. The purpose of the study was to design and test a program to mitigate the physical and fiscal consequences of chronic diseases. Methods Here we report the outcomes for 429 participants with one or more chronic conditions, including obesity, hypertension, hyperlipidemia and diabetes mellitus, many of whom had failed traditional disease management programs, who enrolled into a comprehensive lifestyle intervention. The Lifestyle 180 program integrates nutrition, physical activity and stress management interventions and was conducted at the Wellness Institute of the Cleveland Clinic, United States. An intensive 6 week immersion course, with 8 hours of group instruction per week, was followed by 3 follow-up, 4 hour-long sessions over the course of 6 months. Results Changes in biometric (weight, height, waist circumference, resting heart rate and blood pressure) and laboratory variables (fasting lipid panel, blood glucose, insulin, hemoglobin A1c, ultra sensitive C-reactive protein) at 6 months were compared with baseline (pre-post analysis). At week 30, biometric and laboratory data were available for 244 (57%) and 299 (70%) participants, respectively. These had a mean ± SD reduction in weight (6.8 ± 6.9 kg, P < 0.001), waist circumference (6.1 ± 7.3 cm, P < 0.001), glucose (4.5 ± 29.6 mg/dL or 0.25 ± 1.64 mmol/L, P = 0.009), triglycerides (26.4 ± 58.5 mg/dL or 0.30 ± 0.66 mmol/L, P < 0.001), low-density lipoprotein cholesterol (LDL) (7.9 ± 25.1 mg/dL or 0.2 ± 0.65 mmol/L, P < 0.001), hemoglobin A1c (HgbA1c) (0.20 ± 0.64%, P = 0.001), insulin (3.8 ± 11 microU/ml or 26.6 ± 76.4 ρmol, P < 0.001) and ultra sensitive C-reactive protein (US - CRP) (0.9 ± 4.8 mg/dL or 7.3 ± 40.2 nmol/L, P = 0.012), an increase in mean high-density lipoprotein cholesterol (HDL) (3.7 ± 8.4 mg/dL or 0.1 ± 0.22, P < 0.001), and decreased use of medications. Conclusion

  20. Endotoxemia and the effects of dopamine on renal functions of neonatal piglets.

    PubMed

    Chin, Anthony; O'Conner, Linh Nguyen; Radhakrishnan, Jayant; Fornell, Linda; John, Eunice

    2002-01-01

    In this study, we observed the effects of moderate and high doses of dopamine on the renal functions of neonatal piglets during endotoxic shock. We found that fluid therapy alone was better at maintaining cardiac index and preventing elevation of systemic vascular resistance, than dopamine at 10 and at 20 microg/kg/min. Furthermore, urine output and glomerular filtration rate were reduced by dopamine. Following endotoxin administration dopamine decreased SVR and maintained a CI better than fluid alone. However, in spite of a better CI, greater deterioration in renal functions occurred in the dopamine groups as compared to the fluid group.

  1. Different roles of retinal dopamine in albino Guinea pig myopia.

    PubMed

    Mao, Junfeng; Liu, Shuangzhen

    2017-02-03

    To investigate whether the different role of ocular dopamine was involved in the myopic development between spontaneous myopia (SM) and form deprivation myopia (FDM) in albino guinea pigs. 55 myopic animals were randomly divided into SM, Levodapa (L-DOPA), L-DOPA+carbidopa and vehicle. 70 non-myopic animals were randomly divided into normal control, FDM, L-DOPA+FDM, L-DOPA+carbidopa+FDM and vehicle. Once per day, for 14days, L-DOPA (10mg/kg) was injected intraperitoneally, and carbidopa (1μg) was injected at the same time into the peribulbar space of the right eye. Refractive parameters and dopamine content in neural retina and RPE/choroid complex were measured. In SM animals, high myopia was formed at 5 week of ages. L-DOPA treatment could reduce its myopic degree, and inhibit the increase of axial length and vitreous chamber depth with the increase of retinal dopamine in both eyes. Administration of carbidopa could prevent the increase of retinal dopamine induced by L-DOPA, but no influenced on its refractive state in the injected eyes. In non-SM animals, intraperitoneal L-DOPA could inhibit FDM, accompanied by the increase of retinal dopamine. Carbidopa treatment diminished the inhibition of FDM and prevented the increase in retinal dopamine by L-Dopa. Retinal dopamine was highly correlated with ocular refraction in FDM, but not in SM. There was no significant difference in dopamine content of RPE/choroid complex among all groups. The role of retinal dopamine was different between SM and FDM in albino guinea pigs. Although systemic L-DOPA could inhibit the development of SM and FDM, retinal dopamine was only involved in the L-DOPA inhibition on FDM, but not on SM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Investigation of Chitosan for Prevention of Diabetic Progression Through Gut Microbiota Alteration in Sugar Rich Diet Induced Diabetic Rats.

    PubMed

    Prajapati, Bhumika; Rajput, Parth; Jena, Prasant Kumar; Seshadri, Sriram

    2015-01-01

    Sugar rich diet induces inflammation and insulin resistance mainly through gut microbiota alteration. Gut microflora dysbiosis increases plasma lipopolysaccharide and reduces short chain fatty acids to impair the insulin signaling cascades by different molecular pathways to progress into diabetes. Chitosan based formulations have major significance in insulin delivery system due to their ability to protect the insulin from enzymatic degradation and its efficient inter-epithelial transport. This study was designed to investigate the effect of chitosan administration on gut microflora mediated signaling pathways to prevent the diet induced diabetes. Male wistar rats were divided into non-diabetic group with a normal diet (CD), diabetic group with high sucrose diet (HSD) and treatment group with HSD and chitosan (60 mg/kg). After 8 weeks of the study, significant alterations in two major gut dominant microbial phyla i.e Firmicutes and Bacteroides and four dominant microbial species i.e. Lactobacilli, Bifidobacteria, Escherichia and Clostridia were observed in HSD group compared to CD. This microbial dysbiosis in dominant phyla was significantly prevented in chitosan administrated HSD group. Chitosan administration had also reduced the HSD induced activation of Toll like receptors and Nod like receptors signaling pathways compared to HSD control group to reduce the inflammation. These suggest that chitosan can prevent the progression of Type 2 Diabetes through gut microbiota alteration, reducing endotoxin and microbes mediated inflammation.

  3. ERECTA-family receptor kinase genes redundantly prevent premature progression of secondary growth in the Arabidopsis hypocotyl.

    PubMed

    Ikematsu, Shuka; Tasaka, Masao; Torii, Keiko U; Uchida, Naoyuki

    2017-03-01

    Secondary growth is driven by continuous cell proliferation and differentiation of the cambium that acts as vascular stem cells, producing xylem and phloem to expand vascular tissues laterally. During secondary growth of hypocotyls in Arabidopsis thaliana, the xylem undergoes a drastic phase transition from a parenchyma-producing phase to a fiber-producing phase at the appropriate time. However, it remains to be fully elucidated how progression of secondary growth is properly controlled. We focused on phenotypes of hypocotyl vasculatures caused by double mutation in ERECTA (ER) and ER-LIKE1 (ERL1) receptor-kinase genes to elucidate their roles in secondary growth. ER and ERL1 redundantly suppressed excessive radial growth of the hypocotyl vasculature during secondary growth. ER and ERL1 also prevented premature initiation of the fiber differentiation process mediated by the NAC SECONDARY WALL THICKENING PROMOTING FACTORs in the hypocotyl xylem. Upon floral transition, the hypocotyl xylem gained a competency to respond to GA in a BREVIPEDICELLUS-dependent manner, which was a prerequisite for fiber differentiation. However, even after the floral transition, ER and ERL1 prevented precocious initiation of the GA-mediated fiber formation. Collectively, our findings reveal that ER and ERL1 redundantly prevent premature progression of sequential events in secondary growth.

  4. Preventive effect of teprenone on acute gastric mucosal lesion progression in compound 48/80-treated rats.

    PubMed

    Ohta, Yoshiji; Kobayashi, Takashi; Inui, Kazuo; Yoshino, Junji; Kitagawa, Akira; Nakazawa, Saburo

    2004-03-08

    The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.

  5. Loss of NHERF-1 expression prevents dopamine-mediated Na-K-ATPase regulation in renal proximal tubule cells from rat models of hypertension: aged F344 rats and spontaneously hypertensive rats.

    PubMed

    Barati, Michelle T; Ketchem, Corey J; Merchant, Michael L; Kusiak, Walter B; Jose, Pedro A; Weinman, Edward J; LeBlanc, Amanda J; Lederer, Eleanor D; Khundmiri, Syed J

    2017-08-01

    Dopamine decreases Na-K-ATPase (NKA) activity by PKC-dependent phosphorylation and endocytosis of the NKA α1. Dopamine-mediated regulation of NKA is impaired in aging and some forms of hypertension. Using opossum (OK) proximal tubule cells (PTCs), we demonstrated that sodium-hydrogen exchanger regulatory factor-1 (NHERF-1) associates with NKA α1 and dopamine-1 receptor (D1R). This association is required for the dopamine-mediated regulation of NKA. In OK cells, dopamine decreases NHERF-1 association with NKA α1 but increases its association with D1R. However, it is not known whether NHERF-1 plays a role in dopamine-mediated NKA regulation in animal models of hypertension. We hypothesized that defective dopamine-mediated regulation of NKA results from the decrease in NHERF-1 expression in rat renal PTCs isolated from animal models of hypertension [spontaneously hypertensive rats (SHRs) and aged F344 rats]. To test this hypothesis, we isolated and cultured renal PTCs from 22-mo-old F344 rats and their controls, normotensive 4-mo-old F344 rats, and SHRs and their controls, normotensive Wistar-Kyoto (WKY) rats. The results demonstrate that in both hypertensive models (SHR and aged F344), NHERF-1 expression, dopamine-mediated phosphorylation of NKA, and ouabain-inhibitable K(+) transport are reduced. Transfection of NHERF-1 into PTCs from aged F344 and SHRs restored dopamine-mediated inhibition of NKA. These results suggest that decreased renal NHERF-1 expression contributes to the impaired dopamine-mediated inhibition of NKA in PTCs from animal models of hypertension.

  6. Preventing Progression in Men with Mild Symptoms of Benign Prostatic Hyperplasia: A Potential Role for Phytotherapy

    PubMed Central

    Fong, Yan Kit; Marihart, Sibylle; Harik, Mike; Djavan, Bob

    2004-01-01

    Prevalence of benign prostate hyperplasia (BPH) is increasing with the aging population worldwide. Throughout the 20th century, men with minimally symptomatic BPH were generally advised to defer treatment. Treatment deferral or watchful waiting has always appeared reasonable because mild lower urinary tract symptoms suggestive of bladder outlet obstruction are not bothersome and are often regarded as part of the aging process, progression is usually slow, and symptoms often regress spontaneously. This review examines the evidence of the natural history of BPH, highlighting the group of patients with mild symptoms, the risk factors for progression, and the potential role of phytotherapy in this group of men. PMID:16985600

  7. Dopamine triggers Heterosynaptic Plasticity

    PubMed Central

    Ishikawa, Masago; Otaka, Mami; Huang, Yanhua; Neumann, Peter A.; Winters, Bradley D.; Grace, Anthony A.; Schlüter, Oliver M.; Dong, Yan

    2013-01-01

    As a classic neuromodulator, dopamine has long been thought to modulate, rather than trigger, synaptic plasticity. In contrast, our present results demonstrate that within the parallel projections of dopaminergic and GABAergic terminals from the ventral tegmental area (VTA) to nucleus accumbens core (NAcCo), action potential-activated release of dopamine heterosynaptically triggers LTD at GABAergic synapses, which is likely mediated by activating presynaptically-located dopamine D1 class receptors and expressed by inhibiting presynaptic release of GABA. Moreover, this dopamine-mediated heterosynaptic LTD is abolished after withdrawal from cocaine exposure. These results suggest that action potential-dependent dopamine release triggers very different cellular consequences from those induced by volume release or pharmacological manipulation. Activation of the VTA-to-NAcCo projections is essential for emotional and motivational responses. This dopamine-mediated LTD allows a flexible output of NAcCo neurons, whereas disruption of this LTD may contribute to the rigid emotional and motivational state observed in addicts during cocaine withdrawal. PMID:23595734

  8. Hub and switches: endocannabinoid signalling in midbrain dopamine neurons.

    PubMed

    Melis, Miriam; Pistis, Marco

    2012-12-05

    The last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Because dysfunctions of the dopamine system underlie diverse neuropsychiatric disorders, including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, because dopamine neurons are critical in controlling incentive-motivated behaviours, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light on the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse.

  9. 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells.

    PubMed

    Goldstein, David S; Jinsmaa, Yunden; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J; Sharabi, Yehonatan

    2016-09-01

    The catecholaldehyde hypothesis predicts that monoamine oxidase (MAO) inhibition should slow the progression of Parkinson's disease, by decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). Inhibiting MAO, however, diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) is an abundant anti-oxidant phenol in constituents of the Mediterranean diet. Whether hydroxytyrosol alters enzymatic or spontaneous oxidation of dopamine has been unknown. Rat pheochromocytoma PC12 cells were incubated with hydroxytyrosol (10 µM, 180 min) alone or with the MAO-A inhibitor clorgyline (1 nM) or the MAO-B inhibitors rasagiline or selegiline (0.5 µM). Hydroxytyrosol decreased levels of DOPAL by 30 % and Cys-DA by 49 % (p < 0.0001 each). Co-incubation with hydroxytyrosol prevented the increases in Cys-DA seen with all 3 MAO inhibitors. Hydroxytyrosol therefore inhibits both enzymatic and spontaneous oxidation of endogenous dopamine and mitigates the increase in spontaneous oxidation during MAO inhibition.

  10. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

    PubMed

    Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

    2016-05-01

    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

  11. Prevention

    MedlinePlus

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  12. Malignant transformation of oral lichen planus by a chronic inflammatory process. Use of topical corticosteroids to prevent this progression?

    PubMed

    Otero-Rey, Eva Maria; Suarez-Alen, Fatima; Peñamaria-Mallon, Manuel; Lopez-Lopez, Jose; Blanco-Carrion, Andres

    2014-11-01

    Oral lichen planus is a potentially malignant disorder with a capacity, although low, for malignant transformation. Of all the factors related to the process of malignant transformation, it is believed that the chronic inflammatory process plays a key role in the development of oral cancer. This inflammatory process is capable of providing a microenvironment based on different inflammatory cells and molecules that affect cellular growth, proliferation and differentiation. The objectives of our study are: to review the available evidence about the possible relationship between the chronic inflammatory process present in oral lichen planus and its malignant transformation, to discuss the potential therapeutic implications derived from this relationship and to study the role that topical corticosteroids play in the control of oral lichen planus inflammation and its possible progression to malignant transformation. The maintenance of a minimum dose of topical corticosteroids could prevent the inflammatory progression of oral lichen planus to oral cancer.

  13. Intrarectal vaccination with recombinant vaccinia virus expressing carcinoembronic antigen induces mucosal and systemic immunity and prevents progression of colorectal cancer.

    PubMed

    Kim-Schulze, Seunghee; Kim, Hong Sung; Wainstein, Alberto; Kim, Dae Won; Yang, Wein Cui; Moroziewicz, Dorota; Mong, Phyllus Y; Bereta, Michal; Taback, Bret; Wang, Qin; Kaufman, Howard L

    2008-12-01

    The gastrointestinal mucosa contains an intact immune system that protects the host from pathogens and communicates with the systemic immune system. Absorptive epithelial cells in the mucosa give rise to malignant tumors although the interaction between tumor cells and the mucosal immune system is not well defined. The pathophysiology of colorectal cancer has been elucidated through studies of hereditary syndromes, such as familial adenomatous polyposis, a cancer predisposition syndrome caused by germline mutations in the adenomatous polyposis coli tumor suppressor gene. Patients with FAP develop adenomas and inevitably progress to invasive carcinomas by the age of 40. To better delineate the role of mucosal immunity in colorectal cancer, we evaluated the efficacy of intrarectal recombinant vaccinia virus expressing the human carcinoembryonic Ag (CEA) in a murine FAP model in which mice are predisposed to colorectal cancer and also express human CEA in the gut. Mucosal vaccination reduced the incidence of spontaneous adenomas and completely prevented progression to invasive carcinoma. The therapeutic effects were associated with induction of mucosal CEA-specific IgA Ab titers and CD8(+) CTLs. Mucosal vaccination was also associated with an increase in systemic CEA-specific IgG Ab titers, CD4(+) and CD8(+) T cell responses and resulted in growth inhibition of s.c. implanted CEA-expressing tumors suggesting communication between mucosal and systemic immune compartments. Thus, intrarectal vaccination induces mucosal and systemic antitumor immunity and prevents progression of spontaneous colorectal cancer. These results have implications for the prevention of colorectal cancer in high-risk individuals.

  14. Mutant FGF23 prevents the progression of chronic kidney disease but aggravates renal osteodystrophy in uremic rats.

    PubMed

    Kusano, Kenichiro; Saito, Hitoshi; Segawa, Hiroko; Fukushima, Naoshi; Miyamoto, Ken-ichi

    2009-04-01

    Phosphorus is one of the important factors that accelerate the progression of chronic kidney disease. Phosphorus restriction or phosphate binders have been reported to have the ability to prevent the progression of chronic kidney disease. FGF23 is a circulating factor that regulates renal phosphorus reabsorption and 1 alpha-hydroxylase activity. We focused on the phosphaturic activity of FGF23 and investigated whether a pharmacological dose of FGF23 is beneficial to the progression of renal insufficiency in uremic rats. To this end, we administered one of the mutant FGF23 expression plasmids into irreversible Thy1 rats. Chronic renal failure rats were established by intravenous injection of anti-rat CD90 (Thy1.1) monoclonal antibody to unilaterally nephrectomized Wistar rats. The rats were then intravenously injected every 2 wk with a naked DNA solution containing 10 microg of MOCK vector or a mutant FGF23 expression plasmid for 13 wk. Renal function was assessed biochemically and histopathologically. Mutant FGF23 significantly decreased serum creatinine and serum urea nitrogen. The marked glomerular sclerosis observed in uremic rats receiving the MOCK vector was ameliorated in rats treated with mutant FGF23. However, mutant FGF23 not only significantly decreased serum 1,25(OH)(2)D and calcium but also aggravated high-turnover renal osteodystrophy from extremely high levels of PTH. These results might be a result of the mechanisms of FGF23 such as phosphaturic activity and lowering the level of 1,25(OH)(2)D. In conclusion, mutant FGF23 prevented the progression of chronic renal failure by regulating serum phosphorus but aggravated renal osteodystrophy from the lowered levels of 1,25(OH)(2)D.

  15. [Research progress on a nanodrug delivery system for prevention and control of dental caries and periodontal diseases].

    PubMed

    Yaling, Jiang; Mingye, Feng; Lei, Cheng

    2017-02-01

    Dental caries and periodontal diseases are common chronic infectious diseases that cause serious damage to oral health. Bacteria is the primary factor leading to such conditions. As a dental plaque control method, chemotherapeutic agents face serious challenges in dental care because of the specific physiological and anatomical characteristics of the oral cavity. Nanodrug delivery system is a series of new drug delivery systems at nanoscale, and it can target cells, promote sustainedrelease effects, and enhance biodegradation. This review focuses on research progress on nanodrug delivery systems for prevention and control of dental caries and periodontal diseases.

  16. Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats.

    PubMed

    Xi, Zheng-Xiong; Gilbert, Jeremy G; Pak, Arlene C; Ashby, Charles R; Heidbreder, Christian A; Gardner, Eliot L

    2005-06-01

    In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in

  17. Halfway There: A Prescription for Continued Progress in Preventing Teen Pregnancy.

    ERIC Educational Resources Information Center

    National Campaign To Prevent Teen Pregnancy, Washington, DC.

    This report offers findings and recommendations by the National Campaign To Prevent Teen Pregnancy. Nearly one million teens become pregnant annually. The teen birth rate increased 24 percent between 1986-91 and has fallen 20 percent since then. Overall, too many parents and adult leaders do not take a strong stand against teen pregnancy. Strident…

  18. Installing the Communities that Care Prevention System: Implementation Progress and Fidelity in a Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Quinby, Rose K.; Hanson, Koren; Brooke-Weiss, Blair; Arthur, Michael W.; Hawkins, J. David; Fagan, Abigail A.

    2008-01-01

    This article describes the degree to which high fidelity implementation of the Communities That Care (CTC) prevention operating system was reached during the first 18 months of intervention in 12 communities in the Community Youth Development Study, a 5-year group randomized controlled trial designed to test the efficacy of the CTC system. CTC…

  19. EPODE approach for childhood obesity prevention: methods, progress and international development.

    PubMed

    Borys, J-M; Le Bodo, Y; Jebb, S A; Seidell, J C; Summerbell, C; Richard, D; De Henauw, S; Moreno, L A; Romon, M; Visscher, T L S; Raffin, S; Swinburn, B

    2012-04-01

    Childhood obesity is a complex issue and needs multi-stakeholder involvement at all levels to foster healthier lifestyles in a sustainable way. 'Ensemble Prévenons l'Obésité Des Enfants' (EPODE, Together Let's Prevent Childhood Obesity) is a large-scale, coordinated, capacity-building approach for communities to implement effective and sustainable strategies to prevent childhood obesity. This paper describes EPODE methodology and its objective of preventing childhood obesity. At a central level, a coordination team, using social marketing and organizational techniques, trains and coaches a local project manager nominated in each EPODE community by the local authorities. The local project manager is also provided with tools to mobilize local stakeholders through a local steering committee and local networks. The added value of the methodology is to mobilize stakeholders at all levels across the public and the private sectors. Its critical components include political commitment, sustainable resources, support services and a strong scientific input--drawing on the evidence-base--together with evaluation of the programme. Since 2004, EPODE methodology has been implemented in more than 500 communities in six countries. Community-based interventions are integral to childhood obesity prevention. EPODE provides a valuable model to address this challenge. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity.

  20. EPODE approach for childhood obesity prevention: methods, progress and international development

    PubMed Central

    Borys, J-M; Le Bodo, Y; Jebb, S A; Seidell, J C; Summerbell, C; Richard, D; De Henauw, S; Moreno, L A; Romon, M; Visscher, T L S; Raffin, S; Swinburn, B

    2012-01-01

    Summary Childhood obesity is a complex issue and needs multistakeholder involvement at all levels to foster healthier lifestyles in a sustainable way. ‘Ensemble Prévenons l'ObésitéDes Enfants’ (EPODE, Together Let's Prevent Childhood Obesity) is a large-scale, coordinated, capacity-building approach for communities to implement effective and sustainable strategies to prevent childhood obesity. This paper describes EPODE methodology and its objective of preventing childhood obesity. At a central level, a coordination team, using social marketing and organizational techniques, trains and coaches a local project manager nominated in each EPODE community by the local authorities. The local project manager is also provided with tools to mobilize local stakeholders through a local steering committee and local networks. The added value of the methodology is to mobilize stakeholders at all levels across the public and the private sectors. Its critical components include political commitment, sustainable resources, support services and a strong scientific input – drawing on the evidence-base – together with evaluation of the programme. Since 2004, EPODE methodology has been implemented in more than 500 communities in six countries. Community-based interventions are integral to childhood obesity prevention. EPODE provides a valuable model to address this challenge. PMID:22106871

  1. Contributions of Peer Support to Health, Health Care, and Prevention: Papers from Peers for Progress.

    PubMed

    Fisher, Edwin B; Ayala, Guadalupe X; Ibarra, Leticia; Cherrington, Andrea L; Elder, John P; Tang, Tricia S; Heisler, Michele; Safford, Monika M; Simmons, David

    2015-08-01

    SUBSTANTIAL: evidence documents the benefits of peer support provided by community health workers, lay health advisors, promotores de salud, and others. The papers in this supplement, all supported by the Peers for Progress program of the American Academy of Family Physicians Foundation, contribute to the growing body of literature addressing the efficacy, effectiveness, feasibility, reach, sustainability, and adoption of peer support for diabetes self-management. They and additional papers supported by Peers for Progress contribute to understanding how peer support can be implemented in real world settings. Topics include examination of the peers who provide peer support, reaching the hardly reached, success factors in peer support interventions, proactive approaches, attention to emotions, peer support in behavioral health, dissemination models and their application in China, peer support in the patient-centered medical home, research challenges, and policy implications.

  2. Contributions of Peer Support to Health, Health Care, and Prevention: Papers from Peers for Progress

    PubMed Central

    Fisher, Edwin B.; Ayala, Guadalupe X.; Ibarra, Leticia; Cherrington, Andrea L.; Elder, John P.; Tang, Tricia S.; Heisler, Michele; Safford, Monika M.; Simmons, David

    2015-01-01

    SUBSTANTIAL evidence documents the benefits of peer support provided by community health workers, lay health advisors, promotores de salud, and others. The papers in this supplement, all supported by the Peers for Progress program of the American Academy of Family Physicians Foundation, contribute to the growing body of literature addressing the efficacy, effectiveness, feasibility, reach, sustainability, and adoption of peer support for diabetes self-management. They and additional papers supported by Peers for Progress contribute to understanding how peer support can be implemented in real world settings. Topics include examination of the peers who provide peer support, reaching the hardly reached, success factors in peer support interventions, proactive approaches, attention to emotions, peer support in behavioral health, dissemination models and their application in China, peer support in the patient-centered medical home, research challenges, and policy implications. PMID:26304968

  3. Preventive effects of eastern medication (Kampo) on the progression of chronic renal failure.

    PubMed

    Mitsuma, T

    1996-01-01

    Twenty-two patients with chronic renal failure (CRF) were investigated. The patients were mainly administered decoctions of rhubarb (symbol in text) for 4 weeks. After that, traditional Chinese (Kampo) prescriptions, most of them involving Wen-Pi-Tang were given for another 4 weeks. Following administration of these prescriptions, the levels of serum methylguanidine (MG), blood urea nitrogen and serum inorganic phosphorus improved significantly, although the values of serum creatinine (Cr) were not changed remarkably. The fact that the serum MG/Cr ratio was reduced after the therapy suggested that rhubarb possessed the potential to scavenge hydroxyl radicals by which MG was produced from Cr through creatol, as reported recently. The serum Cr concentration was determined over an observation period of more than 40 weeks in each of the 7 cases. Evaluation of the progression rate of CRF was made from the slopes of the regression lines. After analysis, 5 of the 7 cases showed significant retardation of progression after the administration of Kampo prescriptions during 106 ± 32 (mean ± SD) weeks. Of the 5 cases, 2 were prescribed Wen-Pi-Tang, another 2 cases were treated with Wen-Pi-Tang and Bu-Zhong-Yi-Qi-Tang and the last was treated with Ba-Wei-Di-Huang-Wan. This study demonstrated that the traditional Chinese prescriptions, most of them comprising Wen-Pi-Tang and/or Bu-Zhong-Yi-Qi-Tang, retarded the progression of CRF.

  4. Cyclooxygenase and Alzheimer's disease: implications for preventive initiatives to slow the progression of clinical dementia.

    PubMed

    Pasinetti, G M.

    2001-08-01

    Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimer's disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given the large number of candidates in the pool of anti-inflammatory drugs and given their widely divergent activities, it is essential to use methods which optimizes drug selection and study design. Pilot studies of anti-inflammatory regimens are useful in determining tolerability. However, these studies have limited value in estimating effective size since disease-modification, rather than symptomatic improvement, is the ultimate goal. Better understanding of the influence of inflammatory activity and the specific mechanisms which play an early role in the progression of the disease, will improve the likelihood of successfully identifying an effective anti-inflammatory treatment strategy. This review outlines directions in research that address possible contributions of cyclooxygenase (COX)-2, COX-1 and other inflammatory mediators to AD neurodegeneration. Finally, this article addresses potential interventions designed to control segments of classical inflammatory cascades in the brain in which cyclooxygenase is highly implicated. These considerations are critical to understand the role of cyclooxygenase in the clinical progression of AD.

  5. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

    PubMed

    Morgan, Jessie; Young, Lauren; McGuire, William

    2011-03-16

    The introduction of progressive enteral feeds for very low birth weight (VLBW) infants is often delayed for several days or longer after birth due to concern that earlier introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in VLBW infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 4), MEDLINE (1966 to December 2010), EMBASE (1980 to December 2010), CINAHL (1982 to December 2010), conference proceedings, and previous reviews. Randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days' postnatal age) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in VLBW infants. Data collection and analysis were performed in accordance with the standard methods of the Cochrane Neonatal Review Group. We identified five randomised controlled trials (RCT) in which a total of 600 infants participated. The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Two of the trials, in which a total of 488 infants participated, only recruited growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Meta-analyses did not detect statistically significant effects on the risk of NEC [typical relative risk 0.89, 95% confidence interval (CI) 0.58 to 1.37] or all cause mortality (typical relative risk 0.93, 95% CI 0.53 to 1.64). Infants who had delayed introduction of enteral feeds took significantly longer to

  6. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model.

    PubMed

    Capell, Brian C; Olive, Michelle; Erdos, Michael R; Cao, Kan; Faddah, Dina A; Tavarez, Urraca L; Conneely, Karen N; Qu, Xuan; San, Hong; Ganesh, Santhi K; Chen, Xiaoyan; Avallone, Hedwig; Kolodgie, Frank D; Virmani, Renu; Nabel, Elizabeth G; Collins, Francis S

    2008-10-14

    Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.

  7. Challenges and Progress in Building a Comprehensive Statewide System for Fetal Alcohol Spectrum Disorders Prevention in Hawai'i.

    PubMed

    Onoye, Jane M; Thompson, Mika D

    2017-05-01

    Introduction Fetal Alcohol Spectrum Disorders (FASD) has been a maternal and child public health concern in Hawai'i for over the past decade. Methods A historical assessment of FASD related activities was conducted to map the challenges and progress made in building a comprehensive statewide system for FASD prevention and intervention in an island state. Results Progress has primarily been reflected in increasing the number of individuals receiving FASD education and training, as well as some initiatives in public awareness. The creation of a State FASD Coordinator position was significant in catalyzing support for FASD initiatives and extending collaborative networks with national experts/teams, community-based organizations, and other local agencies to leverage resources in a time of economic strain. Major challenges and barriers included loss of the FASD Coordinator position, reliance on external resources and lack of local capacity for training and education integration into existing practice systems, and inadequate surveillance infrastructure. Discussion Lack of funding and resources were a common factor overall, and impeded the development of a state strategic plan which was needed to guide overall efforts and policies into a more coordinated system to reduce and prevent FASDs in Hawai'i.

  8. A research agenda to guide progress on childhood obesity prevention in Latin America.

    PubMed

    Kline, L; Jones-Smith, J; Jaime Miranda, J; Pratt, M; Reis, R S; Rivera, J A; Sallis, J F; Popkin, B M

    2017-07-01

    Childhood obesity rates in Latin America are among the highest in the world. This paper examines and evaluates the many efforts underway in the region to reduce and prevent further increases in obesity, identifies and discusses unique research challenges and opportunities in Latin America, and proposes a research agenda in Latin America for the prevention of childhood obesity and concomitant non-communicable diseases. Identified research gaps include biological challenges to healthy growth across the life cycle, diet and physical activity dynamics, community interventions promoting healthy child growth, and rigorous evaluation of national food and activity programs and regulatory actions. Addressing these research gaps is critical to advance the evidence-based policy and practice in childhood obesity tailored to the Latin American context that will be effective in addressing obesity. © 2017 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity.

  9. A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion

    PubMed Central

    Glazier, James A.

    2016-01-01

    We developed a computational model of the propagation of retinal ischemia in diabetic retinopathy and analyzed the consequences of various patterns and sizes of burns in peripheral retinal photocoagulation. The model addresses retinal ischemia as a phenomenon of adverse local feedback in which once a capillary is occluded there is an elevated probability of occlusion of adjacent capillaries resulting in enlarging areas of retinal ischemia as is commonly seen clinically. Retinal burns of different sizes and patterns, treated as local oxygen sources, are predicted to have different effects on the propagation of retinal ischemia. The patterns of retinal burns are optimized with regard to minimization of the sum of the photocoagulated retina and computer predicted ischemic retina. Our simulations show that certain patterns of retinal burns are effective at preventing the spatial spread of ischemia by creating oxygenated boundaries across which the ischemia does not propagate. This model makes no statement about current PRP treatment of avascular peripheral retina and notes that the usual spot sizes used in PRP will not prevent ischemic propagation in still vascularized retinal areas. The model seems to show that a properly patterned laser treatment of still vascularized peripheral retina may be able to prevent or at least constrain the propagation of diabetic retinal ischemia in those retinal areas with intact capillaries. PMID:27847828

  10. [The research progress of accelerating tendon healing and preventing tendon adhesion].

    PubMed

    Shi, Jixiang

    2005-05-01

    To study the status quo of the methods and materials for accelerating the tendon healing and preventing the tendon adhesion as to provide an essential reference for future research and clinical application. The recent articles on methods of accelerating tendon healing and preventing tendon adhesion were extensively reviewed. Tendon healing was decided by the co-effects of both endogenous and exogenous ways, and the former was more important. It was affected by the tendon sheath, vincula tendinum and synovial fluid as well. Tendon adhesion was mostly caused by excessive participation of exogenous healing factors and serious damage of the situations around the tendon. Tendon healing was accelerated by methods like repairing, reconstruction of peri-tendon tissues, electric stimulation, physiotherapy, adding herbs or growth factors, and gene intervention. Tendon adhesion was reduced or prevented by methods like the restoration of tendon sheath, using substitutions, adding herbs/drugs, and improving suturing techniques. Via the appropriate methods and techniques combining the Chinese traditional and modern medicine, tendon healing can be accelerated and the quality of tendon healing can be improved.

  11. Targeting mTOR Signaling Can Prevent the Progression of FSGS.

    PubMed

    Zschiedrich, Stefan; Bork, Tillmann; Liang, Wei; Wanner, Nicola; Eulenbruch, Kristina; Munder, Stefan; Hartleben, Björn; Kretz, Oliver; Gerber, Simon; Simons, Matias; Viau, Amandine; Burtin, Martine; Wei, Changli; Reiser, Jochen; Herbach, Nadja; Rastaldi, Maria-Pia; Cohen, Clemens D; Tharaux, Pierre-Louis; Terzi, Fabiola; Walz, Gerd; Gödel, Markus; Huber, Tobias B

    2017-07-01

    Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both Raptor alleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just one Raptor allele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatment with the mTORC1 inhibitor rapamycin efficiently diminished disease progression. Mechanistically, complete pharmacologic inhibition of mTOR in immortalized podocytes shifted the cellular energy metabolism toward reduced rates of oxidative phosphorylation and anaerobic glycolysis, which correlated with increased production of reactive oxygen species. Together, these data suggest that podocyte injury and loss is commonly followed by adaptive mTOR activation. Prolonged mTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition. Copyright © 2017 by the American Society of Nephrology.

  12. Identifying risk and preventing progression to Type 2 diabetes in vulnerable and disadvantaged adults: a pragmatic review.

    PubMed

    Taylor, J; Cottrell, C; Chatterton, H; Hill, J; Hughes, R; Wohlgemuth, C; Holt, R I G

    2013-01-01

    To identify effective approaches to recognize diabetes risk and prevent progression to Type 2 diabetes in vulnerable groups, whose diabetes risk may be difficult to identify or manage. UK-based interventions that assess diabetes risk and/or target known risk factors were identified through four main sources: submissions to two calls for evidence by the National Institute for Health and Clinical Excellence; local practice examples collected via a targeted email questionnaire; selected electronic databases; and a focused search of relevant websites. No restriction was placed on the study type or evaluation methods used. Key themes and sub-themes on outcomes, as well as facilitators and barriers to successful delivery, are reported. Twenty-four interventions met all inclusion criteria: 15 included a risk identification element and 14 included preventative activities. A range of risk identification tools were used to improve diagnosis of unmet diabetes-related health needs and raise awareness of diabetes risk factors. All preventative interventions focused on lifestyle change. No interventions monitored blood glucose as an outcome and only one reported improvements in baseline risk scores. Facilitators included tailored and flexible programme design, outreach delivery in familiar locations and effective inter-agency working. Barriers included literacy and language difficulties, transient participant populations, low prioritization of diabetes prevention and cost. It is possible to engage successfully with high-risk adults in vulnerable groups to achieve positive health outcomes relevant to the prevention of diabetes. However, more robust evidence on longer-term outcomes is required to ensure that programmes are targeted and delivered appropriately. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  13. Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling

    PubMed Central

    Deeb, Dorrah; Gao, Xiaohua; Liu, Yongbo; Jiang, Daniel; Divine, George W.; Arbab, Ali S.; Dulchavsky, Scott A.; Gautam, Subhash C.

    2011-01-01

    In an extension of our previous studies showing potent antitumorigenic activity of synthetic triterpenoids of oleanolic acid against prostate cancer cell lines, we examined the efficacy of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preventing the development and/or progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Data show that oral gavage with CDDO (10 μmol/kg) for 20 weeks resulted in inhibition of the progression of preneoplastic lesions in the dorsolateral prostate and ventral prostate to adenocarcinoma without toxicity. CDDO also inhibited metastasis of tumor to the distant organs. Treatment with CDDO significantly inhibited cell proliferation, reduced the density of blood vessels and promoted apoptosis in the prostatic tissue. Further, Akt, NF-κB and NF-κB regulated Bcl-2, Bcl-xL, survivin and cIAP1 appear to be the molecular targets of CDDO for inhibiting the progression of prostate cancer in TRAMP mice. Thus, these studies show for the first time the potential of CDDO for chemoprevention of human prostate cancer. PMID:21325633

  14. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

    PubMed

    Olmos-Alonso, Adrian; Schetters, Sjoerd T T; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V Hugh; Gomez-Nicola, Diego

    2016-03-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

  15. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology

    PubMed Central

    Olmos-Alonso, Adrian; Schetters, Sjoerd T. T.; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V. Hugh

    2016-01-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease. PMID:26747862

  16. A dopamine-secreting pheochromocytoma.

    PubMed

    Yasunari, K; Kohno, M; Minami, M; Kano, H; Ohhira, M; Nakamura, K; Yoshikawa, J

    2000-01-01

    We describe a patient with pheochromocytoma, which secretes dopamine. He was admitted to hospital because of chronic diarrhea. After surgical resection of the tumor, dramatic cessation of the diarrhea and blood pressure elevation were observed. Decreased expression of dopamine beta-hydroxylase in the tumor was considered a possible mechanism of producing a pathophysiological concentration of dopamine. This case shows that excessive excretion of dopamine, a vasodilative hormone, may affect blood pressure.

  17. Antibody-based antiangiogenic and antilymphangiogenic therapies to prevent tumor growth and progression.

    PubMed

    Bzowska, Monika; Mężyk-Kopeć, Renata; Próchnicki, Tomasz; Kulesza, Małgorzata; Klaus, Tomasz; Bereta, Joanna

    2013-01-01

    Blood and lymphatic vessel formation is an indispensable factor for cancer progression and metastasis. Therefore, various strategies designed to block angiogenesis and lymphangiogenesis are being investigated in the hope to arrest and reverse tumor development. Monoclonal antibodies, owing to their unequalled diversity and specificity, might be applied to selectively inhibit the pathways that cancer cells utilize to build up a network of blood vessels and lymphatics. Among the possible targets of antibody-based therapies are proangiogenic and prolymphangiogenic growth factors from the VEGF family and the receptors to which they bind (VEGFRs). Here, we present molecular mechanisms of angiogenesis and lymphangiogenesis exploited by tumors to progress and metastasise, with examples of antibody-based therapeutic agents directed at interfering with these processes. The expanding knowledge of vascular biology helps to explain some of the problems encountered in such therapies, that arise due to the redundancy in signaling networks controlling the formation of blood and lymphatic vessels, and lead to tumor drug resistance. Nonetheless, combined treatments and treatments focused on newly discovered proangiogenic and prolymphangiogenic factors give hope that more prominent therapeutic effects might be achieved in the future.

  18. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    PubMed

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

  19. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

    PubMed

    Morgan, Jessie; Young, Lauren; McGuire, William

    2014-01-01

    The introduction of enteral feeds for very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW; less than 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014), CINAHL (1982 to September 2014), conference proceedings and previous reviews. We included randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks' gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four

  20. Prevention

    Treesearch

    Kerry Britton; Barbara Illman; Gary Man

    2010-01-01

    Prevention is considered the most cost-effective element of the Forest Service Invasive Species Strategy (USDA Forest Service 2004). What makes prevention difficult is the desire to maximize free trade and the resulting benefits to society while, at the same time, protecting natural resources. The role of science is to first identify which commodities pose an...

  1. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): study design and progress.

    PubMed

    Kivipelto, Miia; Solomon, Alina; Ahtiluoto, Satu; Ngandu, Tiia; Lehtisalo, Jenni; Antikainen, Riitta; Bäckman, Lars; Hänninen, Tuomo; Jula, Antti; Laatikainen, Tiina; Lindström, Jaana; Mangialasche, Francesca; Nissinen, Aulikki; Paajanen, Teemu; Pajala, Satu; Peltonen, Markku; Rauramaa, Rainer; Stigsdotter-Neely, Anna; Strandberg, Timo; Tuomilehto, Jaakko; Soininen, Hilkka

    2013-11-01

    Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a multi-center, randomized, controlled trial ongoing in Finland. Participants (1200 individuals at risk of cognitive decline) are recruited from previous population-based non-intervention studies. Inclusion criteria are CAIDE Dementia Risk Score ≥6 and cognitive performance at the mean level or slightly lower than expected for age (but not substantial impairment) assessed with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery. The 2-year multidomain intervention consists of: nutritional guidance; exercise; cognitive training and social activity; and management of metabolic and vascular risk factors. Persons in the control group receive regular health advice. The primary outcome is cognitive performance as measured by the modified Neuropsychological Test Battery, Stroop test, and Trail Making Test. Main secondary outcomes are: dementia (after extended follow-up); disability; depressive symptoms; vascular risk factors and outcomes; quality of life; utilization of health resources; and neuroimaging measures. Screening began in September 2009 and was completed in December 2011. All 1200 persons are enrolled and the intervention is ongoing as planned. Baseline clinical characteristics indicate that several vascular risk factors and unhealthy lifestyle-related factors are present, creating a window of opportunity for prevention. The intervention will be completed during 2014. The FINGER is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia. Copyright © 2013. Published by Elsevier Inc.

  2. Progress on obesity prevention over 20 years in Australia and New Zealand.

    PubMed

    Swinburn, B; Wood, A

    2013-11-01

    The lessons learned from over 20 years of obesity prevention efforts in Australia and New Zealand are presented. The obesity epidemic started in the 1980s but poor monitoring systems meant the rise in obesity prevalence initially went undetected. In the 1990 s, experts started advocating for government action; however, it was the rapid increase in media reports on obesity in the early 2000s which created the pressure for action. Several, comprehensive reports produced some programme investment but no regulatory policies were implemented. The powerful food industry lobby ensured this lack of policies on front-of-pack food labelling, restrictions on unhealthy food marketing to children, or taxes on unhealthy foods. The New Zealand government even backpedalled by rescinding healthy school food guidelines and withdrawing funding for the comprehensive national obesity strategy. In 2007, Australian Governments started a major long term-investment in preventive health in order to improve economic productivity. Other positive initiatives, especially in Australia, were: the establishment of several advocacy organizations; successful, long-term, whole-of-community projects reducing childhood obesity; a national knowledge exchange system for practitioners; and some innovative programmes and social marketing. However, despite multiple reports and strong advocacy, key recommended regulatory policies remain unimplemented, largely due to the private sector interests dominating public policy development. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.

  3. [Progress of researches on prevention and treatment of sports fatigue with moxibustion therapy].

    PubMed

    Xu, Hui-Qian; Zhang, Hong-Ru; Gu, Yi-Huang

    2014-04-01

    Sports fatigue belongs to the category of functional deficiency-syndrome according to the theory of traditional Chinese medicine. The moxibustion therapy has a long history and possesses a definite therapeutic effect in the prevention and treatment of sports fatigue. In the present paper, the authors reviewed development of researches on the effects of moxibustion intervention in the prevention and treatment of sports fatigue in recent 5 years. Results of researches showed that moxibustion intervention can 1) eliminate free radicals and reduce oxidative damage; 2) increase energy (glycogen) supply to delay the production of fatigue; 3) raise serum testosterone level (relieve exercise-induced neuroendocrine disorder) and reduce post-sports fatigue; 4) raise the anaerobic exercise ability, reduce the accumulation of metabolic products in the body and strengthen the endurance capacity of the skeletal muscle; and 5) improve ischemic cardiac function, and suppress cardiomyocyte apopotosis, etc. However, we should further strengthen our investigations on the moxibustion therapy in the ancient classical literature and sum up academic thoughts of different academic schools in the successive dynasties, put emphasis on the large sample randomized controlled clinical trails, establish united treatment standards, etc., and provide much evidence for effectively treating sports fatigue in the future.

  4. Politics of science: Progress toward prevention of the dementia-Alzheimer's syndrome.

    PubMed

    Khachaturian, Zaven S; Khachaturian, Ara S

    2015-01-01

    There exist many challenges hampering the discovery and development of effective interventions to prevent dementia. Three major trends have now intersected to influence the emerging interest in disease modifying therapies that may delay or halt dementia. The three crucial factors shaping this current focus are: (1) the emergence of the longevity revolution and the impact of a aging society, (2) the effects of the US Federal investment in research in advancing knowledge about the neurobiology of aging and dementia, and (3) the problem of US legislators and health policy makers to balance the allocation of evermore scarce research funding resources. The purpose of this essay is to provide a survey of the politics of science and to describe efforts to correctly manage the high level of expectations of both the patient and research communities. The perspective offered reviews the history and evolution of the ideas to treat or prevent dementia and Alzheimer's disease as a national strategic goal. The aim is to evaluate the interplay between science and formulation of public policy for setting research priority. We use the history of developing US National Institute of Aging's extramural research programs on brain aging and Alzheimer's disease (Khachaturian, 2006; 2007) as an initial case study. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. [Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency].

    PubMed

    Gusev, E I; Skvortsova, V I; Chukanova, E I

    2005-01-01

    One hundred and eighty-seven patients with different stages of cerebrovascular insufficiency (CI) have been examined. A diagnosis of CI was based on the results of neurological and neuropsychological study, ultrasonic dopplerography, rheo- and encephalography, electrocardiography, brain MRI and eyegrounds examination. Neurological scales were used for neurological status assessment and further data processing. The study aimed at evaluation of tolerability and clinical efficacy of the medication and complications in CI course. Semax treatment resulted in significant clinical improvement, stabilization of the disease progress and reduced a risk of stroke and transitory ischemic attacks in the disease course. The drug is featured by minor percent of side-effects and is well tolerated by patients, including those of older age groups.

  6. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

    PubMed

    Morgan, Jessie; Young, Lauren; McGuire, William

    2013-05-31

    The introduction of enteral feeds for very preterm (< 32 weeks) or very low birth weight (< 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. To determine the effect of delayed introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very preterm or very low birth weight infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), CINAHL (1982 to April 2013), conference proceedings, and previous reviews. Randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or very low birth weight infants. We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. We identified seven randomised controlled trials in which a total of 964 infants participated. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 g). The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical risk ratio (RR) 0.92 (95% confidence interval (CI) 0.64 to 1.34) or all-cause mortality (typical RR 1.26 (95% CI 0.78 to 2.01)). Three of the trials restricted participation to growth

  7. AAV2/1-TNFR:Fc Gene Delivery Prevents Periodontal Disease Progression

    PubMed Central

    Cirelli, Joni A; Park, Chan Ho; MacKool, Kathryn; Taba, Mario; Lustig, Kurt H; Burstein, Haim; Giannobile, William V

    2008-01-01

    SUMMARY Periodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor alpha (TNF-α) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of disease activity after treatment cessation and repeated dosing regimens. In this study, we used pseudotyped adeno-associated virus vector based on serotype 1 (AAV2/1) to deliver the TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene to rats subjected to experimental Porphyromonas gingivalis (Pg)-lipopolysaccharide (LPS)-mediated bone loss. Animals received Pg-LPS delivered to the gingivae thrice weekly for 8 weeks, vehicle alone, Pg-LPS and intramuscular delivery of pseudotyped AAV2/1-TNFR:Fc vector (1×1011 DNase I-resistant particles) or AAV2/1-TNFR:Fc vector delivered to naïve animals. AAV2/1-TNFR:Fc therapy led to sustained therapeutic levels of serum TNFR protein and protected against Pg-LPS-mediated loss of bone volume and density. Furthermore, AAV2/1-TNFR:Fc administration reduced local levels of multiple pro-inflammatory cytokines and osteoclast-like cells at the periodontal lesions. These findings suggest that delivery of AAV2/1-TNFR:Fc may be a viable approach to modulate periodontal disease progression. PMID:19078994

  8. Dopamine depresses cholinergic oscillatory network activity in rat hippocampus.

    PubMed

    Weiss, Torsten; Veh, Rüdiger W; Heinemann, Uwe

    2003-11-01

    The dopaminergic neuronal system is implicated in cognitive processes in a variety of brain regions including the mesolimbic system. We have investigated whether dopamine also affects synchronized network activity in the hippocampus, which has been ascribed to play a pivotal role in memory formation. Gamma frequency (20-80 Hz) oscillations were induced by the cholinergic agonist carbachol. Oscillatory activity was examined in area CA3 of Wistar rat hippocampal slices, employing field potential and intracellular recordings. Application of carbachol initiated synchronized population activity in the gamma band at 40 Hz. Induced gamma activity persisted over hours and required GABAA receptors. Dopamine reversibly decreased the integrated gamma band power of the carbachol rhythm by 62%, while its frequency was not changed. By contrast, individual pyramidal cells recorded during carbachol-induced field gamma activity exhibited theta frequency (5-15 Hz) membrane potential oscillations that were not altered by dopamine. The dopamine effect on the field gamma activity was mimicked by the D1 receptor agonist SKF-383393 and partially antagonized by the D1 antagonist SCH-23390. Conversely, the D2 receptor agonist quinpirole failed to depress the oscillations, and the D2 antagonist sulpiride did not prevent the suppressive dopamine effect. The data indicate that dopamine strongly depresses cholinergic gamma oscillations in area CA3 of rat hippocampus by activation of D1-like dopamine receptors and that this effect is most likely mediated via impairment of interneurons involved in generation and maintenance of the carbachol-induced network rhythm.

  9. Effect of dopamine on viability of BHK-21 cells.

    PubMed

    Moshkov, D A; Abramova, M B; Shubina, V S; Lavrovskaya, V P; Pavlik, L L; Lezhnev, E I

    2010-09-01

    We studied the effects of dopamine added to culture medium on survival of floating or adherent BHK-21 cells differing by organization of actin cytoskeleton. The viability of floating cells more drastically decreased with increasing dopamine concentration and duration of exposure than that of adherent cells. The cells worse adhered to the substrate and formed a monolayer. The formed monolayer degrades, cell borders become blurred, cells, polygonal in the control, are rounded. Preliminary blockade of dopamine receptors with haloperidol, inessential for cell survival and morphology, does not prevent the destructive effect of dopamine on the cells. Ultrastructural study revealed increased density of filamentous actin threads in deep compartments of cell cytoplasm after dopamine treatment, this increase being more pronounced in cells grown in suspension. Bearing in mind the polymerizing effect of dopamine on globular actin in vitro and the fact that the content of this protein in floating cells is higher than in adherent cells, we can conclude that the decrease in viability of BHK-21 cells is caused by interaction of dopamine with cytoplasmic globular actin.

  10. Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

    PubMed Central

    Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

    2013-01-01

    Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

  11. The School Food Environment and Obesity Prevention: Progress Over the Last Decade.

    PubMed

    Welker, Emily; Lott, Megan; Story, Mary

    2016-06-01

    The school food environment-including when and where children obtain food and the types of options available during the school day-plays an important role in children's consumption patterns. Thus, childhood obesity prevention efforts often focus on altering the school food environment as a mechanism for improving student dietary intake. This review examines the role school food programs and policies play in improving children's diet, weight, and health. Overall, research suggests that significant improvements have been made in school nutrition policies and programs. Due to the recent program changes made as a result of the 2010 Healthy, Hunger-Free Kids Act, an emphasis was placed on research conducted over the past decade and especially on the evaluation of foods and beverages served and sold since implementation of this national law. This review also examines remaining gaps in the literature and opportunities for further improvements in school food programs and policies.

  12. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine

    PubMed Central

    Brumbaugh, Ariel R; Mobley, Harry LT

    2012-01-01

    Uncomplicated urinary tract infections (UTIs) are common, with nearly half of all women experiencing at least one UTI in their lifetime. This high frequency of infection results in huge annual economic costs, decreased workforce productivity and high patient morbidity. At least 80% of these infections are caused by uropathogenic Escherichia coli (UPEC). UPEC can reside side by side with commensal strains in the gastrointestinal tract and gain access to the bladder via colonization of the urethra. Antibiotics represent the current standard treatment for UTI; however, even after treatment, patients frequently suffer from recurrent infection with the same or different strains. In addition, successful long-term treatment has been complicated by a rise in both the number of antibiotic-resistant strains and the prevalence of antibiotic-resistance mechanisms. As a result, preventative approaches to UTI, such as vaccination, have been sought. This review summarizes recent advances in UPEC vaccine development and outlines future directions for the field. PMID:22873125

  13. Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression

    PubMed Central

    Gucalp, Ayca; Iyengar, Neil M.; Hudis, Clifford A.; Dannenberg, Andrew J.

    2016-01-01

    The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies. PMID:26970134

  14. Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression.

    PubMed

    Gucalp, Ayca; Iyengar, Neil M; Hudis, Clifford A; Dannenberg, Andrew J

    2016-02-01

    The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Progress in the development of preventive and therapeutic vaccines for hepatitis C virus.

    PubMed

    Torresi, Joseph; Johnson, Doug; Wedemeyer, Heiner

    2011-06-01

    Hepatitis C virus (HCV) is a blood borne disease estimated to chronically infect 3% of the worlds' population causing significant morbidity and mortality. Current medical therapy is curative in approximately 50% of patients. While recent treatment advances of genotype 1 infection using directly acting antiviral agents (DAAs) are encouraging, there is still a need to develop vaccine strategies capable of preventing infection. Moreover, vaccines may also be used in future in combination with DAAs enabling interferon-free treatment regimens. Viral and host specific factors contribute to viral evasion and present important impediments to vaccine development. Both, innate and adaptive immune responses are of major importance for the control of HCV infection. However, HCV has evolved ways of evading the host's immune response in order to establish persistent infection. For example, HCV inhibits intracellular interferon signalling pathways, impairs the activation of dendritic cells, CD8(+) and CD4(+) T cell responses, induces a state of T-cell exhaustion and selects escape variants with mutations CD8(+) T cell epitopes. An effective vaccine will need to produce strong and broadly cross-reactive CD4(+), CD8(+) T cell and neutralising antibody (NAb) responses to be successful in preventing or clearing HCV. Vaccines in clinical trials now include recombinant proteins, synthetic peptides, virosome based vaccines, tarmogens, modified vaccinia Ankara based vaccines, and DNA based vaccines. Several preclinical vaccine strategies are also under development and include recombinant adenoviral vaccines, virus like particles, and synthetic peptide vaccines. This paper will review the vaccines strategies employed, their success to date and future directions of vaccine design. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  16. Methamphetamine Regulation of Firing Activity of Dopamine Neurons.

    PubMed

    Lin, Min; Sambo, Danielle; Khoshbouei, Habibeh

    2016-10-05

    Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca(2+) homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca(2+)-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane.

  17. Preventing the progression of chronic kidney disease: two case reports and review of the literature.

    PubMed

    Toor, Muhammad R; Singla, Anjali; Kim, Jin K; Sumin, Xenia; DeVita, Maria V; Michelis, Michael F

    2014-11-01

    A variety of therapeutic modalities are available to alter the abnormalities seen in patients with chronic kidney disease (CKD). A comprehensive plan can now be developed to slow the progression of CKD. Two clinical cases of delay in the need for renal replacement therapy are described. This delay was achieved by using recognized recommendations for optimal diabetes therapy (HbA1c target 7 %), goals for blood pressure levels, reduction of proteinuria, and the proper use of ACEI/ARB therapies. Recent recommendations include BP <140/90 mmHg for patients <60 years old and <150/90 mmHg for older patients unless they have CKD or diabetes. Limits on dietary sodium and protein intake and body weight reduction will decrease proteinuria. Proper treatment for elevated serum phosphorous and parathyroid hormone levels is now appreciated as well as the benefits of therapy for dyslipidemias and anemia. Concerns regarding unfavorable outcomes with excess ESA therapy have led to hemoglobin goals in the 10-12 g/dL range. Finally, new therapeutic considerations for the treatment of acidosis and hyperuricemia are presented with data available to suggest that increasing serum bicarbonate to >22 mmol/L is beneficial, while serum uric acid therapeutic goals are still uncertain. Also, two as yet insufficiently understood approaches to altering the course of CKD (FGF-23 level reduction and balancing gut microbiota) are noted.

  18. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment

    PubMed Central

    Li, Kang; Dan, Zeng; Nie, Yu-Qiang

    2014-01-01

    In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gastric cancer. They may be derived from gastric stem cells in gastric tissues, or bone marrow mesenchymal stem cells. As with other stem cells, GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance, which are resistant to chemotherapy and thus form the basis of drug resistance. Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs, diagnosis and grading of gastric cancer, and research on GCSC-targeted therapy for gastric cancer. Therefore, discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment. PMID:24833872

  19. A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models.

    PubMed

    Gao, Congxiao; Fujinawa, Reiko; Yoshida, Takayuki; Ueno, Manabu; Ota, Fumi; Kizuka, Yasuhiko; Hirayama, Tetsuya; Korekane, Hiroaki; Kitazume, Shinobu; Maeno, Toshitaka; Ohtsubo, Kazuaki; Yoshida, Keiichi; Yamaguchi, Yoshiki; Lepenies, Bernd; Aretz, Jonas; Rademacher, Christoph; Kabata, Hiroki; Hegab, Ahmed E; Seeberger, Peter H; Betsuyaku, Tomoko; Kida, Kozui; Taniguchi, Naoyuki

    2017-02-01

    Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3(-)-6]Galβ1-4[SO3(-)-6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation.

  20. Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression

    PubMed Central

    Schmitt, Erica G.; Haribhai, Dipica; Jeschke, Jonathan C.; Co, Dominic O.; Ziegelbauer, Jennifer; Yan, Ke; Iwakura, Yoichiro; Mishra, Manoj K.; Simpson, Pippa; Salzman, Nita H.; Williams, Calvin B.

    2014-01-01

    In order to study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme (mHEL) and a hemoglobin (Hb) epitope tag under the control of the Clara cell secretory protein (CCSP) promoter, which largely limited transgene expression to the respiratory bronchioles. When CCSP-mHEL/Hb transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the Hb epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4+ T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng−/− and Il17a−/− mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of antigen-specific Treg cells accumulated in the lesions and Treg cell-depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease. PMID:24163409

  1. Clinical outcomes of nitinol staples for preventing curve progression in idiopathic scoliosis.

    PubMed

    Lavelle, William F; Samdani, Amer F; Cahill, Patrick J; Betz, Randal R

    2011-01-01

    Although bracing for idiopathic scoliosis is moderately successful, its efficacy has been called into question and it carries associated psychosocial ramifications. In this study we report the background, rationale, indications, surgical techniques, and early results of vertebral body stapling (VBS) in patients with idiopathic scoliosis. We reviewed the literature on growth modulation of the growing spine and the concepts behind the use of VBS as a fusionless strategy. The indications are derived from retrospectively reviewed patients with idiopathic scoliosis treated with VBS followed for a minimum of 2 years. Indications for staple use included: (a) age <13 years in girls and 15 in boys, (b) Risser 0 or 1 and/or 1 year of growth remaining on wrist radiograph, (c) coronal curve <45 degrees with minimal rotation and flexible to <25 degrees on a side bending radiograph, and (d) sagittal thoracic curve <40 degrees. Thoracic curves measuring <35 degrees had a success rate of 77.7%. Curves which reached ≤ 20 degrees on first erect radiograph had a success rate of 85.7%. Thoracic curves greater than 35 degrees were not successful and require alternative treatments. Lumbar curves demonstrated a success rate of 86.7%. Some patients with idiopathic scoliosis with moderate curves (25 to 45 degrees) and high risk of progression can be safely treated with VBS as an alternative to bracing. Level III.

  2. Dopamine and anorexia nervosa.

    PubMed

    Södersten, P; Bergh, C; Leon, M; Zandian, M

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein.

    PubMed

    Lam, Hoa A; Wu, Nanping; Cely, Ingrid; Kelly, Rachel L; Hean, Sindalana; Richter, Franziska; Magen, Iddo; Cepeda, Carlos; Ackerson, Larry C; Walwyn, Wendy; Masliah, Eliezer; Chesselet, Marie-Françoise; Levine, Michael S; Maidment, Nigel T

    2011-07-01

    Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine. Copyright © 2011 Wiley-Liss, Inc.

  4. VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for α-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease

    PubMed Central

    Tang, Fu-Lei; Erion, Joanna R.; Tian, Yun; Liu, Wei; Yin, Dong-Min; Ye, Jian; Tang, Baisha; Mei, Lin

    2015-01-01

    Vacuolar protein sorting-35 (VPS35) is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with autosomal dominant PD. However, it remains poorly understood if and how VPS35 deficiency or mutation contributes to PD pathogenesis. Here we provide evidence that links VPS35 deficiency to PD-like neuropathology. VPS35 was expressed in mouse dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and STR (striatum)—regions that are PD vulnerable. VPS35-deficient mice exhibited PD-relevant deficits including accumulation of α-synuclein in SNpc-DA neurons, loss of DA transmitter and DA neurons in SNpc and STR, and impairment of locomotor behavior. Further mechanical studies showed that VPS35-deficient DA neurons or DA neurons expressing PD-linked VPS35 mutant (D620N) had impaired endosome-to-Golgi retrieval of lysosome-associated membrane glycoprotein 2a (Lamp2a) and accelerated Lamp2a degradation. Expression of Lamp2a in VPS35-deficient DA neurons reduced α-synuclein, supporting the view for Lamp2a as a receptor of chaperone-mediated autophagy to be critical for α-synuclein degradation. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis. SIGNIFICANCE STATEMENT VPS35 is a key component of the retromer complex that is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with PD. However, if and how VPS35 deficiency or mutation contributes to PD pathogenesis remains unclear. We demonstrated that VPS35 deficiency or mutation (D620N) in mice leads to α-synuclein accumulation and aggregation in the substantia nigra, accompanied with DA neurodegeneration. VPS35-deficient DA neurons exhibit impaired endosome-to-Golgi retrieval of Lamp2a, which may contribute to the reduced α-synuclein degradation through

  5. Emdogain does not prevent progressive root resorption after replantation of avulsed teeth: a clinical study.

    PubMed

    Schjøtt, M; Andreasen, J O

    2005-02-01

    Emdogain has been shown in clinical and experimental studies to promote regeneration of all periodontal tissues: cementum with anchoring fibres, a functional, periodontal ligament and alveolar bone in connection with treatment of marginal periodontitis. The intention of this study was to analyse whether this regenerative capacity upon the periodontal ligament also worked in a trauma situation where a significant number of PDL cells have been eliminated because of unphysiologic storage or actual damage during avulsion or replantation. Furthermore if ankylosis sites already established because of earlier replantation after avulsion could be surgical removed and application of Emdogain could revert the ankylosis stage to a normal PDL situation. The first treatment situation was tested in seven patients with a total of 16 avulsed teeth with varying time of extra oral storage. The teeth were extra-orally endodontically treated and the root and socket covered with Emdogain before replantation. All teeth demonstrated subsequent ankylosis, primarily diagnosed by a percussion test. The second treatment situation where an ankylosis was already established constituted of seven patients with a total of 11 teeth because of previous replantation after avulsion. These teeth were all extracted, the ankylosis sites removed and the root and socket treated with Emdogain. After 6 months all teeth showed recurrence of ankylosis. It is concluded that Emdogain was not able to prevent or cure ankylosis.

  6. Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

    PubMed Central

    Willard, Amanda M.; Bouchard, Rachel S.; Gittis, Aryn H.

    2015-01-01

    Parkinson’s disease (PD) is a movement disorder whose cardinal motor symptoms arise due to the progressive loss of dopamine. Although this dopamine loss typically progresses slowly over time, currently there are very few animal models that enable incremental dopamine depletion over time within the same animal. This type of gradual dopamine depletion model would be useful in studies aimed at the prodromal phase of PD, when dopamine levels are pathologically low but motor symptoms have not yet presented. Utilizing the highly characterized neurotoxin 6-hydroxydopamine (6-OHDA), we have developed a paradigm to gradually deplete dopamine levels in the striatum over a user-defined time course – spanning weeks to months – in C57BL/6 mice. Dopamine depletions were achieved by administration of five low dose injections (0.75 µg) of 6-OHDA through an implanted intracranial bilateral cannula targeting the medial forebrain bundle. Levels of dopamine within the striatum declined linearly with successive injections, quantified using tyrosine hydroxylase immunostaining and high-performance liquid chromatography. Behavioral testing was carried out at each time point to study the onset and progression of motor impairments as a function of dopamine loss over time. We found that spontaneous locomotion, measured in an open field, was robust to loss of dopamine until ~70% of striatal dopamine was lost. Beyond this point, additional dopamine loss caused a sharp decline in motor performance, reaching a final level comparable to that of acutely depleted mice. Similarly, although rearing behavior was more sensitive to dopamine loss and declined linearly as a function of dopamine levels, it eventually declined to levels similar to that seen in acutely depleted mice. In contrast, motor coordination, measured on a vertical pole task, was only moderately impaired in gradually depleted mice, despite severe impairments observed in acutely depleted mice. These results demonstrate the

  7. Adenosine A(2A) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation.

    PubMed

    Garcia, Gabriela E; Truong, Luan D; Chen, Jiang-Fan; Johnson, Richard J; Feng, Lili

    2011-08-01

    Crescentic glomerulonephritis (GN) in Wistar-Kyoto rats progresses to lethal kidney failure by macrophage (Mφ)-mediated mechanisms. Mφs in nephritic glomeruli express adenosine A(2A) receptors (A(2A)Rs), the activation of which suppresses inflammation. Here, we pharmacologically activated the A(2A)Rs with a selective agonist, CGS 21680, and inactivated them with a selective antagonist, ZM241385, to test the effects on established GN. When activation was delayed until antiglomerular basement membrane GN and extracellular matrix deposition were established, glomerular Mφ infiltration was reduced by 83%. There was also a marked improvement in glomerular lesion histology, as well as decreased proteinuria. A(2A)R activation significantly reduced type I, III, and IV collagen deposition, and E-cadherin expression was restored in association with a reduction of α-smooth muscle actin-positive myofibroblasts in the interstitium and glomeruli. In contrast, pharmacological inactivation of A(2A)Rs increased glomerular crescent formation, type I, III, and IV collagen expression, and enhanced E-cadherin loss. Activation of A(2A)Rs suppressed the expression of the Mφ-linked glomerular damage mediators, transforming growth factor-β, osteopontin-1, thrombospondin-1, and tissue inhibitor of metalloproteinase-1. Thus, A(2A)R activation can arrest GN and prevent progressive fibrosis in established pathological lesions.

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

    PubMed

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

    2016-06-01

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

  9. Delayed Treatment with a Small Pigment Epithelium Derived Factor (PEDF) Peptide Prevents the Progression of Diabetic Renal Injury.

    PubMed

    Awad, Alaa S; You, Hanning; Gao, Ting; Gvritishvili, Anzor; Cooper, Timothy K; Tombran-Tink, Joyce

    2015-01-01

    Our recent publication showed that a small bioactive pigment epithelium derived factor (PEDF) peptide (P78-PEDF) prevents the development of diabetic nephropathy (DN). However, its effects on the progression of established DN were not clear. Therefore, the purpose of this study was to determine the effect of P78-PEDF in the progression of DN and to compare the effects of P78-PEDF and an ACE inhibitor (ACEi), a standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with P78-PEDF or captopril starting at 6 wks of age for 12 wks (early treatment) or starting at 12 wks of age for 6 wks (late treatment). We first established the optimal dose of the P78-PEDF peptide to ameliorate DN in Ins2(Akita) mouse for a 6 wk study period and found that the peptide was effective at 0.1- 0.5 µg/g/day. We next showed that early or late treatment with P78-PEDF resulted in protection from DN as indicated by reduced albuminuria, kidney macrophage recruitment, histological changes, inflammatory cytokines and fibrotic markers (kidney TNF-α, fibronectin, VEGFA and EGFR), and restored nephrin expression compared with vehicle-treated Ins2(Akita) mice. Interestingly, only early but not late treatment with captopril was as effective as P78-PEDF in reducing most DN complications, despite its lack of effect on nephrin, VEGFA and EGFR expression. These findings highlight the importance of P78-PEDF peptide as a potential therapeutic modality in both the development and progression of diabetic renal injury.

  10. Testosterone Induces Molecular Changes in Dopamine Signaling Pathway Molecules in the Adolescent Male Rat Nigrostriatal Pathway

    PubMed Central

    Purves-Tyson, Tertia D.; Owens, Samantha J.; Double, Kay L.; Desai, Reena; Handelsman, David J.; Weickert, Cynthia Shannon

    2014-01-01

    Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor

  11. Project Energize: intervention development and 10 years of progress in preventing childhood obesity.

    PubMed

    Rush, Elaine; Cairncross, Carolyn; Williams, Margaret Hinepo; Tseng, Marilyn; Coppinger, Tara; McLennan, Steph; Latimer, Kasha

    2016-01-26

    Prevention of childhood obesity is a global priority. The school setting offers access to large numbers of children and the ability to provide supportive environments for quality physical activity and nutrition. This article describes Project Energize, a through-school physical activity and nutrition programme that celebrated its 10-year anniversary in 2015 so that it might serve as a model for similar practices, initiatives and policies elsewhere. The programme was envisaged and financed by the Waikato District Health Board of New Zealand in 2004 and delivered by Sport Waikato to 124 primary schools as a randomised controlled trial from 2005 to 2006. The programme has since expanded to include all 242 primary schools in the Waikato region and 70 schools in other regions, including 53,000 children. Ongoing evaluation and development of Project Energize has shown it to be sustainable (ongoing for >10 years), both effective (lower obesity, higher physical fitness) and cost effective (one health related cost quality adjusted life year between $18,000 and $30,000) and efficient ($45/child/year) as a childhood 'health' programme. The programme's unique community-based approach is inclusive of all children, serving a population that is 42% Māori, the indigenous people of New Zealand. While the original nine healthy eating and seven quality physical activity goals have not changed, the delivery and assessment processes has been refined and the health service adapted over the 10 years of the programme existence, as well as adapted over time to other settings including early childhood education and schools in Cork in Ireland. Evaluation and research associated with the programme delivery and outcomes are ongoing. The dissemination of findings to politicians and collaboration with other service providers are both regarded as priorities.

  12. Progress in the prevention and control of diarrhoeal diseases since Independence.

    PubMed

    Bhattacharya, S K

    2003-01-01

    Acute diarrhoeal diseases constitute one of the major health problems among young children in India. It was estimated in 1978 that 1.5 million children under the age of 5 years die due to diarrhoea every year, which declined to 0.6-0.7 million in the estimate revised in 1992. A similar declining trend has also been noted in hospitalized cases in Calcutta (present Kolkata) during 1980-95 as well as from other parts of India. Even today, cholera epidemics occur regularly in India. The cholera epidemic caused by a novel strain of Vibrio cholerae, designated as V. cholerae 0139 Bengal in 1992 and multidrug-resistant shigellosis in eastern India in 1984 are matters of grave concern. The launching of the National Diarrhoeal Diseases Control Programme (CDD) in 1978, based on a three-tier approach, is of great importance. The rate of use of oral rehydration salt (ORS) solution and oral rehydration therapy (ORT) remain suboptimal in India. In spite of the launching of the 'Ganga Action Plan' and the 'National River Action Plan', India faces a major problem of diarrhoeal diseases. Lack of safe water supply, poor environmental sanitation, improper disposal of human excreta and poor personal hygiene help to perpetuate and spread diarrhoeal diseases in India. Since diarrhoeal diseases are caused by 20-25 pathogens, vaccination, though an attractive disease prevention strategy, is not feasible. However, as the majority of childhood diarrhoeas are caused by V. cholerae, Shigellae dysenteriae type 1, rotavirus and enterotoxigenic Escherichia coli (E. coli) which have a high morbidity and mortality, vaccines against these organisms are essential for the control of epidemics. A strong political will with appropriate budgetary allocation is essential for the control of childhood diarrhoeal diseases in India, a formidable task in a country with a population of over 1 billion.

  13. Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism

    SciTech Connect

    Bartalena, L.; Marcocci, C.; Bogazzi, F.; Panicucci, M.; Lepri, A.; Pinchera, A. )

    1989-11-16

    We studied the effects of radioiodine treatment of hyperthyroidism due to Graves' disease on Graves' ophthalmopathy and the possible protective role of corticosteroids. Between June 1985 and June 1988, 26 patients were randomly assigned to treatment with radioiodine alone (group 1) and 26 to treatment with this agent and concomitant administration of systemic prednisone for four months (group 2). The initial dose of prednisone was 0.4 to 0.5 mg per kilogram of body weight for one month; the drug was gradually withdrawn over the next three months. All patients were evaluated at 3-month intervals for 18 months after they underwent radioiodine therapy. Ocular changes were assessed with the ophthalmopathy index; patients with moderate-to-severe changes (scores greater than or equal to 4) were excluded from the study. Before treatment, 10 patients in group 1 and 5 in group 2 had no evidence of ophthalmopathy: in none of them did ocular symptoms appear after radioiodine therapy. Among the patients in group 1 with an initial ophthalmopathy index greater than or equal to 1, ocular disease worsened in 56 percent (mostly involving soft-tissue changes and extraocular-muscle function) and did not change in 44 percent. In contrast, ophthalmopathy improved in 52 percent and did not change in 48 percent of group 2. The mean ophthalmopathy index increased from 1.5 to 3.0 in group 1 (P less than 0.005) and decreased from 2.2 to 1.3 in group 2 (P less than 0.05). We conclude that systemic corticosteroid treatment prevents the exacerbations of Graves' ophthalmopathy that occur after radioiodine therapy in a substantial proportion of patients with hyperthyroidism who have some degree of ocular involvement before treatment.

  14. Towards safe injection practices for prevention of hepatitis C transmission in South Asia: Challenges and progress

    PubMed Central

    Janjua, Naveed Zafar; Butt, Zahid Ahmad; Mahmood, Bushra; Altaf, Arshad

    2016-01-01

    AIM: To summarize the available information about injection use and its determinants in the South Asian region. METHODS: We searched published and unpublished literature on injection safety in South Asia published during 1995-2016 using the keywords “injection” “unsafe injection” and “immunization injection” and combined these with each of the countries and/or their respective states or provinces in South Asia. We used a standardized questionnaire to abstract the following data from the articles: the annual number of injections per capita, the proportion of injections administered with a reused syringe or needle, the distribution of injections with respect to prescribers and providers and determinants of injection use. RESULTS: Although information is very limited for certain countries (i.e., Bhutan, Maldives and Sri Lanka), healthcare injection use is very common across South Asia, with cross-country rates ranging from 2.4 to 13.6 injections/person/year. Furthermore, recent studies show that 5% to 50% of these injections are provided with reused syringes, thus creating potential to transmission of blood-borne pathogens. Qualified and unqualified practitioners, especially in the private sector, are the major drivers behind injection use, but patients also prefer injections, especially among the rural, poor or uneducated in certain countries. According to available data, Pakistan and India have recently taken steps towards achieving safe injection. Potential interventions include the introduction of reuse prevention devices, and patient-, community- and patient/community and provider-centered interventions to change population and practitioner behavior. CONCLUSION: Injection use is common in South Asian countries. Multilevel interventions aiming at patients, providers and the healthcare system are needed to reduce injection use and reuse. PMID:27433097

  15. Sclerostin antibody prevented progressive bone loss in combined ovariectomized and concurrent functional disuse.

    PubMed

    Zhang, Dongye; Hu, Minyi; Chu, Timothy; Lin, Liangjun; Wang, Jingyu; Li, Xiaodong; Ke, Hua Zhu; Qin, Yi-Xian

    2016-06-01

    Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator for bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study was to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25mg/kg were made twice per week for 5weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS+OVX (bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvements of various trabecular bone parameters (bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading.

  16. Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications

    PubMed Central

    Ohta, Shigeo

    2011-01-01

    Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H2) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H2 has a number of advantages as a potential antioxidant: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H2. There are several methods to ingest or consume H2, including inhaling hydrogen gas, drinking H2-dissolved water (hydrogen water), taking a hydrogen bath, injecting H2-dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H2 by bacteria. Since the publication of the first H2 paper in Nature Medicine in 2007, the biological effects of H2 have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H2 shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H2 regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H2 remain elusive. PMID:21736547

  17. Beyond cAMP: The Regulation of Akt and GSK3 by Dopamine Receptors

    PubMed Central

    Beaulieu, Jean-Martin; Del’Guidice, Thomas; Sotnikova, Tatyana D.; Lemasson, Morgane; Gainetdinov, Raul R.

    2011-01-01

    Brain dopamine receptors have been preferred targets for numerous pharmacological compounds developed for the treatment of various neuropsychiatric disorders. Recent discovery that D2 dopamine receptors, in addition to cAMP pathways, can engage also in Akt/GSK3 signaling cascade provided a new framework to understand intracellular signaling mechanisms involved in dopamine-related behaviors and pathologies. Here we review a recent progress in understanding the role of Akt, GSK3, and related signaling molecules in dopamine receptor signaling and functions. Particularly, we focus on the molecular mechanisms involved, interacting partners, role of these signaling events in the action of antipsychotics, psychostimulants, and antidepressants as well as involvement in pathophysiology of schizophrenia, bipolar disorder, and Parkinson’s disease. Further understanding of the role of Akt/GSK3 signaling in dopamine receptor functions could provide novel targets for pharmacological interventions in dopamine-related disorders. PMID:22065948

  18. Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research.

    PubMed Central

    Wogan, G N

    1992-01-01

    these changes are known to occur in chemically induced tumors of experimental animals, the possible role of chemical carcinogens in the induction of genetic abnormalities in human cancers has yet to be determined. Continuing investigations employing the methods of molecular epidemiology promise to provide further evidence concerning these relationships. Future investigations employing newly developed molecular biological methods, in particular those based on polymerase chain reaction amplification of DNA, to identify alterations in DNA and chromosomal structure, combined with methods for characterizing exposure to carcinogens and early effects, have great potential for further elucidating the role of genotoxic agents in the etiology of human cancers and also for the development of strategies for their prevention. PMID:1486846

  19. Transdermal delivery of dopamine receptor agonists.

    PubMed

    Reichmann, Heinz

    2009-12-01

    Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. Copyright 2009 Elsevier Ltd. All rights reserved.

  20. Laser treatment of drusen to prevent progression to advanced age-related macular degeneration

    PubMed Central

    Virgili, Gianni; Michelessi, Manuele; Parodi, Maurizio B; Bacherini, Daniela; Evans, Jennifer R

    2016-01-01

    Background Drusen are amorphous yellowish deposits beneath the sensory retina. People with drusen, particularly large drusen, are at higher risk of developing age-related macular degeneration (AMD). The most common complication in AMD is choroidal neovascularisation (CNV), the growth of new blood vessels in the centre of the macula. The risk of CNV is higher among people who are already affected by CNV in one eye. It has been observed clinically that laser photocoagulation of drusen leads to their disappearance and may prevent the occurrence of advanced disease (CNV or geographic atrophy) associated with visual loss. Objectives To examine the effectiveness and adverse effects of laser photocoagulation of drusen in AMD. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. Selection criteria Randomised controlled trials (RCTs) of laser treatment of drusen in AMD in which laser treatment had been compared with no intervention or sham treatment. Two types of trials were included. Some trials studied one eye of each participant (unilateral studies); other studies recruited participants with bilateral drusen and randomised one eye to photocoagulation or control and the fellow eye to the other group. Data collection and analysis Two review authors independently

  1. Blockade of dopamine D1-family receptors attenuates the mania-like hyperactive, risk-preferring, and high motivation behavioral profile of mice with low dopamine transporter levels.

    PubMed

    Milienne-Petiot, Morgane; Groenink, Lucianne; Minassian, Arpi; Young, Jared W

    2017-10-01

    Patients with bipolar disorder mania exhibit poor cognition, impulsivity, risk-taking, and goal-directed activity that negatively impact their quality of life. To date, existing treatments for bipolar disorder do not adequately remediate cognitive dysfunction. Reducing dopamine transporter expression recreates many bipolar disorder mania-relevant behaviors (i.e. hyperactivity and risk-taking). The current study investigated whether dopamine D1-family receptor blockade would attenuate the risk-taking, hypermotivation, and hyperactivity of dopamine transporter knockdown mice. Dopamine transporter knockdown and wild-type littermate mice were tested in mouse versions of the Iowa Gambling Task (risk-taking), Progressive Ratio Breakpoint Test (effortful motivation), and Behavioral Pattern Monitor (activity). Prior to testing, the mice were treated with the dopamine D1-family receptor antagonist SCH 23390 hydrochloride (0.03, 0.1, or 0.3 mg/kg), or vehicle. Dopamine transporter knockdown mice exhibited hyperactivity and hyperexploration, hypermotivation, and risk-taking preference compared with wild-type littermates. SCH 23390 hydrochloride treatment decreased premature responding in dopamine transporter knockdown mice and attenuated their hypermotivation. SCH 23390 hydrochloride flattened the safe/risk preference, while reducing activity and exploratory levels of both genotypes similarly. Dopamine transporter knockdown mice exhibited mania-relevant behavior compared to wild-type mice. Systemic dopamine D1-family receptor antagonism attenuated these behaviors in dopamine transporter knockdown, but not all effects were specific to only the knockdown mice. The normalization of behavior via blockade of dopamine D1-family receptors supports the hypothesis that D1 and/or D5 receptors could contribute to the mania-relevant behaviors of dopamine transporter knockdown mice.

  2. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. A genetic link between discriminative fear coding by the lateral amygdala, dopamine, and fear generalization.

    PubMed

    Jones, Graham L; Soden, Marta E; Knakal, Cerise R; Lee, Heather; Chung, Amanda S; Merriam, Elliott B; Zweifel, Larry S

    2015-09-24

    The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

  4. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones.

    PubMed

    Doyon, William M; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M; Zhang, Tao A; Dani, John A

    2013-08-07

    Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.

  5. Nicotine Decreases Ethanol-induced Dopamine Signaling and Increases Self-administration via Stress Hormones

    PubMed Central

    Doyon, William M.; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M.; Zhang, Tao A.; Dani, John A.

    2013-01-01

    SUMMARY Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement. PMID:23871233

  6. Vascular dopamine-I receptors and atherosclerosis.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J

    1997-01-01

    Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.

  7. Growth of dopamine crystals

    SciTech Connect

    Patil, Vidya Patki, Mugdha

    2016-05-06

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  8. Growth of dopamine crystals

    NASA Astrophysics Data System (ADS)

    Patil, Vidya; Patki, Mugdha

    2016-05-01

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  9. Updating dopamine reward signals

    PubMed Central

    Schultz, Wolfram

    2013-01-01

    Recent work has advanced our knowledge of phasic dopamine reward prediction error signals. The error signal is bidirectional, reflects well the higher order prediction error described by temporal difference learning models, is compatible with model-free and model-based reinforcement learning, reports the subjective rather than physical reward value during temporal discounting and reflects subjective stimulus perception rather than physical stimulus aspects. Dopamine activations are primarily driven by reward, and to some extent risk, whereas punishment and salience have only limited activating effects when appropriate controls are respected. The signal is homogeneous in terms of time course but heterogeneous in many other aspects. It is essential for synaptic plasticity and a range of behavioural learning situations. PMID:23267662

  10. Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression After Whole-Brain Irradiation

    PubMed Central

    Wong-Goodrich, Sarah J.E.; Pfau, Madeline L.; Flores, Catherine T.; Fraser, Jennifer A.; Williams, Christina L.; Jones, Lee W.

    2010-01-01

    Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention, and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to four months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting one month after sham- or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdU) immunolabeling and ELISA indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdU+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor, and occurred despite irradiation-induced elevations in hippocampal pro-inflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. PMID:20884629

  11. Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation.

    PubMed

    Wong-Goodrich, Sarah J E; Pfau, Madeline L; Flores, Catherine T; Fraser, Jennifer A; Williams, Christina L; Jones, Lee W

    2010-11-15

    Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. Copyright © 2010 AACR.

  12. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice

    PubMed Central

    Miyazaki, Tsuneyuki; Shirakami, Yohei; Kubota, Masaya; Ideta, Takayasu; Kochi, Takahiro; Sakai, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Shimizu, Masahito

    2016-01-01

    Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects. PMID:26871288

  13. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice.

    PubMed

    Miyazaki, Tsuneyuki; Shirakami, Yohei; Kubota, Masaya; Ideta, Takayasu; Kochi, Takahiro; Sakai, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Shimizu, Masahito

    2016-03-01

    Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects.

  14. Dopamine-Induced Conformational Changes in Alpha-Synuclein

    PubMed Central

    Outeiro, Tiago F.; Klucken, Jochen; Bercury, Kathryn; Tetzlaff, Julie; Putcha, Preeti; Oliveira, Luis M. A.; Quintas, Alexandre; McLean, Pamela J.; Hyman, Bradley T.

    2009-01-01

    Background Oligomerization and aggregation of α-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, α-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2], [3], [4]. A number of in vitro studies showed that dopamine can modulate the aggregation of α-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5], [6], [7]. Methodology/Principal Findings Here, we show that α-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in α-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in α-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance Our results show, for the first time, a direct effect of dopamine on the conformation of α-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease. PMID:19730729

  15. Photoaffinity ligand for dopamine D2 receptors: azidoclebopride

    SciTech Connect

    Niznik, H.B.; Guan, J.H.; Neumeyer, J.L.; Seeman, P.

    1985-02-01

    In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind (/sup 3/H)spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol.

  16. High levels of anti-Nef antibodies may prevent AIDS disease progression in vertically HIV-1-infected infants

    PubMed Central

    Corró, Guillermo; Crudeli, Cintia Milena; Rocco, Carlos Alberto; Marino, Silvia Alejandra; Sen, Luisa

    2014-01-01

    Introduction HIV-1-associated CD4+ T-cell depletion is a consequence of uninfected cell death. Nef is one of the viral factors that trigger apoptosis on bystander cells, though the plasma Nef levels do not correlate with Th lymphocytes counts. The aim of our study was to evaluate whether anti-Nef antibodies were involved in paediatric AIDS development and whether they can prevent the CD4+ T-cell depletion in vertically infected children. Methods Two hundred and seventy three HIV-1 vertically infected children seen at Garrahan Paediatric Hospital were randomly included in the study, adding 13 selected cases: seven LTNP (long-term non-progressors) and six RP (rapid progressors) children (n total=286). Specific anti-HIV-1-Nef antibodies were titrated by indirect ELISA and compared between groups. The plasma blocking effect on Nef-dependent cytotoxicity was evaluated in Jurkat cells using recombinant Nef as apoptotic stimulus and patient plasmas as blockers, measuring the apoptotic levels using Annexin-V stain and flow cytometry. Results Only 63.4% of the patients had specific anti-Nef antibodies, and the levels of anti-Nef antibodies found in the selected LTNPs plasmas were always significantly higher (p=1.55×10−4) than those in RPs or general HIV-1+ paediatric populations. The LTNPs’ plasma had a strong inhibitory effect on Nef-dependent cytotoxicity even at high dilutions, while RP plasmas had little or no effect on Nef-induced apoptosis. Discussion and conclusions High anti-Nef antibody levels are associated and predict slow or non-progression to AIDS in vertically HIV-1-infected children. They could be an efficient tool in preventing Nef-associated bystander effect, preserving CD4+ T-cells and the immune function in the context of paediatric HIV-1 infection. PMID:24560340

  17. Research progress on prevention and treatment of glucolipid metabolic disease with integrated traditional Chinese and Western medicine.

    PubMed

    Guo, Jiao

    2017-06-01

    Hyperlipidemia, type 2 diabetes mellitus, nonalcoholic fatty liver and many other metabolic disorder are frequently co-existing in patients. In addition, these diseases are closely related in pathophysiological settings. However, increasing of the disease incidence, lacking of comprehensive prevention and control measurements against the key pathology point concomitant occurrence with the pattern of the single disease, single target therapy, that is leading therapeutic strategy for these metabolic disorders in the setting of Western medicine (WM). On the basis of the combination of the advantages of integrated Chinese medicine (CM) and WM, with unified understanding of such diseases, the new concept of glucolipid metabolic disease (GLMD) is introduced. In this new concept, disorders in glucose and lipid metabolism are recognized as the key trigger and major driving force for the progress of GLMD. The key points of pathology included dysfunction of neuronal-endocrine-immune system, insulin resistance, oxidative stress, inflammation and intestinal flora imbalance. In the core pathogenic perspective of CM, it can be explained as "Gan (Liver) Shi Shu Xie" (dysfunction of Gan in metabolism and emotion regulation) that will lead to the occurence/production of endogenous dampness and phlegm, blood stasis and turbid. This leads to the new concept of "Liver-based regulatory system for metabolic homeostasis" to be introduced further. The comprehensive prevention and control strategy "Tiao Gan Qi Shu Hua Zhuo" (modulating Gan, trigging key metabolic system to resolve pathogenic factors such as phlegm retention and dampness). Its representative formula Fufang Zhenzhu Tiaozhi Capsule () is innovated under such rationales. Comment for some commonly-used CM GLMD therapeutic drugs was presented. High-level evidence-based and epidemiological and mechanism studies should be carried out to further interpret and explain of the scientific connotation of GLMD.

  18. Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats.

    PubMed

    Deminice, Rafael; Cella, Paola Sanches; Padilha, Camila S; Borges, Fernando H; da Silva, Lilian Eslaine Costa Mendes; Campos-Ferraz, Patrícia L; Jordao, Alceu Afonso; Robinson, Jason Lorne; Bertolo, Robert F; Cecchini, Rubens; Guarnier, Flávia Alessandra

    2016-08-01

    The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10(7) cells in 0.5 mL of PBS). The progressive increase (P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher (P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight (P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations.

  19. Dopamine receptor agonists for protection and repair in Parkinson's disease.

    PubMed

    Ferrari-Toninelli, Giulia; Bonini, Sara A; Cenini, Giovanna; Maccarinelli, Giuseppina; Grilli, Mariagrazia; Uberti, Daniela; Memo, Maurizio

    2008-01-01

    Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.

  20. Evaluating Progress in Radon Control Activities for Lung Cancer Prevention in National Comprehensive Cancer Control Program Plans, 2011-2015.

    PubMed

    Acree, Pascal; Puckett, Mary; Neri, Antonio

    2017-04-04

    Radon is the second leading cause of lung cancer among smokers and the leading cause among nonsmokers. The Centers for Disease Control and Prevention's National Comprehensive Cancer Control Program (NCCCP) funds every state, seven tribes, seven territories and the District of Columbia to develop formal cancer plans that focus efforts in cancer control. A 2010 review of cancer plans identified radon-related activities in 27 (42%) plans. Since then, 37 coalitions have updated their plans with new or revised cancer control objectives. There has also been recent efforts to increase awareness about radon among cancer coalitions. This study assesses NCCCP grantees current radon activities and changes since the 2010 review. We reviewed all 65 NCCCP grantee cancer plans created from 2005 to 2015 for radon related search terms and categorized plans by radon activities. The program's most recent annual progress report to CDC was also reviewed. We then compared the results from the updated plans with the findings from the 2010 review to assess changes in radon activities among cancer coalitions. Changes in state radon laws between 2010 and 2015 were also assessed. While a number of cancer plans have added or expanded radon-specific activities since 2010, approximately one-third of NCCCP grantees still do not include radon in their cancer plans. Cancer programs can consider addressing radon through partnership with existing radon control programs to further reduce the risk of lung cancer, especially among non-smokers.

  1. Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients.

    PubMed

    Lerner, Michael Zvi; Mor, Niv; Paek, Hyung; Blitzer, Andrew; Strome, Marshall

    2017-04-01

    Metformin is an oral anti-hyperglycemic agent used to treat type 2 diabetes mellitus (DM). In vitro and animal models have shown that metformin can prevent the progression of oral lesions to carcinoma; however, there is conflicting data in the clinical literature regarding risk reduction for malignancy in head and neck cancer (HNC). Case series. We present 3 cases in which adjuvant metformin therapy was used to treat recurrent and multifocal dysplastic lesions in previously treated nondiabetic HNC patients. Patients included 1 with a history of oral cavity squamous cell carcinoma (SCC) and 2 with a history of laryngeal SCC. Follow-up time ranged between 3 and 33 months. All 3 patients showed complete or partial regression of the remaining mucosal lesions and did not require any additional surgeries. We present 3 cases of nondiabetic HNC patients with field cancerization who showed a good response to adjuvant therapy with metformin. The nondiabetic population is not affected by confounding factors such as increased risk of malignancy and decreased overall survival that is itself associated with abnormal glucose metabolism and is therefore an excellent cohort in which to study the use of adjuvant metformin therapy in HNC patients.

  2. Evaluation of the implementation and impact of an integrated prevention model on the academic progress of students with disabilities.

    PubMed

    Barlow, Alexandra; Humphrey, Neil; Lendrum, Ann; Wigelsworth, Michael; Squires, Garry

    2014-11-12

    In this paper we report on the implementation and impact of an integrated prevention model (Achievement for All - AfA) to improve the educational experiences and outcomes of students with disabilities. It comprises three inter-related strands: assessment, tracking and intervention; structured conversations with parents; and, developing provision for wider outcomes. Participants were 12,038 students with disabilities from 431 mainstream primary and secondary schools across 10 Local Authorities in England involved in the two-year AfA pilot. Pre- and post-test data on academic attainment in English and Maths were compared with national data on academic progress for students with and without disabilities over an equivalent period of time. School-level contextual and implementation data and student-level socio-demographic and psychosocial data were also collected. Four hypotheses were tested regarding the impact of AfA on academic attainment in English (H1) and Maths (H2); the influence of aspects of the implementation context and processes (H3); and individual differences between students (H4). Our findings are discussed in relation to the identification and validation of critical intervention components and standards for assessing the practical significance of attempts to improve outcomes for students.

  3. Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration.

    PubMed

    Qi, Xiaoping; Pay, S Louise; Yan, Yuanqing; Thomas, James; Lewin, Alfred S; Chang, Lung-Ji; Grant, Maria B; Boulton, Michael E

    2017-04-05

    Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis. Importantly, electroretinography and optokinetic response tests confirmed that visual function was significantly improved. Mice treated with non-modified BMDCs or BMDCs pre-programmed with LacZ did not exhibit significant improvement in visual deficit. RPE65-BMDC administration was most effective in early disease, when visual function and retinal morphology returned to near normal, and less effective in late-stage disease. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential to arrest progression in early AMD and other RPE-based diseases.

  4. Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats.

    PubMed

    Almomen, Salwa M K; Guan, Qiunong; Liang, Peihe; Yang, Kaidi; Sidiqi, Ahmad M; Levin, Adeera; Du, Caigan

    2017-03-31

    Individuals living with metabolic syndrome (MetS) such as diabetes and obesity are at high risk for developing chronic kidney disease (CKD). This study investigated the beneficial effect of whole grape powder (WGP) diet on MetS-associated CKD. Obese diabetic ZSF1 rats, a kidney disease model with MetS, were fed WGP (5%, w/w) diet for six months. Kidney disease was determined using blood and urine chemical analyses, and histology. When compared to Vehicle controls, WGP intake did not change the rat bodyweight, but lowered their kidney, liver and spleen weight, which were in parallel with the lower serum glucose and the higher albumin or albumin/globin ratio. More importantly, WGP intake improved the renal function as urination and proteinuria decreased, or it prevented kidney tissue damage in these diabetic rats. The renal protection of WGP diet was associated with up-regulation of antioxidants (Dhcr24, Gstk1, Prdx2, Sod2, Gpx1 and Gpx4) and downregulation of Txnip (for ROS production) in the kidneys. Furthermore, addition of grape extract reduced H₂O₂-induced cell death of cultured podocytes. In conclusion, daily intake of WGP reduces the progression of kidney disease in obese diabetic rats, suggesting a protective function of antioxidant-rich grape diet against CKD in the setting of MetS.

  5. Diabetic nephropathy: preventing progression

    PubMed Central

    2010-01-01

    Introduction Up to one third of people with type 1 or 2 diabetes will develop microalbuminuria or macroalbuminuria after 20 years. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with type 1 diabetes and early nephropathy? What are the effects of treatments in people with type 1 diabetes and late nephropathy? What are the effects of treatments in people with type 2 diabetes and early nephropathy? What are the effects of treatments in people with type 2 diabetes and late nephropathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, glycaemic control, protein restriction, and tight control of blood pressure. PMID:21418671

  6. PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension

    PubMed Central

    2014-01-01

    Abstract The platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)- and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4 ± 2.6 mmHg in the vehicle MCT group (n = 6), 44.4 ± 5.8 mmHg in the D4 MCT group (n = 6), and 37.1 ± 4.5 mmHg in the D8 MCT group (n = 5; P < 0.001 vs. vehicle); RVSP was 75.7 ± 7.1 mmHg in the vehicle MCT+PN group (n = 9), 40.4 ± 2.7 mmHg in the D4 MCT+PN group (n = 10), and 43.0 ± 3.0 mmHg in the D8 MCT+PN group (n = 8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGFβ receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGFα receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGFα and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGFα and PDGFβ receptors may have a therapeutic advantage over selective PDGFα receptor inhibition in PAH. PMID:25006424

  7. Development and function of the midbrain dopamine system: what we know and what we need to.

    PubMed

    Bissonette, G B; Roesch, M R

    2016-01-01

    The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study.

  8. Development and function of the midbrain dopamine system: what we know and what we need to

    PubMed Central

    Bissonette, G. B.; Roesch, M. R.

    2017-01-01

    The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson’s disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study. PMID:26548362

  9. Cyclooxygenase-independent neuroprotective effects of aspirin against dopamine quinone-induced neurotoxicity.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko

    2012-09-01

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

  10. [Long-term efficacy of laser peripheral iridotomy in preventing progression in eyes with pigment dispersion syndrome].

    PubMed

    Qing, Guoping; Zhang, Shaodan; Wang, Huaizhou; Wang, Tao; Wang, Shuhua; Chen, Hong; Wang, Hua; Wang, Ningli

    2014-07-01

    To evaluate the long-term efficacy of laser peripheral iridotomy (LPI) in preventing deterioration in eyes with pigment dispersion syndrome (PDS). A cohort study. Nineteen patients with PDS were treated with LPI and followed up periodically in Beijing Tongren Eye Center from May 2006 to April 2007. One eye of each patient was chosen randomly for the study. Main investigating items included iris configuration, intraocular pressure (IOP), anterior chamber pigmentation, and visual field analysis. The average follow-up period was (6.5 ± 0.3) years. A paired sample t test was used to determine whether there is a significant difference between average values of pre- and post-LPI IOP and mean deviation of Humphrey visual field analysis in these PDS eyes. The average age of the 19 patients were (35.8 ± 7.1) years on admission. The initial IOP of the 19 eyes was (24.7 ± 2.2) mmHg (1 mmHg = 0.133 kPa) before LPI. The mean deviation (MD) of Humphrey visual field analysis (VFA) were (-1.82 ± 1.26) dB (-4.34--0.28 dB) . All 19 eyes had concave iris and heavy trabecular pigmentation. The iris became flat in all PDS eyes after the laser treatment. At the last follow-up visit, the average IOP was 14.8 ± 2.0 (12-20) mmHg, which was statistically lower than that of baseline (t = 11.49, P < 0.01) . Extent of trabecular pigmentation reduced obviously in 16 eyes. No deterioration or new visual field defect was detected in any of the PDS eyes. MD of the last VFA was -1.79 ± 1.21 (-4.39--0.21 dB) . There was no statistical difference between MD of the last VFA and baseline (t = -0.26, P = 0.798). The long-term follow-up results showed that LPI prevents progression effectively in eyes with PDS.

  11. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.

    PubMed

    Burt, Richard K; Cohen, Bruce A; Russell, Eric; Spero, Kenneth; Joshi, Akash; Oyama, Yu; Karpus, William J; Luo, Kehuan; Jovanovic, Borko; Traynor, Ann; Karlin, Karyn; Stefoski, Dusan; Burns, William H

    2003-10-01

    There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.

  12. [Corneal collagen cross-linking novel technique for prevention of keratoconus progression: results after one-year at the Sheba Medical Center].

    PubMed

    Berger, Yoav; Ezra-Nimni, Orit; Skaat, Alon; Fogel, Miri; Grinbaum, Aaron; Barequet, Irina

    2015-02-01

    Keratoconus is a progressive corneal degenerative disease that appears in young adults and causes progressive myopia and irregular astigmatism affecting visual acuity. The quality of life may be severely impaired in these young adults. Corneal Collagen Cross-Linking (CXL) is a novel technique aimed at stopping disease progression. To evaluate the refractive and topographic outcome 12 months after CXL treatment in patients with progressive keratoconus. In this retrospective case series, 15 eyes of 14 patients with progressive keratoconus were treated with standard CXL. Patients were assessed preoperatively, at week 1 and at months 1, 3, 6, and 12 after treatment. Outcome measures included best-corrected visual acuity (BCVA) refraction, biomicroscopy and fundus examination, corneal topography and pachymetry. Comparing the preoperative data with 12 months postoperative results, we observed stabilization of the average keratometry values 51.2 to 50.67 (diopters), P = 0.605. The BCVA values remained stable 0.47 to 0.57 (decimal point) P = 0.6626. Our series of patients with progressive keratoconus supports the effect of crosslinking to prevent disease progression. Regularization of the corneal keratometry values and minor improvement of the visual acuity may be additional benefits of this procedure.

  13. Complexity of dopamine metabolism

    PubMed Central

    2013-01-01

    Parkinson’s disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability. In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD. PMID:23683503

  14. Strategic Prevention Framework State Incentive Grant Progress Report: Building a Sustainable Substance Abuse Prevention System, State of Hawai'i, 2006-2010

    ERIC Educational Resources Information Center

    Yuan, S.; Lai, M.C.; Heusel, K.

    2011-01-01

    In 2006, the Hawai'i State Department of Health (DOH) received the Strategic Prevention Framework State Incentive Grant (SPF-SIG) from the Substance Abuse and Mental Health Services Administration (SAMHSA) to establish a comprehensive, coordinated, and sustainable substance abuse prevention infrastructure in Hawai'i. The SPF-SIG Project is funded…

  15. Strategic Prevention Framework State Incentive Grant Progress Report: Building a Sustainable Substance Abuse Prevention System, State of Hawai'i, 2006-2010

    ERIC Educational Resources Information Center

    Yuan, S.; Lai, M.C.; Heusel, K.

    2011-01-01

    In 2006, the Hawai'i State Department of Health (DOH) received the Strategic Prevention Framework State Incentive Grant (SPF-SIG) from the Substance Abuse and Mental Health Services Administration (SAMHSA) to establish a comprehensive, coordinated, and sustainable substance abuse prevention infrastructure in Hawai'i. The SPF-SIG Project is funded…

  16. New trends in the electrochemical sensing of dopamine.

    PubMed

    Jackowska, Krystyna; Krysinski, Pawel

    2013-04-01

    Since the early 70s electrochemistry has been used as a powerful analytical technique for monitoring electroactive species in living organisms. In particular, after extremely rapid evolution of new micro and nanotechnology it has been established as an invaluable technique ranging from experiments in vivo to measurement of exocytosis during communication between cells under in vitro conditions. This review highlights recent advances in the development of electrochemical sensors for selective sensing of one of the most important neurotransmitters--dopamine. Dopamine is an electroactive catecholamine neurotransmitter, abundant in the mammalian central nervous system, affecting both cognitive and behavioral functions of living organisms. We have not attempted to cover a large time-span nor to be comprehensive in presenting the vast literature devoted to electrochemical dopamine sensing. Instead, we have focused on the last five years, describing recent progress as well as showing some problems and directions for future development.

  17. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    PubMed

    Razgado-Hernandez, Luis F; Espadas-Alvarez, Armando J; Reyna-Velazquez, Patricia; Sierra-Sanchez, Arturo; Anaya-Martinez, Veronica; Jimenez-Estrada, Ismael; Bannon, Michael J; Martinez-Fong, Daniel; Aceves-Ruiz, Jorge

    2015-01-01

    The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring

  18. Treatment with acetylsalicylic acid prevents short to mid-term radiographic progression of nontraumatic osteonecrosis of the femoral head: a pilot study

    PubMed Central

    Albers, Anthony; Carli, Alberto; Routy, Bertrand; Harvey, Edward J.; Séguin, Chantal

    2015-01-01

    Background Nontraumatic osteonecrosis of the femoral head (ONFH) is a progressive disease in young adults producing substantial morbidity and frequently resulting in total hip arthroplasty. Although hip-preserving surgical procedures represent the current mainstay of treatment for early disease, medical therapies targeting specific pathways in the ONFH pathogenesis could help prevent disease progression while producing less morbidity. Acetylsalicylic acid (ASA) is a promising alternative to other therapies for ONFH owing to its anti-inflammatory and antithrombotic mechanisms of action and its relatively benign side effect profile. Methods We followed a prospective cohort of 10 patients (12 hips) with precollapse ONFH who were given ASA to prevent disease progression. Their outcomes were compared with those of a historic control group taken from the literature. Results Progression occurred in 1 of 12 (8%) patients taking ASA compared with 30 of 45 (66.6%) controls (p = 0.002) at a mean follow-up of 3.7 years. Patients taking ASA also tended to exhibit decreased femoral head involvement at the end of therapy. Conclusion This hypothesis-generating study leads us to believe that ASA may be a simple and effective treatment option for delaying disease progression in patients with early-stage ONFH. PMID:26011853

  19. Does dopamine connect the dots in ADPKD?

    PubMed

    Chapman, Arlene B

    2015-02-01

    Healthy autosomal dominant polycystic kidney disease (ADPKD) patients with normal kidney function demonstrate reduced endothelial-dependent vasodilation that improves with increasing local dopamine levels. Dopamine regulates renal sodium excretion, and dopamine receptors are located on primary cilia in both vascular and renal tubular epithelial cells. The study by Lorthioir and colleagues links endothelial function and dopamine availability in ADPKD patients.

  20. In Situ Controlled Release of Dopamine for Treatment of Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Lopez, Tessy; Ortiz, Emma; Kozina, Anna; Esquivel, Dulce; Espinoza, Karla

    2013-09-01

    Parkinson's disease (PD) is a progressive, neurodegenerative disorder of the central nervous system. The primary symptoms of PD result from greatly reduced activity of dopamine-secreting cells due to cell death in the pars compacta region of the substantia nigra. The loss of dopamine as a result of death of dopamine neurons accounts for most of the movementrelated symptoms of the disease. There is no cure for Parkinson's disease, but medications can provide relief from the symptoms. Since dopamine cannot cross the hemathoencephalic barrier, the drug delivery to the brain remains a big challenge. In this chapter we will discuss a novel way of dopamine release in situ from inorganic nanostructured reservoirs that may be potentially used in PD treatment.

  1. Dopamine receptors set the pattern of activity generated in subthalamic neurons.

    PubMed

    Baufreton, J; Zhu, Z-T; Garret, M; Bioulac, B; Johnson, S W; Taupignon, A I

    2005-11-01

    Information processing in the brain requires adequate background neuronal activity. As Parkinson's disease progresses, patients typically become akinetic; the death of dopaminergic neurons leads to a dopamine-depleted state, which disrupts information processing related to movement in a brain area called the basal ganglia. Using agonists of dopamine receptors in the D1 and D2 families on rat brain slices, we show that dopamine receptors in these two families govern the firing pattern of neurons in the subthalamic nucleus, a crucial part of the basal ganglia. We propose a conceptual frame, based on specific properties of dopamine receptors, to account for the dominance of different background firing patterns in normal and dopamine-depleted states.

  2. High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients

    PubMed Central

    2013-01-01

    Background Metabolic acidosis leads to chronic kidney disease (CKD) progression. The guidelines recommend a lower limit of serum bicarbonate level, but no upper limit. For serum bicarbonate level to be clinically useful as a therapeutic target marker, it is necessary to investigate the target serum bicarbonate level within the normal range to prevent CKD progression. Methods One hundred and thirteen elderly CKD patients, whose serum bicarbonate level was controlled within the normal range, were enrolled in this retrospective cohort study in Ibaraki, Japan. Outcome was defined as a decrease of 25% or more in estimated glomerular filtration rate (eGFR) or starting dialysis. We used Cox proportional hazard models adjusted for patients’ characteristics to examine the association between serum bicarbonate level and the outcome. Results Female patients were 36.3%: average age (SD), 70.4 (6.6) years; eGFR, 25.7 (13.6) ml/min/1.73 m2; serum bicarbonate level, 27.4 (3.2) mEq/l. Patients with the lowest quartile of serum bicarbonate levels [23.4 (1.8) mEq/l] showed a high risk of CKD progression compared with patients with high serum bicarbonate levels [28.8 (2.3) mEq/l]: adjusted hazard ratio (HR), 3.511 (95% CI, 1.342-9.186). A 1 mEq/l increase in serum bicarbonate level was associated with a low risk of CKD progression: adjusted HR, 0.791 [95% confidence interval (CI), 0.684-0.914]. Conclusions In elderly CKD patients, our findings suggest that serum bicarbonate level is independently associated with CKD progression, and that a high serum bicarbonate level is associated with a low risk of CKD progression. A high target serum bicarbonate level within the normal range may be effective for preventing CKD progression. PMID:23298330

  3. High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients.

    PubMed

    Kanda, Eiichiro; Ai, Masumi; Yoshida, Masayuki; Kuriyama, Renjiro; Shiigai, Tatsuo

    2013-01-09

    Metabolic acidosis leads to chronic kidney disease (CKD) progression. The guidelines recommend a lower limit of serum bicarbonate level, but no upper limit. For serum bicarbonate level to be clinically useful as a therapeutic target marker, it is necessary to investigate the target serum bicarbonate level within the normal range to prevent CKD progression. One hundred and thirteen elderly CKD patients, whose serum bicarbonate level was controlled within the normal range, were enrolled in this retrospective cohort study in Ibaraki, Japan. Outcome was defined as a decrease of 25% or more in estimated glomerular filtration rate (eGFR) or starting dialysis. We used Cox proportional hazard models adjusted for patients' characteristics to examine the association between serum bicarbonate level and the outcome. Female patients were 36.3%: average age (SD), 70.4 (6.6) years; eGFR, 25.7 (13.6) ml/min/1.73 m(2); serum bicarbonate level, 27.4 (3.2) mEq/l. Patients with the lowest quartile of serum bicarbonate levels [23.4 (1.8) mEq/l] showed a high risk of CKD progression compared with patients with high serum bicarbonate levels [28.8 (2.3) mEq/l]: adjusted hazard ratio (HR), 3.511 (95% CI, 1.342-9.186). A 1 mEq/l increase in serum bicarbonate level was associated with a low risk of CKD progression: adjusted HR, 0.791 [95% confidence interval (CI), 0.684-0.914]. In elderly CKD patients, our findings suggest that serum bicarbonate level is independently associated with CKD progression, and that a high serum bicarbonate level is associated with a low risk of CKD progression. A high target serum bicarbonate level within the normal range may be effective for preventing CKD progression.

  4. Repeated Exposure to Methamphetamine, Cocaine or Morphine Induces Augmentation of Dopamine Release in Rat Mesocorticolimbic Slice Co-Cultures

    PubMed Central

    Nakagawa, Takayuki; Suzuki, Yuichi; Nagayasu, Kazuki; Kitaichi, Maiko; Shirakawa, Hisashi; Kaneko, Shuji

    2011-01-01

    Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1–1000 µM), cocaine (0.1–300 µM) or morphine (0.1–100 µM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1–1000 µM) had little effect. Following repeated exposure to methamphetamine (10 µM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1–300 µM) or morphine (10 and 100 µM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 µM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA

  5. Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism.

    PubMed

    Brown, Abigail M; Deutch, Ariel Y; Colbran, Roger J

    2005-07-01

    Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKIIalpha) at Thr286, a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIalpha or other synaptic proteins. Dopamine depletion decreased CaMKIIalpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr34, but increased DARPP-32 phosphorylation at Thr75. Levodopa administration reversed the increased phosphorylation of both CaMKIIalpha and DARPP-32. Normal ageing increased the levels of PP1(gamma1 isoform) but decreased levels of the PP1gamma1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIalpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKIIalpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.

  6. [Effectiveness of various dopamine doses in acute myocardial ischemia complicated by cardiogenic shock (an experimental study)].

    PubMed

    Kipshidze, N N; Korotkov, A A; Marsagishvili, L A; Prigolashvili, T Sh; Bokhua, M R

    1981-06-01

    The effect of various doses of dopamine on the values of cardiac contractile and hemodynamic function under conditions of acute two-hour ischemia complicated by cardiogenic shock was studied in 27 experiments on dogs. In a dose of 5 microgram/kg/min dopamine caused an optimum increase in cardiac productive capacity, reduction of peripheral resistance, adequate increase in coronary circulation and decrease in ST segment depression on the ECG. Infusion of 10 microgram/kg/min dopamine usually caused myocardial hyperfunction with an increase in total peripheral resistance and cardiac performance. Maximum dopamine doses (10 microgram/kg/min and more) were effective in the areactive form of cardiogenic shock. In longterm dopamine infusion it is necessary to establish continuous control over the hemodynamic parameters and the ECG to prevent aggravation of ischemia and for stage-by-stage reduction of the drug concentration and determination of the minimum maintenance dose.

  7. What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

    PubMed Central

    Nishijima, Haruo; Tomiyama, Masahiko

    2016-01-01

    Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease. PMID:28018168

  8. Dopamine reward prediction error coding

    PubMed Central

    Schultz, Wolfram

    2016-01-01

    Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

  9. Dopamine reward prediction error coding.

    PubMed

    Schultz, Wolfram

    2016-03-01

    Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.

  10. Effectiveness of initial treatment allocation based on expert opinion for prevention of rapid radiographic progression in daily practice of an early RA cohort.

    PubMed

    Durnez, Anne; Vanderschueren, Geert; Lateur, Luc; Westhovens, René; Verschueren, Patrick

    2011-04-01

    To evaluate expert treatment selection for early rheumatoid arthritis and to validate a prediction model for rapid radiographic progression (RRP) in daily practice. Patients received initial combination therapy with steroids (ICTS) or disease-modifying antirheumatic drug monotherapy (IMT) after informal evaluation of prognostic factors, followed by a tight control strategy. Changes in Sharp/van der Heijde score (total Sharp score (TSS)) of >5 units over 1 year (=RRP) were documented. The mean change in TSS and proportion with RRP were compared between groups. Based on the 28 swollen joint count, rheumatoid factor titre and C reactive protein/erythrocyte sedimentation rate, patients were placed in the ASPIRE prediction matrix, yielding a RRP risk. Numbers needed to treat (NNT) intensively to avoid one RRP after 1 year were calculated. The mean change in TSS after 1 year and the proportion with RRP was lower in the ICTS group (n=37) than in the IMT group (n=43). The mean calculated risk of RRP was higher in patients with radiographic progression. The mean NNT intensively to prevent RRP was lower in the ICTS group than in the IMT group. The positive predictive value of NNT for RRP prevention was 12.6%, but the negative predictive value reached 100%. ICTS seems more effective in preventing RRP than IMT. The predictive matrix model could be helpful in preventing overtreatment in practice.

  11. Dopamine, Affordance and Active Inference

    PubMed Central

    Friston, Karl J.; Shiner, Tamara; FitzGerald, Thomas; Galea, Joseph M.; Adams, Rick; Brown, Harriet; Dolan, Raymond J.; Moran, Rosalyn; Stephan, Klaas Enno; Bestmann, Sven

    2012-01-01

    The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level. PMID:22241972

  12. Ih Current Is Necessary to Maintain Normal Dopamine Fluctuations and Sleep Consolidation in Drosophila

    PubMed Central

    Gonzalo-Gomez, Alicia; Turiegano, Enrique; León, Yolanda; Molina, Isabel; Torroja, Laura; Canal, Inmaculada

    2012-01-01

    HCN channels are becoming pharmacological targets mainly in cardiac diseases. But apart from their well-known role in heart pacemaking, these channels are widely expressed in the nervous system where they contribute to the neuron firing pattern. Consequently, abolishing Ih current might have detrimental consequences in a big repertoire of behavioral traits. Several studies in mammals have identified the Ih current as an important determinant of the firing activity of dopaminergic neurons, and recent evidences link alterations in this current to various dopamine-related disorders. We used the model organism Drosophila melanogaster to investigate how lack of Ih current affects dopamine levels and the behavioral consequences in the sleep∶activity pattern. Unlike mammals, in Drosophila there is only one gene encoding HCN channels. We generated a deficiency of the DmIh core gene region and measured, by HPLC, levels of dopamine. Our data demonstrate daily variations of dopamine in wild-type fly heads. Lack of Ih current dramatically alters dopamine pattern, but different mechanisms seem to operate during light and dark conditions. Behaviorally, DmIh mutant flies display alterations in the rest∶activity pattern, and altered circadian rhythms. Our data strongly suggest that Ih current is necessary to prevent dopamine overproduction at dark, while light input allows cycling of dopamine in an Ih current dependent manner. Moreover, lack of Ih current results in behavioral defects that are consistent with altered dopamine levels. PMID:22574167

  13. Dynamic Nigrostriatal Dopamine Biases Action Selection.

    PubMed

    Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

    2017-03-22

    Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions.

    PubMed

    Goñi-Allo, Beatriz; Ramos, Mar'a; Herv'as, Isabel; Lasheras, Berta; Aguirre, Norberto

    2006-03-01

    The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

  15. Pharmacological evidence for common mechanisms underlying the effects of neurotensin and neuroleptics on in vivo dopamine efflux in the rat nucleus accumbens.

    PubMed

    Blaha, C D; Phillips, A G

    1992-08-01

    The effects of the neuropeptide neurotensin and the typical neuroleptic haloperidol on dopamine efflux were compared in the posteromedial nucleus accumbens of the chloral hydrate-anesthetized rat using in vivo chronoamperometry. Both neurotensin and haloperidol administration elicited an immediate increase in dopamine efflux in the nucleus accumbens. Gamma-hydroxybutyric acid lactone, an agent known to block impulse flow in dopamine neurons, either prevented when given before neurotensin or reversed neurotensin-induced increases in accumbens dopamine efflux. Haloperidol-induced increases in accumbens dopamine efflux were similarly affected by gamma-hydroxybutyric acid lactone. The dopamine receptor agonist apomorphine reversed neurotensin- and haloperidol-induced increases in dopamine efflux. Amphetamine, administered during the peak dopamine stimulatory effects induced by neurotensin or haloperidol, resulted in increases above baseline which were significantly greater than the effects of amphetamine alone. These combined drug treatment effects on baseline dopamine efflux were additive, indicating that the effects of amphetamine were not potentiated by neurotensin or haloperidol pretreatments. These in vivo results suggest that neurotensin and haloperidol may augment dopamine efflux in the nucleus accumbens via common mechanisms of action which may involve activation of mesotelencephalic dopamine neuronal firing. The inability of neurotensin to block amphetamine-induced efflux in the nucleus accumbens further suggests that neurotensin blockade of amphetamine-elicited locomotor activity is mediated by an action of neurotensin postsynaptic to dopamine nerve terminals in the nucleus accumbens.

  16. Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review.

    PubMed

    Yin, John; Barr, Alasdair M; Ramos-Miguel, Alfredo; Procyshyn, Ric M

    2017-01-01

    Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

  17. Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review

    PubMed Central

    Yin, John; Barr, Alasdair M.; Ramos-Miguel, Alfredo; Procyshyn, Ric M.

    2017-01-01

    Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes. PMID:27264948

  18. Imaging of Brain Dopamine Pathways

    PubMed Central

    Wang, Gene-Jack; Volkow, Nora D.; Thanos, Panayotis K.; Fowler, Joanna S.

    2011-01-01

    Obesity is typically associated with abnormal eating behaviors. Brain imaging studies in humans implicate the involvement of dopamine (DA)-modulated circuits in pathologic eating behavior(s). Food cues increase striatal extracellular DA, providing evidence for the involvement of DA in the nonhedonic motivational properties of food. Food cues also increase metabolism in the orbitofrontal cortex indicating the association of this region with the motivation for food consumption. Similar to drug-addicted subjects, striatal DA D2 receptor availability is reduced in obese subjects, which may predispose obese subjects to seek food as a means to temporarily compensate for understimulated reward circuits. Decreased DA D2 receptors in the obese subjects are also associated with decreased metabolism in prefrontal regions involved in inhibitory control, which may underlie their inability to control food intake. Gastric stimulation in obese subjects activates cortical and limbic regions involved with self-control, motivation, and memory. These brain regions are also activated during drug craving in drug-addicted subjects. Obese subjects have increased metabolism in the somatosensory cortex, which suggests an enhanced sensitivity to the sensory properties of food. The reduction in DA D2 receptors in obese subjects coupled with the enhanced sensitivity to food palatability could make food their most salient reinforcer putting them at risk for compulsive eating and obesity. The results from these studies suggest that multiple but similar brain circuits are disrupted in obesity and drug addiction and suggest that strategies aimed at improving DA function might be beneficial in the treatment and prevention of obesity. PMID:21603099

  19. Pyrethroid pesticide-induced alterations in dopamine transporter function

    SciTech Connect

    Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W. . E-mail: gary.miller@emory.edu

    2006-03-15

    Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 {mu}M) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 {mu}M) or 24 h (1, 5, and 10 {mu}M) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.

  20. A Role for Accumbal Glycine Receptors in Modulation of Dopamine Release by the Glycine Transporter-1 Inhibitor Org25935

    PubMed Central

    Lidö, Helga Höifödt; Ericson, Mia; Marston, Hugh; Söderpalm, Bo

    2010-01-01

    Accumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc) as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935–ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol's effects within this system. PMID:21556278

  1. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism.

    PubMed

    Tanda, G; Pontieri, F E; Di Chiara, G

    1997-06-27

    The effects of the active ingredient of Cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. Delta9-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Delta9-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of micro1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, Delta9-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common mu1 opioid receptor mechanism located in the ventral mesencephalic tegmentum.

  2. Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.

    PubMed

    Sikiric, P; Separovic, J; Buljat, G; Anic, T; Stancic-Rokotov, D; Mikus, D; Duplancic, B; Marovic, A; Zoricic, I; Prkacin, I; Lovric-Bencic, M; Aralica, G; Ziger, T; Perovic, D; Jelovac, N; Dodig, G; Rotkvic, I; Mise, S; Seiwerth, S; Turkovic, B; Grabarevic, Z; Petek, M; Rucman, R

    2000-01-01

    Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either

  3. Dopamine as a novel antioxidative agent for rat vascular smooth muscle cells through dopamine D(1)-like receptors.

    PubMed

    Yasunari, K; Kohno, M; Kano, H; Minami, M; Yoshikawa, J

    2000-05-16

    To elucidate the roles of vascular D(1)-like receptors in atherosclerosis, the effects of the specific D(1)-like agonists on platelet-derived growth factor (PDGF)-BB-mediated oxidative stress in vascular smooth muscle cells (VSMCs) were studied. Immunohistochemical studies demonstrated the coexistence of D(1A) and D(1B) dopamine receptors in VSMCs. Western blotting revealed a band of approximately 70 kDa for D(1A) and D(1B) dopamine receptors. VSMCs stimulated by PDGF-BB exhibited increased oxidative stress directly measured by flow cytometry. These effects were prevented by dopamine, SKF 38393, or YM 435, and this prevention was reversed by Sch 23390. These effects were blocked by a specific protein kinase A (PKA) inhibitor, N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H 89). The PDGF-BB-mediated increase in oxidative stress of VSMCs was significantly suppressed by the indirect phospholipase D (PLD) inhibitor suramin or the specific protein kinase C (PKC) inhibitor calphostin C. Both antisense but neither sense nor scrambled oligonucleotides to D(1A) and D(1B) receptors inhibited dopamine-induced suppression of increase in oxidative stress of VSMCs induced by PDGF-BB. These findings suggest that vascular D(1)-like receptors (D(1A) and D(1B) receptors) inhibit any increase in oxidative stress of VSMCs, possibly through activation of PKA and suppression of PLD and PKC.

  4. Dopamine Receptors and Neurodegeneration

    PubMed Central

    Rangel-Barajas, Claudia; Coronel, Israel; Florán, Benjamín

    2015-01-01

    Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases. PMID:26425390

  5. The science of youth violence prevention. Progressing from developmental epidemiology to efficacy to effectiveness to public policy.

    PubMed

    Dodge, K A

    2001-01-01

    Public policy in the United States has historically considered youth violence as a moral problem to be punished after the fact, but growing scientific evidence supports a public health perspective on violent behavior as an interaction between cultural forces and failures in development. Prevention science has provided a bridge between an understanding of how chronic violence develops and how prevention programs can interrupt that development. Articles in this journal supplement provide yet another bridge between efficacious university-based programs and effective community-based programs. It is suggested that yet one more bridge will need to be constructed in future research between community-based programs that are known to be effective and community-wide implementation of prevention efforts at full scale. This last bridge integrates the science of children's development, the science of prevention, and the science of public policy.

  6. Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma.

    PubMed

    Lattier, John M; Yang, Hua; Crawford, Susan; Grossniklaus, Hans E

    2013-12-01

    Uveal melanoma (UM) has a 30 % 5-year mortality rate, primarily due to liver metastasis. Both angiogenesis and stromagenesis are important mechanisms for the progression of liver metastasis. Pigment epithelium-derived factor (PEDF), an anti-angiogenic and anti-stromagenic protein, is produced by hepatocytes. Exogenous PEDF suppresses metastasis progression; however, the effects of host-produced PEDF on metastasis progression are unknown. We hypothesize that host PEDF inhibits liver metastasis progression through a mechanism involving angiogenesis and stromagenesis. Mouse melanoma cells were injected into the posterior ocular compartment of PEDF-null mice and control mice. After 1 month, the number, size, and mean vascular density (MVD) of liver metastases were determined. The stromal component of hepatic stellate cells (HSCs) and the type III collagen they produce was evaluated by immunohistochemistry. Host PEDF inhibited the total area of liver metastasis and the frequency of macrometastases (diameter >200 μm) but did not affect the total number of metastases. Mice expressing PEDF exhibited significantly lower MVD and less type III collagen production in metastases. An increase in activated HSCs was seen in the absence of PEDF, but this result was not statistically significant. In conclusion, host PEDF inhibits the progression of hepatic metastases in a mouse model of UM, and loss of PEDF is accompanied by an increase in tumor blood vessel density and type III collagen.

  7. Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation.

    PubMed

    Bernichtein, Sophie; Pigat, Natascha; Barry Delongchamps, Nicolas; Boutillon, Florence; Verkarre, Virginie; Camparo, Philippe; Reyes-Gomez, Edouard; Méjean, Arnaud; Oudard, Stéphane M; Lepicard, Eve M; Viltard, Mélanie; Souberbielle, Jean-Claude; Friedlander, Gérard; Capiod, Thierry; Goffin, Vincent

    2017-01-15

    Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca(2+) resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355-65. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. Glycemic control with insulin prevents progression of dental caries and caries-related periodontitis in diabetic WBN/KobSlc rats.

    PubMed

    Nakahara, Yutaka; Sano, Tomoya; Kodama, Yasushi; Ozaki, Kiyokazu; Matsuura, Tetsuro

    2013-07-01

    We have previously reported that dental caries progress in spontaneously and chemically induced diabetic rodent models. The aim of this study was to clarify the relationship between hyperglycemia and dental caries by evaluating the preventive effect of glycemic control with insulin on the progression of the lesions in diabetic rats. Male WBN/KobSlc rats aged 15 weeks were divided into groups of spontaneously diabetic rats (intact group), spontaneously diabetic rats with insulin treatment (INS group), alloxan-induced prolonged diabetic rats (AL group), and alloxan-induced prolonged diabetic rats with insulin treatment (AL + INS group). The animals were killed at 90 weeks of age, and their oral tissue was examined. Dental caries and periodontitis were frequently detected in the intact group, and the lesions were enhanced in the AL group (in which there was an increased duration of diabetes). Meanwhile, glycemic control with insulin reduced the incidence and severity of dental caries and periodontitis in the INS group, and the effects became more pronounced in the AL + INS group. In conclusion, glycemic control by insulin prevented the progression of dental caries and caries-related periodontitis in the diabetic rats.

  9. Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet.

    PubMed

    Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Wang, Hongqin; Dinh, Chi H L; Huang, Xu-Feng

    2016-01-05

    Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. In vivo vulnerability of dopamine neurons to inhibition of energy metabolism.

    PubMed

    Zeevalk, G D; Manzino, L; Hoppe, J; Sonsalla, P

    1997-02-12

    In vitro studies indicate that mesencephalic dopamine neurons are more vulnerable than other neurons to impairment of energy metabolism. Such findings may have bearing on the loss of dopamine neurons in Parkinson's disease, in which mitochondrial deficiencies have been identified, but would only be relevant if the selective vulnerability were maintained in vivo. To examine this, rats were stereotaxically administered various concentrations of the succinate dehydrogenase inhibitor, malonate (0.25-4 mumol), either into the left substantia nigra or striatum. One week following injection, dopamine and gamma-aminobutyric acid (GABA) levels in the mesencephalon and striatum were measured. Intranigral injection of malonate caused nigral dopamine and GABA to be comparably reduced at all doses tested. The 50% dose level for malonate vs. dopamine and GABA loss was 0.39 and 0.42 mumol, respectively. Tyrosine hydroxylase immunocytochemistry of the midbrains of rats which received an intranigral injection of malonate showed normal staining with 0.25 mumol malonate, but almost complete loss of tyrosine hydroxylase positive nigral pars compacta cells with 1 mumol malonate. Intrastriatal injection of malonate produced a loss of both tyrosine hydroxylase activity and dopamine. In contrast to what was seen in substantia nigra, there was a greater loss of dopamine than GABA in striatal regions nearest the injection site. In striatal regions most distal to the injection site, and which received the lowest concentration of malonate due to diffusion, dopamine levels were significantly reduced with all doses of malonate (0.5-4 mumol), whereas GABA levels were unaffected. Intrastriatal coinfusion of succinate along with malonate completely prevented the loss of dopamine and GABA indicating that succinate dehydrogenase inhibition was the cause of toxicity. These findings indicate that dopamine terminals in the striatum of adult rats are selectively more vulnerable than are the GABA neurons

  11. Dopamine, reward learning, and active inference

    PubMed Central

    FitzGerald, Thomas H. B.; Dolan, Raymond J.; Friston, Karl

    2015-01-01

    Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings. PMID:26581305

  12. Dopamine regulates body size in Caenorhabditis elegans.

    PubMed

    Nagashima, Takashi; Oami, Eitaro; Kutsuna, Natsumaro; Ishiura, Shoichi; Suo, Satoshi

    2016-04-01

    The nervous system plays a critical role in the regulation of animal body sizes. In Caenorhabditis elegans, an amine neurotransmitter, dopamine, is required for the tactile perception of food and food-dependent behavioral changes, while its role in development is unknown. In this study, we show that dopamine negatively regulates body size through a D2-like dopamine receptor, DOP-3, in C. elegans. Dopamine alters body size without affecting food intake or developmental rate. We also found that dopamine promotes egg-laying, although the regulation of body size by dopamine was not solely caused by this effect. Furthermore, dopamine negatively regulates body size through the suppression of signaling by octopamine and Gq-coupled octopamine receptors, SER-3 and SER-6. Our results demonstrate that dopamine and octopamine regulate the body size of C. elegans and suggest a potential role for perception in addition to ingestion of food for growth.

  13. Diet-induced obesity: dopamine transporter function, impulsivity and motivation

    PubMed Central

    Narayanaswami, V; Thompson, AC; Cassis, LA; Bardo, MT; Dwoskin, LP

    2013-01-01

    OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The

  14. Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

    PubMed

    Narayanaswami, V; Thompson, A C; Cassis, L A; Bardo, M T; Dwoskin, L P

    2013-08-01

    A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that

  15. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.

    PubMed

    Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András

    2011-04-08

    Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

  16. Cost-effectiveness of anti-oxidant vitamins plus zinc treatment to prevent the progression of intermediate age-related macular degeneration. A Singapore perspective

    PubMed Central

    Saxena, Nakul; George, Pradeep Paul; Heng, Bee Hoon; Lim, Tock Han; Yong, Shao Onn

    2015-01-01

    Purpose: To determine if providing high dose anti-oxidant vitamins and zinc treatment age-related eye disease study (AREDS formulation) to patients with intermediate age-related macular degeneration (AMD) aged 40–79 years from Singapore is cost-effective in preventing progression to wet AMD. Methods: A hypothetical cohort of category 3 and 4 AMD patients from Singapore was followed for 5 calendar years to determine the number of patients who would progress to wet AMD given the following treatment scenarios: (a) AREDS formulation or placebo followed by ranibizumab (as needed) for wet AMD. (b) AREDS formulation or placebo followed by bevacizumab (monthly) for wet AMD. (c) AREDS formulation or placebo followed by aflibercept (VIEW I and II trial treatment regimen). Costs were estimated for the above scenarios from the providers’ perspective, and cost-effectiveness was measured by cost per disability-adjusted life year (DALY) averted with a disability weight of 0.22 for wet AMD. The costs were discounted at an annual rate of 3%. Results: Over 5400 patients could be prevented from progressing to wet AMD cumulatively if AREDS formulation were prescribed. AREDS formulation followed by ranibizumab was cost-effective compared to placebo-ranibizumab or placebo-aflibercept combinations (cost per DALY averted: SGD$23,662.3 and SGD$21,138.8, respectively). However, bevacizumab (monthly injections) alone was more cost-effective compared to AREDS formulation followed by bevacizumab. Conclusion: Prophylactic treatment with AREDS formulation for intermediate AMD patients followed by ranibizumab or for patients who progressed to wet AMD was found to be cost-effective. These findings have implications for intermediate AMD screening, treatment and healthcare planning in Singapore. PMID:26265643

  17. Cost-effectiveness of anti-oxidant vitamins plus zinc treatment to prevent the progression of intermediate age-related macular degeneration. A Singapore perspective.

    PubMed

    Saxena, Nakul; George, Pradeep Paul; Heng, Bee Hoon; Lim, Tock Han; Yong, Shao Onn

    2015-06-01

    To determine if providing high dose anti-oxidant vitamins and zinc treatment age-related eye disease study (AREDS formulation) to patients with intermediate age-related macular degeneration (AMD) aged 40-79 years from Singapore is cost-effective in preventing progression to wet AMD. A hypothetical cohort of category 3 and 4 AMD patients from Singapore was followed for 5 calendar years to determine the number of patients who would progress to wet AMD given the following treatment scenarios: (a) AREDS formulation or placebo followed by ranibizumab (as needed) for wet AMD. (b) AREDS formulation or placebo followed by bevacizumab (monthly) for wet AMD. (c) AREDS formulation or placebo followed by aflibercept (VIEW I and II trial treatment regimen). Costs were estimated for the above scenarios from the providers' perspective, and cost-effectiveness was measured by cost per disability-adjusted life year (DALY) averted with a disability weight of 0.22 for wet AMD. The costs were discounted at an annual rate of 3%. Over 5400 patients could be prevented from progressing to wet AMD cumulatively if AREDS formulation were prescribed. AREDS formulation followed by ranibizumab was cost-effective compared to placebo-ranibizumab or placebo-aflibercept combinations (cost per DALY averted: SGD$23,662.3 and SGD$21,138.8, respectively). However, bevacizumab (monthly injections) alone was more cost-effective compared to AREDS formulation followed by bevacizumab. Prophylactic treatment with AREDS formulation for intermediate AMD patients followed by ranibizumab or for patients who progressed to wet AMD was found to be cost-effective. These findings have implications for intermediate AMD screening, treatment and healthcare planning in Singapore.

  18. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

    PubMed Central

    Hansen, Freja H.; Skjørringe, Tina; Yasmeen, Saiqa; Arends, Natascha V.; Sahai, Michelle A.; Erreger, Kevin; Andreassen, Thorvald F.; Holy, Marion; Hamilton, Peter J.; Neergheen, Viruna; Karlsborg, Merete; Newman, Amy H.; Pope, Simon; Heales, Simon J.R.; Friberg, Lars; Law, Ian; Pinborg, Lars H.; Sitte, Harald H.; Loland, Claus; Shi, Lei; Weinstein, Harel; Galli, Aurelio; Hjermind, Lena E.; Møller, Lisbeth B.; Gether, Ulrik

    2014-01-01

    Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies. PMID:24911152

  19. Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas.

    PubMed

    Costello, Leslie C; Franklin, Renty B

    2017-01-01

    Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered: 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion: ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large.

  20. Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

    PubMed Central

    Costello, Leslie C.; Franklin, Renty B.

    2016-01-01

    Introduction Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large. PMID:27885880

  1. Chaotic behavior in dopamine neurodynamics.

    PubMed Central

    King, R; Barchas, J D; Huberman, B A

    1984-01-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of mood in some patients with an affective disorder. Moreover our hypothesis offers specific results concerning the appearance or disappearance of erratic solutions as a function of k and the external input to the dopamine neuronal system. PMID:6583705

  2. Chaotic behavior in dopamine neurodynamics.

    PubMed

    King, R; Barchas, J D; Huberman, B A

    1984-02-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of mood in some patients with an affective disorder. Moreover our hypothesis offers specific results concerning the appearance or disappearance of erratic solutions as a function of k and the external input to the dopamine neuronal system.

  3. Effects of dopamine on LC3-II activation as a marker of autophagy in a neuroblastoma cell model.

    PubMed

    Giménez-Xavier, Pol; Francisco, Roser; Santidrián, Antonio F; Gil, Joan; Ambrosio, Santiago

    2009-07-01

    Dopamine at 100-500 microM has toxic effects on human SH-SY5Y neuroblastoma cells, manifested as apoptotic cell loss and strong autophagy. The molecular mechanisms and types of dopamine-induced cell death are not yet well known. Their identification is important in the study of neurodegenerative diseases that specifically involve dopaminergic neurons. We looked for changes in expression and content of proteins involved in apoptosis and autophagy after dopamine treatment. All the changes found were prevented by avoiding dopamine oxidation with N-acetylcysteine, indicating a key role for the products of dopamine oxidation in dopamine toxicity. As early as 1-2h after treatment we found an increase in hypoxia-inducible factor-1alpha (HIF-1alpha) and an accumulation of ubiquitinated proteins. Proteins regulated by HIF-1alpha and involved in apoptosis and/or autophagy, such as p53, Puma and Bnip3, were subsequently increased. However, apoptotic parameters (caspase-3, caspase-7, PARP) were only activated after 12h of 500muM dopamine treatment. Autophagy, monitored by the LC3-II increase after LC3-I linkage to autophagic vacuoles, was evident after 6h of treatment with both 100 and 500 microM dopamine. The mTOR pathway was inhibited by dopamine, probably due to the intracellular redox changes and energy depletion leading to AMPK activation. However, this mechanism is not sufficient to explain the high LC3-II activation caused by dopamine: the LC3-II increase was not reversed by IGF-1, which prevented this effect when caused by the mTOR inhibitor rapamycin. Our results suggest that the aggregation of ubiquitinated non-degraded proteins may be the main cause of LC3-II activation and autophagy. As we have reported previously, cytosolic dopamine may cause damage by autophagy in neuroblastoma cells (and presumably in dopaminergic neurons), which develops to apoptosis and leads to cell degeneration.

  4. Will PEDF Therapy Reverse Chronic Demyelination and Prevent Axon Loss in a Murine Model of Progressive Multiple Sclerosis

    DTIC Science & Technology

    2015-12-01

    Multiple Sclerosis ? PRINCIPAL INVESTIGATOR: David Pleasure MD CONTRACTING ORGANIZATION: University of California Davis, CA 95618 REPORT DATE...Murine Model of Progressive Multiple Sclerosis ? 5b. GRANT NUMBER W81XWH-12-1-0566 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Pleasure MD 5d...enhance central nervous system (CNS) remyelination and preserve CNS axons in mouse models of multiple sclerosis models. After determining the dosage of

  5. Cortical regulation of dopamine depletion-induced dendritic spine loss in striatal medium spiny neurons.

    PubMed

    Neely, M D; Schmidt, D E; Deutch, A Y

    2007-10-26

    The proximate cause of Parkinson's disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson's disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures composed of ventral mesencephalon, striatum, and cortex of the neonatal rat, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson's disease.

  6. Endogenous dopamine is involved in the herbicide paraquat-induced dopaminergic cell death.

    PubMed

    Izumi, Yasuhiko; Ezumi, Masayuki; Takada-Takatori, Yuki; Akaike, Akinori; Kume, Toshiaki

    2014-06-01

    The herbicide paraquat is an environmental factor that may be involved in the etiology of Parkinson's disease (PD). Systemic exposure of mice to paraquat causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta, although paraquat is not selectively incorporated in dopaminergic neurons. Here, we report a contribution of endogenous dopamine to paraquat-induced dopaminergic cell death. Exposure of PC12 cells to paraquat (50μM) caused delayed toxicity from 36 h onward. A decline in intracellular dopamine content achieved by inhibiting tyrosine hydroxylase (TH), an enzyme for dopamine synthesis, conferred resistance to paraquat toxicity on dopaminergic cells. Paraquat increased the levels of cytosolic and vesicular dopamine, accompanied by transiently increased TH activity. Quinone derived from cytosolic dopamine conjugates with cysteine residues in functional proteins to form quinoproteins. Formation of quinoprotein was transiently increased early during exposure to paraquat. Furthermore, pretreatment with ascorbic acid, which suppressed the elevations of intracellular dopamine and quinoprotein, almost completely prevented paraquat toxicity. These results suggest that the elevation of cytosolic dopamine induced by paraquat participates in the vulnerability of dopaminergic cells to delayed toxicity through the formation of quinoproteins.

  7. Cortical Regulation of Dopamine Depletion-Induced Dendritic Spine Loss in Striatal Medium Spiny Neurons

    PubMed Central

    Neely, M. Diana; Schmidt, Dennis E.; Deutch, Ariel Y.

    2007-01-01

    The proximate cause of Parkinson’s Disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson’s Disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures comprised of ventral mesencephalon, striatum, and cortex, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin MPP+ or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson’s Disease. PMID:17888581

  8. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours.

    PubMed

    Sim, Hye-Ri; Choi, Tae-Yong; Lee, Hyo Jin; Kang, Eun Young; Yoon, Sehyoun; Han, Pyung-Lim; Choi, Se-Young; Baik, Ja-Hyun

    2013-01-01

    Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

  9. Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys.

    PubMed

    Morin, Nicolas; Jourdain, Vincent A; Morissette, Marc; Grégoire, Laurent; Di Paolo, Thérèse

    2014-04-01

    Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. MPTP monkeys treated with l-DOPA + MPEP developed significantly less LID than MPTP monkeys treated with l-DOPA alone. [(3)H]SCH-23390 specific binding to D1 receptors of all MPTP monkeys was decreased as compared to controls in the basal ganglia and no difference was observed between all MPTP groups, while striatal D1 receptor mRNA levels remained unchanged. [(3)H]raclopride specific binding to striatal D2 receptors and mRNA levels of D2 receptors were increased in MPTP monkeys compared to controls; l-DOPA treatment reduced this binding in MPTP monkeys while it remained elevated with the l-DOPA + MPEP treatment. Striatal [(3)H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3β levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.

  10. Dopamine effects on identified rat vagal motoneurons

    PubMed Central

    Zheng, Zhongling; Travagli, R. Alberto

    2011-01-01

    Catecholaminergic neurons of the A2 area play a prominent role in brain stem vagal circuits. It is not clear, however, whether these neurons are noradrenergic or adrenergic, i.e., display tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DβH) immunoreactivity (-IR) or dopaminergic (i.e., TH- but not DβH-IR). Our aims were to investigate whether a subpopulation of neurons in the A2 area was dopaminergic and, if so, to investigate the effects of dopamine (DA) on the membrane of gastric-projecting vagal motoneurons. We observed that although the majority of A2 neurons were both TH- and DβH-IR, a small percentage of nucleus tractus solitarius neurons were TH-IR only, suggesting that DA itself may play role in these circuits. Whole cell recordings from thin brain stem slices showed that 71% of identified gastric-projecting motoneurons responded to DA (1–300 µM) with either an excitation (28%) or an inhibition (43%) of the membrane; the remaining 29% of the neurons were unresponsive. The DA-induced depolarization was mimicked by SK 38393 and prevented by pretreatment with SCH 23390. Conversely, the DA-induced inhibition was mimicked by bromoergocryptine and prevented by pretreatment with L741626. When tested on the same neuron, the effects of DA and NE were not always similar. In fact, in neurons in which DA induced a membrane depolarization, 77% were inhibited by NE, whereas 75% of neurons unresponsive to DA were inhibited by NE. Our data suggest that DA modulates the membrane properties of gastric-projecting motoneurons via D1- and D2-like receptors, and DA may play different roles than norepinephrine in brain stem vagal circuits. PMID:17170022

  11. Low dose of insulin detemir controls glycaemia, insulinemia and prevents diabetes mellitus progression in the dog with pituitary-dependent hyperadrenocorticism.

    PubMed

    Miceli, D D; Gallelli, M F; Cabrera Blatter, M F; Martiarena, B; Brañas, M M; Ortemberg, L R; Gómez, N V; Castillo, V A

    2012-08-01

    Diabetes is often associated with pituitary-dependent hyperadrenocorticism (PDH). Hypercortisolism causes insulin resistance and affects β-cell function. The purpose of this study was to test if daily administration of a long-acting insulin analogue during the first month of anti-PDH treatment can prevent progress to diabetes in these animals. Twenty-six PDH dogs were divided into three groups: one group with glycaemia <5.83 mmol/L and two groups with glycaemia >5.83 mmol/L and <9.35 mmol/L, one of which received insulin detemir during 4 months. Dogs with glycaemia <5.83 mmol/L and those with glycaemia >5.83 mmol/L which received insulin did not develop diabetes. In the non-insulin group, 6/7 dogs developed diabetes after the third month. There is a 13-fold higher risk of diabetes in dogs with glycaemia >5.83 mmol/L and no insulin treatment. Administering insulin detemir to dogs with PDH and glycaemia >5.83 mmol/L could prevent progression to diabetes.

  12. [Impact of sleep deprivation on coronary heart disease and progress in prevention and treatment with traditional Chinese medicines].

    PubMed

    Yuan, Rong; Wang, Jie; Guo, Li-li

    2015-05-01

    Sleep deprivation (SD) has been taken as an independent predictor for cardiovascular risks, which was closely related to the increased morbidity and mortality in coronary heart disease (CHD). In this article, after reviewing the impact of modern medical method sleep deprivation on CHD and studies on principle method recipe medicines for preventing and treating CHD, the authors observed the autonomic nerve dysfunction, hormonal metabolism dysfunction, endothelial dysfunction and inflammatory responses after sleep deprivation, which can cause or aggravate CHD. On the basis of the traditional Chinese medicine theories of "heart dominating the blood and vessels and the mind", the authors considered that traditional Chinese medicines can tonify heart and soothe the nerves, reducing all of the risk factors through multi-target and multi-pathway, and improve sleep and decrease the risk factors caused by sleep deprivation, which provides a new idea for the prevention and treatment of CHD.

  13. Rare sugar D-psicose prevents progression and development of diabetes in T2DM model Otsuka Long-Evans Tokushima Fatty rats.

    PubMed

    Hossain, Akram; Yamaguchi, Fuminori; Hirose, Kayoko; Matsunaga, Toru; Sui, Li; Hirata, Yuko; Noguchi, Chisato; Katagi, Ayako; Kamitori, Kazuyo; Dong, Youyi; Tsukamoto, Ikuko; Tokuda, Masaaki

    2015-01-01

    The fundamental cause of overweight and obesity is consumption of calorie-dense foods. We have introduced a zero-calorie sweet sugar, d-psicose (d-allulose), a rare sugar that has been proven to have strong antihyperglycemic and antihyperlipidemic effects, and could be used as a replacement of natural sugar for the obese and diabetic subjects. Above mentioned efficacy of d-psicose (d-allulose) has been confirmed in our previous studies on type 2 diabetes mellitus (T2DM) model Otsuka Long-Evans Tokushima Fatty (OLETF) rats with short-term treatment. In this study we investigated the long-term effect of d-psicose in preventing the commencement and progression of T2DM with the mechanism of preservation of pancreatic β-cells in OLETF rats. Treated OLETF rats were fed 5% d-psicose dissolved in water and control rats only water. Nondiabetic control rats, Long-Evans Tokushima Otsuka (LETO), were taken as healthy control and fed water. To follow the progression of diabetes, periodic measurements of blood glucose, plasma insulin, and body weight changes were continued till sacrifice at 60 weeks. Periodic in vivo body fat mass was measured. On sacrifice, pancreas, liver, and abdominal adipose tissues were collected for various staining tests. d-Psicose prevented the commencement and progression of T2DM till 60 weeks through the maintenance of blood glucose levels, decrease in body weight gain, and the control of postprandial hyperglycemia, with decreased levels of HbA1c in comparison to nontreated control rats. This improvement in glycemic control was accompanied by the maintenance of plasma insulin levels and the preservation of pancreatic β-cells with the significant reduction in inflammatory markers. Body fat accumulation was significantly lower in the treatment group, with decreased infiltration of macrophages in the abdominal adipose tissue. Our findings suggest that the rare sugar d-psicose could be beneficial for the prevention and control of obesity and

  14. Rare sugar d-psicose prevents progression and development of diabetes in T2DM model Otsuka Long-Evans Tokushima Fatty rats

    PubMed Central

    Hossain, Akram; Yamaguchi, Fuminori; Hirose, Kayoko; Matsunaga, Toru; Sui, Li; Hirata, Yuko; Noguchi, Chisato; Katagi, Ayako; Kamitori, Kazuyo; Dong, Youyi; Tsukamoto, Ikuko; Tokuda, Masaaki

    2015-01-01

    Background The fundamental cause of overweight and obesity is consumption of calorie-dense foods. We have introduced a zero-calorie sweet sugar, d-psicose (d-allulose), a rare sugar that has been proven to have strong antihyperglycemic and antihyperlipidemic effects, and could be used as a replacement of natural sugar for the obese and diabetic subjects. Aim Above mentioned efficacy of d-psicose (d-allulose) has been confirmed in our previous studies on type 2 diabetes mellitus (T2DM) model Otsuka Long-Evans Tokushima Fatty (OLETF) rats with short-term treatment. In this study we investigated the long-term effect of d-psicose in preventing the commencement and progression of T2DM with the mechanism of preservation of pancreatic β-cells in OLETF rats. Methods Treated OLETF rats were fed 5% d-psicose dissolved in water and control rats only water. Nondiabetic control rats, Long-Evans Tokushima Otsuka (LETO), were taken as healthy control and fed water. To follow the progression of diabetes, periodic measurements of blood glucose, plasma insulin, and body weight changes were continued till sacrifice at 60 weeks. Periodic in vivo body fat mass was measured. On sacrifice, pancreas, liver, and abdominal adipose tissues were collected for various staining tests. Results d-Psicose prevented the commencement and progression of T2DM till 60 weeks through the maintenance of blood glucose levels, decrease in body weight gain, and the control of postprandial hyperglycemia, with decreased levels of HbA1c in comparison to nontreated control rats. This improvement in glycemic control was accompanied by the maintenance of plasma insulin levels and the preservation of pancreatic β-cells with the significant reduction in inflammatory markers. Body fat accumulation was significantly lower in the treatment group, with decreased infiltration of macrophages in the abdominal adipose tissue. Conclusion Our findings suggest that the rare sugar d-psicose could be beneficial for the

  15. The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

    PubMed

    Howes, Oliver D; McCutcheon, Robert; Owen, Michael J; Murray, Robin M

    2017-01-01

    The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  16. Phasic Dopamine Transmission Reflects Initiation Vigor and Exerted Effort in an Action- and Region-Specific Manner

    PubMed Central

    Ko, Daijin

    2016-01-01

    Initiating a reward-seeking behavior involves deciding on an action, how fast to initiate the action (initiation vigor), as well as how much effort to exert. These processes are thought to involve the mesolimbic dopamine system. Dopamine levels in the ventral striatum rise before initiating a reliably reinforced behavior. However, it is unknown whether dopamine is similarly involved with unreinforced actions (inactive lever presses, premature food port entries, insufficient number of active lever presses). Furthermore, does the dopamine response when initiating an action reflect specific aspects of motivated behavior, such as initiation vigor and exerted effort? Here, we analyzed voltammetry recordings of dopamine levels in the nucleus accumbens (NAcc) core and shell in rats working for food under a progressive ratio reinforcement schedule. We examined dopamine levels when rats initiated distinct actions (active lever presses, inactive lever presses, food port entries) that were temporally separated from cue- and reward-evoked dopamine release. Active lever pressing bouts were preceded by elevated dopamine release in the NAcc shell, as well as in the NAcc core, although only when rats exhibited high initiation vigor. Dopamine levels were transiently reduced in the NAcc core following an unreinforced food port entry and were unchanged throughout the NAcc when initiating inactive lever presses. The effort exerted and vigor to initiate a bout of active lever presses were signaled by dopamine transmission in the NAcc core, but not in the NAcc shell. These results demonstrate that the dopamine response when initiating a behavior is both region- and action-specific. SIGNIFICANCE STATEMENT Exogenous activation of the mesolimbic dopamine system facilitates motivated behavior. However, a direct relationship has not been established between endogenous phasic dopamine transmission and measures of motivation, such as the vigor to initiate an action and the effort exerted in a

  17. Phasic Dopamine Transmission Reflects Initiation Vigor and Exerted Effort in an Action- and Region-Specific Manner.

    PubMed

    Ko, Daijin; Wanat, Matthew J

    2016-02-17

    Initiating a reward-seeking behavior involves deciding on an action, how fast to initiate the action (initiation vigor), as well as how much effort to exert. These processes are thought to involve the mesolimbic dopamine system. Dopamine levels in the ventral striatum rise before initiating a reliably reinforced behavior. However, it is unknown whether dopamine is similarly involved with unreinforced actions (inactive lever presses, premature food port entries, insufficient number of active lever presses). Furthermore, does the dopamine response when initiating an action reflect specific aspects of motivated behavior, such as initiation vigor and exerted effort? Here, we analyzed voltammetry recordings of dopamine levels in the nucleus accumbens (NAcc) core and shell in rats working for food under a progressive ratio reinforcement schedule. We examined dopamine levels when rats initiated distinct actions (active lever presses, inactive lever presses, food port entries) that were temporally separated from cue- and reward-evoked dopamine release. Active lever pressing bouts were preceded by elevated dopamine release in the NAcc shell, as well as in the NAcc core, although only when rats exhibited high initiation vigor. Dopamine levels were transiently reduced in the NAcc core following an unreinforced food port entry and were unchanged throughout the NAcc when initiating inactive lever presses. The effort exerted and vigor to initiate a bout of active lever presses were signaled by dopamine transmission in the NAcc core, but not in the NAcc shell. These results demonstrate that the dopamine response when initiating a behavior is both region- and action-specific. Exogenous activation of the mesolimbic dopamine system facilitates motivated behavior. However, a direct relationship has not been established between endogenous phasic dopamine transmission and measures of motivation, such as the vigor to initiate an action and the effort exerted in a bout of activity. The

  18. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

    PubMed

    Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

    2015-07-01

    High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

  19. Brain-derived neurotrophic factor-dependent cdk1 inhibition prevents G2/M progression in differentiating tetraploid neurons.

    PubMed

    Ovejero-Benito, María C; Frade, José M

    2013-01-01

    Neurodegeneration is often associated with DNA synthesis in neurons, the latter usually remaining for a long time as tetraploid cells before dying by apoptosis. The molecular mechanism preventing G2/M transition in these neurons remains unknown, but it may be reminiscent of the mechanism that maintains tetraploid retinal ganglion cells (RGCs) in a G2-like state during normal development, thus preventing their death. Here we show that this latter process, known to depend on brain-derived neurotrophic factor (BDNF), requires the inhibition of cdk1 by TrkB. We demonstrate that a subpopulation of chick RGCs previously shown to become tetraploid co-expresses TrkB and cdk1 in vivo. By using an in vitro system that recapitulates differentiation and cell cycle re-entry of chick retinal neurons we show that BDNF, employed at concentrations specific for the TrkB receptor, reduces the expression of cdk1 in TrkB-positive, differentiating neurons. In this system, BDNF also inhibits the activity of both endogenous cdk1 and exogenously-expressed cdk1/cyclin B1 complex. This inhibition correlates with the phosphorylation of cdk1 at Tyr15, an effect that can be prevented with K252a, a tyrosine kinase inhibitor commonly used to prevent the activity of neurotrophins through their Trk receptors. The effect of BDNF on cdk1 activity is Tyr15-specific since BDNF cannot prevent the activity of a constitutively active form of cdk1 (Tyr15Phe) when expressed in differentiating retinal neurons. We also show that BDNF-dependent phosphorylation of cdk1 at Tyr15 could not be blocked with MK-1775, a Wee1-selective inhibitor, indicating that Tyr15 phosphorylation in cdk1 does not seem to occur through the canonical mechanism observed in proliferating cells. We conclude that the inhibition of both expression and activity of cdk1 through a BDNF-dependent mechanism contributes to the maintenance of tetraploid RGCs in a G2-like state.

  20. Unpolished Thai rice prevents ACF formation and dysplastic progression in AOM-induced rats and induces apoptosis through redox alteration in CaCo-2 cells.

    PubMed

    Tammasakchai, Achiraya; Chaiyasut, Chaiyavat; Riengrojpitak, Suda; Suwannalert, Prasit

    2015-01-01

    Oxidative stress is associated with colon carcinogenesis including aberrant crypt foci (ACF) formation and it plays an important role in pathophysiological changes in cancer cells. The aims of this study were to investigate the effects of dietary unpolished Thai rice (UTR) on ACF formation and dysplastic progression in azoxymethane (AOM)-treated rats. Anti-cancer efficacy of UTR regarding apoptotic induction and oxidative redox status in human colon cancer (CaCo-2) cells was also investigated. Rats given 20% and 70% of UTR in the diet showed significantly and dose-dependently decreased total number of ACF. UTR treatment also was strongly associated with the low percentage of dysplastic progression and mucin depletion. In addition, we found that UTR significantly induced cancer cell apoptosis, increased cellular oxidants, and decreased the level of GSH/GSSG ratio in CaCo-2 cells. Our study suggests that UTR supplementation may be a useful strategy for CRC prevention with the inhibition of precancerous progression, with induction of cancer cell apoptosis through redox alteration.

  1. Can the use of low-dose dopamine for treatment of acute renal failure be justified?

    PubMed

    Burton, C J; Tomson, C R

    1999-05-01

    The use of dopamine for the prevention and treatment of acute renal failure is widespread. Its use is based on physiology suggesting selective renal vasodilation when it is infused at low dose. This article reviews the available data on the clinical use of dopamine. When used to prevent acute renal failure in high-risk treatments there is no evidence of benefit of dopamine but, given the low incidence of significant renal failure, the studies are underpowered. In treatment of acute renal failure, the quality of the data is poor. Only in one small randomised trial of moderate acute renal failure in patients with malaria was a clinically significant benefit of dopamine shown. The rest of the data, in the form of case series, showed either no benefit of dopamine or small benefits of little clinical significance. Again, these studies are of insufficient power for conclusions to be drawn as to the overall benefits and risks. We conclude that benefits of dopamine use cannot be ruled out by currently available data but its use cannot be advised until trials examining clinically important endpoints in large numbers of patients have been performed.

  2. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

    PubMed

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-10-05

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.

  3. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

    PubMed Central

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-01-01

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

  4. Dopamine transients are sufficient and necessary for acquisition of model-based associations.

    PubMed

    Sharpe, Melissa J; Chang, Chun Yun; Liu, Melissa A; Batchelor, Hannah M; Mueller, Lauren E; Jones, Joshua L; Niv, Yael; Schoenbaum, Geoffrey

    2017-04-03

    Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

  5. Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President's Emergency Plan for AIDS Relief.

    PubMed

    Chi, Benjamin H; Adler, Michelle R; Bolu, Omotayo; Mbori-Ngacha, Dorothy; Ekouevi, Didier K; Gieselman, Anna; Chipato, Tsungai; Luo, Chewe; Phelps, B Ryan; McClure, Craig; Mofenson, Lynne M; Stringer, Jeffrey S A

    2012-08-15

    In June 2011, the Joint United Nations Programme on HIV/AIDS, the US President's Emergency Plan for AIDS Relief (PEPFAR), and other collaborators outlined a transformative plan to virtually eliminate pediatric AIDS worldwide. The ambitious targets of this initiative included a 90% reduction in new pediatric HIV infections and a 50% reduction in HIV-related maternal mortality--all by 2015. PEPFAR has made an unprecedented commitment to the expansion and improvement of prevention of mother-to-child HIV transmission (PMTCT) services globally and is expected to play a critical role in reaching the virtual elimination target. To date, PEPFAR has been instrumental in the success of many national programs, including expanded coverage of PMTCT services, an enhanced continuum of care between PMTCT and HIV care and treatment, provision of more efficacious regimens for antiretroviral prophylaxis, design of innovative but simplified PMTCT approaches, and development of new strategies to evaluate program effectiveness. These accomplishments have been made through collaborative efforts with host governments, United Nations agencies, other donors (eg, the Global Fund for AIDS, Tuberculosis, and Malaria), nongovernmental organizations, and private sector partners. To successfully meet the ambitious global targets to prevent new infant HIV infections, PEPFAR must continue to leverage the existing PMTCT platform, while developing innovative approaches to rapidly expand quality HIV services. PEPFAR must also carefully integrate PMTCT into the broader combination prevention agenda for HIV, so that real progress can be made toward an "AIDS-free generation" worldwide.

  6. Multiplexing signals in reinforcement learning with internal models and dopamine.

    PubMed

    Nakahara, Hiroyuki

    2014-04-01

    A fundamental challenge for computational and cognitive neuroscience is to understand how reward-based learning and decision-making are made and how accrued knowledge and internal models of the environment are incorporated. Remarkable progress has been made in the field, guided by the midbrain dopamine reward prediction error hypothesis and the underlying reinforcement learning framework, which does not involve internal models ('model-free'). Recent studies, however, have begun not only to address more complex decision-making processes that are integrated with model-free decision-making, but also to include internal models about environmental reward structures and the minds of other agents, including model-based reinforcement learning and using generalized prediction errors. Even dopamine, a classic model-free signal, may work as multiplexed signals using model-based information and contribute to representational learning of reward structure.

  7. Strategies for national health care systems in emerging countries: the case of screening and prevention of renal disease progression in Bolivia.

    PubMed

    Perico, Norberto; Plata, Raul; Anabaya, Agustina; Codreanu, Igor; Schieppati, Arrigo; Ruggenenti, Piero; Remuzzi, Giuseppe

    2005-08-01

    There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. In 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled "El Proyecto de Enfermedades Renales en Bolivia" (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center "Aldo e Cele Dacco" of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled "First Clinical and Epidemiological Program of Renal Diseases"-under the auspices of the Renal Sister Center Program of the International Society of Nephrology-was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted

  8. Progress in the development of deposition prevention and cleaning techniques of in-vessel optics in ITER

    NASA Astrophysics Data System (ADS)

    Mukhin, E.; Vukolov, K.; Semenov, V.; Tolstyakov, S.; Kochergin, M.; Kurskiev, G.; Podushnikova, K.; Razdobarin, A.; Gorodetsky, A.; Zalavutdinov, R.; Bukhovets, V.; Zakharov, A.; Bulovich, S.; Veiko, V.; Shakshno, E.

    2009-08-01

    The lifetime of front optical components unprotected from reactor grade plasmas may be very short due to intensive contamination with carbon and beryllium-based materials eroded by the plasma from beryllium walls and carbon tiles. Deposits result in a significant reduction and spectral alterations of optical transmission. In addition, even rather thin and transparent deposits can dramatically change the shape of reflectance spectra, especially for mirrors with rather low reflectivity, such as W or Mo. The distortion of data obtained with various optical diagnostics may affect the safe operation of ITER. Therefore, the development of optics-cleaning and deposition-mitigating techniques is a key factor in the construction and operation of optical diagnostics in ITER. The problem is of particular concern for optical elements positioned in the divertor region. The latest achievements in protection of in-vessel optics are presented using the example of deposition prevention/cleaning techniques for in-machine components of the Thomson scattering system in the divertor. Careful consideration of well-known and novel protection approaches shows that neither of them alone provides guaranteed survivability of the first in-vessel optics in the divertor. Only a set of complementary prevention/cleaning techniques, which include special materials for mirrors and inhibition additives for plasma, is able to manage the challenging task. The essential issue, which needs to be addressed in the immediate future, is an extensive development of techniques tested under experimental conditions (exposure time and contamination fluxes) similar to those expected in ITER.

  9. Calpastatin overexpression prevents progression of S-1,2-dichlorovinyl-L-cysteine (DCVC)-initiated acute renal injury and renal failure (ARF) in diabetes

    SciTech Connect

    Dnyanmote, Ankur V.; Sawant, Sharmilee P.; Lock, Edward A.; Latendresse, John R.; Warbritton, Alan A.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2006-09-01

    Previously we have shown that 90% of streptozotocin (STZ)-induced type-1 diabetic (DB) mice survive from acute renal failure (ARF) and death induced by a normally LD{sub 9} dose (75 mg/kg, i.p.) of the nephrotoxicant S-1,2-dichlorovinyl-L-cysteine (DCVC). This remarkable protection is due to a combination of slower progression of DCVC-initiated renal injury and increased compensatory nephrogenic tissue repair in the DB kidneys. BRDU immunohistochemistry revealed that the DB condition led to 4-fold higher number of proximal tubular cells (PTC) entering S-phase of cell cycle. In the present study, we tested the hypothesis that DB-induced augmentation of PTC into S-phase is accompanied by overexpression of the calpain-inhibitor calpastatin, which endogenously prevents the progression of DCVC-initiated renal injury mediated by the calpain escaping out of damaged PTCs. Immunohistochemical detection of renal calpain and its activity in the urine, over a time course after treatment with the LD{sub 9} dose of DCVC, indicated progressive increase in leakage of calpain into the extracellular spaces of the injured PTCs of the non-diabetic (NDB) kidneys as compared to the DB kidneys. Calpastatin expression was minimally detected in the NDB kidneys, using immunohistochemistry, over the time course. On the other hand, consistently higher number of tubules in the DB kidney showed calpastatin expression over the time course. The lower leakage of calpain in the DB kidneys was commensurate with constitutively higher expression of calpastatin in the S-phase-laden PTCs of these mice. To test the protective role of newly divided/dividing PTCs, DB mice were given the anti-mitotic agent colchicine (CLC) (2 mg/kg and 1.5 mg/kg, i.p., on days 8 and 10 after STZ injection) prior to challenge with a LD{sub 9} dose of DCVC, which led to 100% mortality by 48 h. Mortality was due to rapid progression of DCVC-initiated renal injury, suggesting that newly divided/dividing cells are instrumental

  10. Alzheimer's disease and blood-brain barrier function - Why have anti-β-amyloid therapies failed to prevent dementia progression?

    PubMed Central

    Pahnke, Jens; Walker, Lary C.; Scheffler, Katja; Krohn, Markus

    2009-01-01

    Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-β plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-β aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy. PMID:19481107

  11. Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions.

    PubMed

    Ruiz, Juan C; Campistol, Josep M; Grinyó, Josep M; Mota, Alfredo; Prats, Dolores; Gutiérrez, Jose A; Henriques, Antonio C; Pinto, Jose R; García, Javier; Morales, Jose M; Gómez, Jose M; Arias, Manuel

    2004-11-15

    Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome.

  12. Regulating Inflammatory Immune Response to Atherogenic Antigens Prevents Development and Progression of Atherosclerosis in New Zealand White Rabbits.

    PubMed

    Philip, Sheena; Ponnusamy, Thiruvelselvan; Rao, Lakshmi Narasimha; Biradar, Suryakant; Kumar, Ramesh; Deshpande, Vrushali; Lu, Xinjie; Kakkar, Vijay V; Mundkur, Lakshmi A

    2016-08-01

    Inflammatory immune response to atherogenic self-antigens plays an important role in the development of atherosclerosis. We evaluated the role of oral tolerance to three peptides in controlling atherosclerosis in New Zealand white rabbits. Peptides derived from apolipoprotein B (ApoB), heat shock protein 60, and outer membrane protein from Chlamydia pneumoniae were expressed as part of the dendroaspin protein scaffold (AHC). Groups of 3-month-old rabbits were dosed orally with purified AHC protein either before the onset of disease or 2 months after inducing atherosclerosis; they were euthanized at the age of 7 months to study disease development and progression. Oral treatment with AHC resulted in a marked increase in regulatory T cells in the lymphoid organs and reduced the development and progression of atherosclerosis by 48.6% and 28.4%, respectively (P < 0.05). Oral tolerance decreased plaque inflammation, enhanced expression of anti-inflammatory and regulatory markers in the aorta, and attenuated the adaptive immune response to self-antigens. AHC treatment in rabbits with established disease significantly decreased vascular cell adhesion molecule 1 (VCAM-1) (6.2 fold) and monocyte chemoattractant protein-1(MCP-1) (3 fold) expression and reduced the infiltration of macrophages into the aorta. Collagen content and the smooth muscle cell-to-macrophage ratio were higher in treated animals, whereas markers of plaque vulnerability, including matrix metalloproteinase expression, were reduced. Our results suggest that oral tolerance to multiantigenic AHC molecule restores the immune balance and induces markers of plaque stability in rabbits. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  13. Efficacy and safety of percutaneous transluminal balloon dilation to prevent progression of banding site stenosis after bilateral pulmonary artery banding.

    PubMed

    Hoshino, Shinsuke; Kitano, Masataka; Abe, Tadaaki; Yazaki, Satoshi; Kagisaki, Koji

    2015-06-01

    To investigate the efficacy and safety of percutaneous transluminal balloon dilation (PTBD) for the treatment of bilateral pulmonary artery banding (bil-PAB) site stenosis. Although bil-PAB is an alternative initial treatment for high-risk neonates with hypoplastic left heart syndrome (HLHS) or critical aortic stenosis (cAS), those patients often suffer from desaturation because of progressive stenosis of the bil-PAB sites during the interstage period. We retrospectively evaluated the efficacy and safety of 11 consecutive PTBD procedures performed between 2006 and 2012 to treat bil-PAB site stenosis in four high-risk infants (three females) with HLHS or cAS. PTBD was repeated twice in two patients and three times in one patient over intervals. The mean balloon diameter (BD) and BD-to-band circumference (BC) ratio were 3.1 ± 0.5 mm and 0.31 ± 0.06, respectively. After the procedures, the mean minimum lumen diameter was dilated significantly from 1.1 ± 0.1 mm to 1.7 ± 0.3 mm (P < 0.01), and the mean peripheral oxygen saturation increased significantly from 75 ± 8% to 85 ± 4% (P < 0.01). All patients reached the next stage operation involving the Norwood & bidirectional Glenn or Ross procedure, after growth. No complications such as band rupture occurred. For progressive stenosis of bil-PAB sites, PTBD using a balloon size that did not exceed the BC (BD around 30% of the BC) was an effective and safe procedure. © 2015 Wiley Periodicals, Inc.

  14. Dopamine and glucose, obesity, and reward deficiency syndrome

    PubMed Central

    Blum, Kenneth; Thanos, Panayotis K.; Gold, Mark S.

    2014-01-01

    of powerful dopamine D2 agonists have failed due to chronic down regulation of D2 receptors newer targets based on novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency. PMID:25278909

  15. Striatal plasticity in parkinsonism: dystrophic changes in medium spiny neurons and progression in Parkinson's disease.

    PubMed

    Deutch, A Y

    2006-01-01

    Striatal dopamine loss in Parkinson's Disease (PD) sets into play a variety of compensatory responses to help counter dopamine depletion. Most of these changes involve surviving dopamine neurons, but there are also changes in striatal medium spiny neurons (MSNs), which are the major target of dopamine axons. Among these changes are decreases in MSN dendritic length and spine density, which may dampen excessive corticostriatal glutamatergic drive onto MSNs that occurs secondary to dopamine loss. An increasing knowledge of dendritic changes in PD suggests strategies for tracking progressive worsening of symptoms and is opening new ideas on novel therapeutic strategies for PD.

  16. Multifunctional liposomes delay phenotype progression and prevent memory impairment in a presymptomatic stage mouse model of Alzheimer disease.

    PubMed

    Mancini, Simona; Balducci, Claudia; Micotti, Edoardo; Tolomeo, Daniele; Forloni, Gianluigi; Masserini, Massimo; Re, Francesca

    2017-07-28

    The failure of clinical trials largely focused on mild to moderate stages of Alzheimer disease has suggested to the scientific community that the effectiveness of Amyloid-β (Aβ)-centered treatments should be evaluated starting as early as possible, well before irreversible brain damage has occurred. Accordingly, also the preclinical development of new therapies should be carried out taking into account this suggestion. In the present investigation we evaluated the efficacy of a treatment with liposomes multifunctionalized for crossing the blood-brain barrier and targeting Aβ, carried out on young APP/PS1 Tg mice, taken as a model of pre-symptomatic disease stage. Liposomes were administered once a week to Tg mice for 7months, starting at the age of 5months and up to the age of 12 when they display AD-like cognitive and brain biochemical/anatomical features. The treatment prevented the onset of the long-term memory impairment and slowed down the deposition of brain Aβ; at anatomical level, prevented both ventricle enlargement and entorhinal cortex thickness reduction, otherwise occurring in untreated mice. Strikingly, these effects were maintained 3months after treatment discontinuation. An increase of Aβ levels in the liver was detected at the end of the treatment, then followed also by reduction of brain Amyloid Precursor Protein and increase of Aβ-degrading enzymes. These results suggest that the treatment promotes brain Aβ clearance by a peripheral 'sink' effect and ultimately affects Aβ turnover in the brain. Worth of note, the treatment was apparently not toxic for all the organs analyzed, in particular for brain, as suggested by the lower brain TNF-α and MDA levels, and by higher level of SOD activity in treated mice. Together, these findings promote a very early treatment with multi-functional liposomes as a well-tolerated nanomedicine-based approach, potentially suitable for a disease-modifying therapy of AD, able to delay or prevent relevant

  17. Increased brain dopamine and dopamine receptors in schizophrenia

    SciTech Connect

    Mackay, A.V.; Iversen, L.L.; Rossor, M.; Spokes, E.; Bird, E.; Arregui, A.; Creese, I.; Synder, S.H.

    1982-09-01

    In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients.

  18. Progressive load training for the quadriceps muscle associated with proprioception exercises for the prevention of falls in postmenopausal women with osteoporosis: a randomized controlled trial.

    PubMed

    Teixeira, L E P P; Silva, K N G; Imoto, A M; Teixeira, T J P; Kayo, A H; Montenegro-Rodrigues, R; Peccin, M S; Trevisani, V F M

    2010-04-01

    This study aims to evaluate the effect of 18-week progressive muscular strength and proprioception training program on the muscle strength of the quadriceps, in prevention of falls in postmenopausal women with osteoporosis. The incidence of falls in the intervention group was significantly lower than in the control group (incidence rate ratio (IRR) = 0.263, 95% CI 0.10-0.68). This study aims to evaluate the effect of a progressive muscular strength and proprioception training program on the muscle strength of the quadriceps, balance, quality of life, and reduction in the risk of falls in postmenopausal women with osteoporosis. One hundred sedentary postmenopausal women with osteoporosis, ages ranging from 55 to 75, were selected and randomized into two groups: the intervention group comprised of 50 patients who underwent a 18-week of progressive load training for the quadriceps muscle (50% up to 80% of 1-RM-one maximum repetition) and proprioception training associated to a drug treatment of osteoporosis and the control group that included 50 patients who only underwent a drug treatment of osteoporosis. The muscular strength, balance, functional mobility, and quality of life were evaluated in the beginning and end of the research. The number of falls was evaluated 24 weeks post-treatment. Eighty-five patients concluded the research. The program promoted a significant difference among the groups for SF-36 in the eight sub-scales (p progressive strength training for the quadriceps and the proprioceptive training is effective for the prevention of falls, increasing the muscle power, the static and dynamic balance and increasing the speed of the motor responses, therefore improving the performance of daily activities.

  19. Benchmarking progress in the implementation of the Fourth Joint Societies' Task Force Guidelines on the Prevention of Cardiovascular Disease in Clinical Practice.

    PubMed

    Morgan, Karen; Burke, Helen; McGee, Hannah

    2013-02-01

    The Fourth Joint Societies' Task Force (4th JTF) Guidelines on Cardiovascular Disease Prevention in Clinical Practice are agreed, evidence-based standards of care across European countries and professions. In advance of the publication of the 5th JTF Guidelines in 2012, this work assesses the extent to which the 4th JTF guidelines have been implemented. Qualitative study of guideline implementation in 13 European countries, focusing on the themes of guideline implementation structures, processes, and outcomes. Key personnel in 13 selected countries completed interviews or comparable questionnaires: they were national coordinators for CVD prevention (n = 14) and representatives of the national cardiac society (n = 9), heart foundations (n = 11), health ministry (n = 8), and service providers (n = 3). Interview and service-related data from each country were compiled to provide a detailed overview. Ten of the 13 countries used European Society of Cardiology (ESC) guidelines on prevention at a national level, where three broad approaches to implementation were identified. In all 10 countries, multidisciplinary alliances oversaw implementation, but ongoing promotion of the guidelines was not evident, with just two of the 10 countries conducting evaluation of implementation. Barriers to implementation included weak health authority support, the unwieldy nature of the guidelines, guideline fatigue, and the lesser role of prevention in national healthcare systems. Substantial progress had been made in implementing the guidelines, but countries struggled with the task. Some rebalancing of the ESC focus may be warranted so that part of the effort dedicated to improving guidelines might be redirected at translating them into practice.

  20. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy

    SciTech Connect

    Anscher, Mitchell S. . E-mail: anscher@radonc.duke.edu; Chen, Liguang; Rabbani, Zahid; Kang Song; Larrier, Nicole; Huang Hong; Samulski, Thaddeus V.; Dewhirst, Mark W.; Brizel, David M.; Folz, Rodney J.; Vujaskovic, Zeljko

    2005-05-01

    The ability to optimize treatments for cancer on the basis of relative risks for normal tissue injury has important implications in oncology, because higher doses of radiation might, in some diseases, improve both local control and survival. To achieve this goal, a thorough understanding of the molecular mechanisms responsible for radiation-induced toxicity will be essential. Recent research has demonstrated that ionizing radiation triggers a series of genetic and molecular events, which might lead to chronic persistent alterations in the microenvironment and an aberrant wound-healing response. Disrupted epithelial-stromal cell communication might also be important. With the application of a better understanding of fundamental biology to clinical practice, new approaches to treating and preventing normal tissue injury can focus on correcting these disturbed molecular processes.

  1. [Injuries: preventive approach and progress of injuries in the construction of the line B1 of the underground of Rome].

    PubMed

    Saggio, G; Conti, E; Valentini, F; De Sio, L; Capano, M Perrone

    2010-01-01

    The line B1 is a branch of the existing Metro line B in Rome. The route is long about 5 km, is completely underground and involves the construction of four new stations: Annibaliano, Libia /Gondar, Conca d'Oro and Jonio. The line will have a capacity of transport of 24,000 people/hour in each direction. The works started in 2006 involve about 500 workers. The report provides a statistical analysis of the events that occurred in the period 2005/2010 and aims to introduce the starting and management of this study, also on the basis of the "Operating procedures" issued by the acquisition of OSHAS 18001 certification from the agent of Metro B) / R.I.M.A.T.I. This analysis aims to provide to supervisors, to social security institutions and to workers, a usefull analysis tool in the prevention of the monitored events.

  2. Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial.

    PubMed

    Gerstein, Hertzel C; Ratner, Robert E; Cannon, Christopher P; Serruys, Patrick W; García-García, Héctor M; van Es, Gerrit-Anne; Kolatkar, Nikheel S; Kravitz, Barbara G; Miller, Diane M; Huang, Chun; Fitzgerald, Peter J; Nesto, Richard W

    2010-03-16

    Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http

  3. Antiferroptotic activity of non-oxidative dopamine.

    PubMed

    Wang, Ding; Peng, Yingpeng; Xie, Yangchun; Zhou, Borong; Sun, Xiaofang; Kang, Rui; Tang, Daolin

    2016-11-25

    Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters.

  4. Oral Resveratrol Prevents Osteoarthritis Progression in C57BL/6J Mice Fed a High-Fat Diet.

    PubMed

    Gu, Hailun; Li, Keyu; Li, Xingyao; Yu, Xiaolu; Wang, Wei; Ding, Lifeng; Liu, Li

    2016-04-20

    The effects of resveratrol on osteoarthritis (OA) pathogenesis have been demonstrated in vitro and in animal models employing intra-articular injections. However, the potential for oral resveratrol supplements to mediate protective effects on OA have not been examined. Therefore, the aim of the present study was to investigate the potential anti-OA effects of oral resveratrol on mice fed a high-fat diet (HFD). C57BL/6J male mice were fed either a standard diet or a HFD, and a subset of the latter also received varying doses of resveratrol. Twelve weeks later, all of the animals were sacrificed and knee joints were evaluated with histological, immunohistochemical, and TUNEL analyses. Mice that received a HFD had significantly greater body weights than the control mice and also exhibited features consistent with knee OA. The mice that received a HFD in combination with low, intermediate, or high doses of resveratrol were only slightly heavier than the control mice at the end of 12 weeks. Quantitative histological assessments indicated that resveratrol treatment partly recovered joint structure in the mice that received a HFD, while high doses of resveratrol prevented the degradation of type II collagen into C-telopeptide of type II collagen (CTX-II) and retained type II collagen expression in cartilage. Furthermore, TUNEL analyses revealed a reduction in chondrocyte apoptosis in the resveratrol-treated mice compared with the HFD mice. Thus, oral resveratrol appears to exert anti-OA effects in a mouse model of HFD-induced OA, thereby highlighting the potential preventive and therapeutic value of administering resveratrol for obesity-associated OA.

  5. Oral Resveratrol Prevents Osteoarthritis Progression in C57BL/6J Mice Fed a High-Fat Diet

    PubMed Central

    Gu, Hailun; Li, Keyu; Li, Xingyao; Yu, Xiaolu; Wang, Wei; Ding, Lifeng; Liu, Li

    2016-01-01

    The effects of resveratrol on osteoarthritis (OA) pathogenesis have been demonstrated in vitro and in animal models employing intra-articular injections. However, the potential for oral resveratrol supplements to mediate protective effects on OA have not been examined. Therefore, the aim of the present study was to investigate the potential anti-OA effects of oral resveratrol on mice fed a high-fat diet (HFD). C57BL/6J male mice were fed either a standard diet or a HFD, and a subset of the latter also received varying doses of resveratrol. Twelve weeks later, all of the animals were sacrificed and knee joints were evaluated with histological, immunohistochemical, and TUNEL analyses. Mice that received a HFD had significantly greater body weights than the control mice and also exhibited features consistent with knee OA. The mice that received a HFD in combination with low, intermediate, or high doses of resveratrol were only slightly heavier than the control mice at the end of 12 weeks. Quantitative histological assessments indicated that resveratrol treatment partly recovered joint structure in the mice that received a HFD, while high doses of resveratrol prevented the degradation of type II collagen into C-telopeptide of type II collagen (CTX-II) and retained type II collagen expression in cartilage. Furthermore, TUNEL analyses revealed a reduction in chondrocyte apoptosis in the resveratrol-treated mice compared with the HFD mice. Thus, oral resveratrol appears to exert anti-OA effects in a mouse model of HFD-induced OA, thereby highlighting the potential preventive and therapeutic value of administering resveratrol for obesity-associated OA. PMID:27104565

  6. Dopamine agonists for cocaine dependence.

    PubMed

    Soares, B G; Lima, M S; Reisser, A A; Farrell, M

    2001-01-01

    Cocaine is a major drug of abuse. Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. We searched: The Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity

  7. Dopamine agonists for cocaine dependence.

    PubMed

    Soares, B G O; Lima, M S; Reisser, A A P; Farrell, M

    2003-01-01

    Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence, was performed for the primary version of this review in 2001. Another search of the electronic databases was done in December of 2002 for this update. The specialised register of trials of the Cochrane Group on Drugs and Alcohol was searched until February 2003. The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of

  8. Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression

    PubMed Central

    Biswas, Swati; Guix, Marta; Rinehart, Cammie; Dugger, Teresa C.; Chytil, Anna; Moses, Harold L.; Freeman, Michael L.; Arteaga, Carlos L.

    2007-01-01

    We investigated whether TGF-β induced by anticancer therapies accelerates tumor progression. Using the MMTV/PyVmT transgenic model of metastatic breast cancer, we show that administration of ionizing radiation or doxorubicin caused increased circulating levels of TGF-β1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan–TGF-β antibody. Circulating polyomavirus middle T antigen–expressing tumor cells did not grow ex vivo in the presence of the TGF-β antibody, suggesting autocrine TGF-β is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-β receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-β on the cancer cells. These data implicate TGF-β induced by anticancer therapy as a prometastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-β inhibitors. PMID:17415413

  9. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

    PubMed Central

    Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D.; Funk, Jens Oliver; Hill, Ronald J.; Bradshaw, J. Michael

    2015-01-01

    In T cells, the Tec kinases IL-2–inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/−Rlk−/− mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases. PMID:26466958

  10. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis.

    PubMed

    Sigurgeirsson, B; Ho, V; Ferrándiz, C; Andriano, K; Grinienko, A; Jimenez, P

    2008-11-01

    This study was performed to investigate the efficacy and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in children and adolescents with atopic dermatitis (AD). A 26-week multi-centre, randomized, double-blind, vehicle-controlled study was conducted in 521 patients aged 2-17 years, with a history of mild or moderate AD, who were clear/almost clear of disease before randomization to pimecrolimus cream 1% (n = 256) or vehicle cream (n = 265). Twice-daily treatment with study medication was started at the first signs and/or symptoms of recurring AD. If, despite the application of study medication for at least 3 days, AD worsened (as confirmed by the investigator), treatment with a moderately potent topical corticosteroid (TCS) was allowed in both groups. The primary efficacy end point was the number of days on study without TCS use for a flare. The mean number of TCS-free days was significantly higher (P < 0.0001) in the pimecrolimus cream 1% group (160.2 days) than in the control group (137.7 days). On average, patients on pimecrolimus cream 1% experienced 50% fewer flares requiring TCSs (0.84) than patients on vehicle cream (1.68) (P < 0.0001). Patients on pimecrolimus cream 1% also had fewer unscheduled visits (87) than patients on vehicle cream (246). In children and adolescents with a history of mild or moderate AD but free/almost free of signs or symptoms of the disease, early treatment of subsequent AD exacerbations with pimecrolimus cream 1% prevented progression to flares requiring TCS, leading to fewer unscheduled visits and reducing corticosteroid exposure.

  11. 1999 Annual Report on Waste Generation and Pollution Prevention Progress as Required by DOE Order 5400.1

    SciTech Connect

    SEGALL, P.

    2000-03-01

    Hanford's missions are to safely clean-up and manage the site's legacy wastes, and to develop and deploy science and technology. Through these missions Hanford will contribute to economic diversification of the region. Hanford's environmental management or clean-up mission is to protect the health and safety of the public, workers, and the environment; control hazardous materials; and utilize the assets (people, infrastructure, and site) for other missions. Hanford's science and technology mission is to develop and deploy science and technology in the service of the nation including stewardship of the Hanford Site. Pollution Prevention is a key to the success of these missions by reducing the amount of waste to be managed and identifying/implementing cost effective waste reduction projects. Hanford's original mission, the production of nuclear materials for the nation's defense programs, lasted more than 40 years, and like most manufacturing operations, Hanford's operations generated large quantities of waste and pollution. However, the by-products from Hanford operations pose unique problems like radiation hazards, vast volumes of contaminated water and soil, and many contaminated structures including reactors, chemical plants and evaporation ponds. The clean-up activity is an immense and challenging undertaking. Including characterization and decommissioning of 149 single shell storage tanks, treating 28 double shell tanks, safely disposing of over 2,100 metric tons of spent nuclear fuel stored on site, removing numerous structures, and dealing with significant solid waste, ground water, and land restoration issues.

  12. Prevention and delay in progression of human pancreatic cancer by stable overexpression of the opioid growth factor receptor.

    PubMed

    Zagon, Ian S; Kreiner, Shawn; Heslop, Jeffery J; Conway, Andrea B; Morgan, Clinton R; McLaughlin, Patricia J

    2008-08-01

    This study examined overexpression of the opioid growth factor receptor (OGFr) in pancreatic cancer cells and phenotypic changes in tumorigenicity. Tumors of MIA PaCa-2 cells transfected with OGFr cDNA (OGFr-1) had 3.3 times more OGFr than empty vector (EV) neoplasias, and 4.3 times more OGFr than tumors from wild-type (WT) mice. No differences in OGFr binding were detected between tumors of EV and WT animals. Tumor incidence in OGFr-1 animals was reduced by up to 50% from EV mice. Latency times for OGFr-1 tumor expression were increased 30%, tumor volume was decreased 70%, and DNA synthesis was reduced 24% relative to EV mice. Exogenous OGF reduced OGFr-1 tumor volume up to 55% compared to OGFr-1 mice given vehicle. These data support OGFr gene function as a regulator of cell proliferation that impacts on tumorigenic expression, and suggest that molecular and pharmacological manipulation of OGFr may prevent or delay human pancreatic cancer.

  13. Australasian nutrition research for prevention and management of child obesity: innovation and progress in the last decade.

    PubMed

    Golley, R K; McNaughton, S A; Collins, C E; Magarey, A; Garnett, S P; Campbell, K J; Mallan, K; Burrows, T

    2014-12-01

    The Food and Nutrition stream of Australasian Child and Adolescent Obesity Research Network (ACAORN) aims to improve the quality of dietary methodologies and the reporting of dietary intake within Australasian child obesity research (http://www.acaorn.org.au/streams/nutrition/). With 2012 marking ACAORN's 10th anniversary, this commentary profiles a selection of child obesity nutrition research published over the last decade by Food and Nutrition Stream members. In addition, stream activities have included the development of an online selection guide to assist researchers in their selection of appropriate dietary intake methodologies (http://www.acaorn.org.au/streams/nutrition/dietary-intake/index.php). The quantity and quality of research to guide effective child obesity prevention and treatment has increased substantially over the last decade. ACAORN provides a successful case study of how research networks can provide a collegial atmosphere to foster and coordinate research efforts in an otherwise competitive environment. © 2014 The Authors. Pediatric Obesity © 2014 International Association for the Study of Obesity.

  14. How dietary patterns could have a role in prevention, progression, or management of diabetes mellitus? Review on the current evidence

    PubMed Central

    Maghsoudi, Zahra; Azadbakht, Leila

    2012-01-01

    Objective: To investigate the role of dietary patterns in prevention and management of type 2 diabetes mellitus. Materials and Methods: A systematic review of databases which were published in ISI, Cochrane Central Register of Controlled Trials databases, PubMed, Iran Medex, and MagIran was performed. “Diabetes” and “dietary pattern” were used as the keywords. Results: A total of 58 studies which aimed to focus on diabetes mellitus, insulin resistance, metabolic syndrome, dietary pattern, and other related key words were reviewed. More than 47,447 articles were found and 46,709 entries of the extracted studies were excluded on the basis of the title and abstracts. The major dietary patterns were: “Healthy”, “Western”, “Traditional”, “Prudent”, “Unhealthy”, “Mediterranean”, “Modern”, and “Dietary Approach to Stop Hypertension” (DASH) diets. Comparison of the effects of different diets revealed that dietary patterns containing fiber-rich foods have a protective role in managing diabetes mellitus. “Healthy”, “Mediterranean”, “Prudent”, and “DASH” dietary patterns were associated with lower risk of hyperglycemia. Conclusions: The adherence to the Mediterranean, Prudent, or DASH diets could control hyperglycemia. The higher intake of vegetables, fruits, nuts, whole grains, and lower intake of red meat could reduce the risk of type 2 diabetes mellitus. PMID:23798934

  15. Methotrexate affects HMGB1 expression in rheumatoid arthritis, and the downregulation of HMGB1 prevents rheumatoid arthritis progression.

    PubMed

    Li, Yuan-Bo; Xu, Peng; Xu, Ke; Cai, Yong-Song; Sun, Meng-Yao; Yang, Le; Sun, Jian; Lu, She-Min

    2016-09-01

    High-mobility group box 1 (HMGB1) is associated with the development of rheumatoid arthritis (RA). Recent studies have shown that methotrexate (MTX) may inhibit the expression of HMGB1. This study examined whether HMGB1 might be involved in the treatment of RA using MTX. Synovial tissues were collected from RA patients who were treated with MTX for at least 6 months (RA-MTX group, 7 cases) and from those without MTX treatment (RA-noMTX group, 7 cases). Additionally, patients with osteoarthritis (OA group, 7 cases) were used as controls. The expression and locations of HMGB1 in the tissues were detected using real-time PCR, western blot, and immunohistochemistry. Additionally, OA-fibroblast-like synoviocytes (FLSs) and RA-FLSs were isolated and cultured, and the expression of HMGB1 was reduced in these cells by transfection with HMGB1 siRNA. Cell proliferation, migration, and invasion abilities were detected. Furthermore, the effects of HMGB1 on matrix metalloproteinase (MMP)-2 and MMP-13 were measured using western blot analysis. At the tissue level, HMGB1 expression in synovial membrane did not differ significantly between the OA and RA-MTX groups, but was significantly lower in these groups than in the RA-noMTX group. In cell experiments, the cell doubling time in the RA-FLS HMGB1 siRNA group was significantly extended compared with that in the RA-FLS negative control (NC)-siRNA group. The amount of cell migration and invasion in the RA-FLS HMGB1 siRNA group was significantly lower compared with that in the NC-siRNA group; the MMP-2 and MMP-13 expression levels were also lower. These results showed that MTX reduced HMGB1 expression in RA synovial tissues, and through the downregulation of HMGB1 expression in tissues, MTX may slow disease progression of RA.

  16. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    PubMed Central

    España, Rodrigo A.; Jones, Sara R.

    2013-01-01

    The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

  17. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

    PubMed

    Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Krischer, Jeffrey P; Greenbaum, Carla J; Mahon, Jeffrey; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

    2013-12-01

    We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.

  18. Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation.

    PubMed

    Bermejo, Rodrigo; Doksani, Ylli; Capra, Thelma; Katou, Yuki-Mori; Tanaka, Hirokazu; Shirahige, Katsuhiko; Foiani, Marco

    2007-08-01

    DNA topoisomerases solve topological problems during chromosome metabolism. We investigated where and when Top1 and Top2 are recruited on replicating chromosomes and how their inactivation affects fork integrity and DNA damage checkpoint activation. We show that, in the context of replicating chromatin, Top1 and Top2 act within a 600-base-pair (bp) region spanning the moving forks. Top2 exhibits additional S-phase clusters at specific intergenic loci, mostly containing promoters. TOP1 ablation does not affect fork progression and stability and does not cause activation of the Rad53 checkpoint kinase. top2 mutants accumulate sister chromatid junctions in S phase without affecting fork progression and activate Rad53 at the M-G1 transition. top1 top2 double mutants exhibit fork block and processing and phosphorylation of Rad53 and gamma H2A in S phase. The exonuclease Exo1 influences fork processing and DNA damage checkpoint activation in top1 top2 mutants. Our data are consistent with a coordinated action of Top1 and Top2 in counteracting the accumulation of torsional stress and sister chromatid entanglement at replication forks, thus preventing the diffusion of topological changes along large chromosomal regions. A failure in resolving fork-related topological constrains during S phase may therefore result in abnormal chromosome transitions, DNA damage checkpoint activation, and chromosome breakage during segregation.

  19. Atypical protein kinase C is a novel mediator of dopamine-enhanced firing in nucleus accumbens neurons.

    PubMed

    Hopf, F Woodward; Mailliard, William S; Gonzalez, Gilda F; Diamond, Ivan; Bonci, Antonello

    2005-01-26

    Current concepts suggest that nucleus accumbens (NAcb) dopamine mediates several motivated and addictive behaviors. Although the role of protein kinase A (PKA) and dopamine and cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa in NAcb dopamine receptor throughput has been studied extensively, the contribution of protein kinase C (PKC) to NAcb firing is poorly understood. Here we show that dopamine-mediated enhancement of spike firing in NAcb shell medium spiny neurons was prevented by the PKC inhibitor bisindolylmaleimide but not by the phospholipase C inhibitor 1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione, suggesting a role for a diacylglycerol-independent atypical PKC (aPKC) isoform. In this regard, modulation of firing by dopamine was prevented by intracellular perfusion of a pseudosubstrate peptide inhibitor for aPKCs. We also provide evidence, using an in vitro kinase assay, that dopamine receptor activation increased aPKC activity in striatal membranes. Finally, direct activation of PKA with forskolin enhanced firing even during inhibition of aPKCs, suggesting that aPKCs acted upstream of PKA activation. Thus, aPKCs appear to mediate dopaminergic enhancement of spike firing in the NAcb shell, and may therefore play a critical role in NAcb- and dopamine-dependent goal-directed behaviors.

  20. On the pH-dependent quenching of quantum dot photoluminescence by redox active dopamine.

    PubMed

    Ji, Xin; Palui, Goutam; Avellini, Tommaso; Na, Hyon Bin; Yi, Chongyue; Knappenberger, Kenneth L; Mattoussi, Hedi

    2012-04-04

    We investigated the charge transfer interactions between luminescent quantum dots (QDs) and redox active dopamine. For this, we used pH-insensitive ZnS-overcoated CdSe QDs rendered water-compatible using poly (ethylene glycol)-appended dihydrolipoic acid (DHLA-PEG), where a fraction of the ligands was amine-terminated to allow for controlled coupling of dopamine-isothiocyanate onto the nanocrystal. Using this sample configuration, we probed the effects of changing the density of dopamine and the buffer pH on the fluorescence properties of these conjugates. Using steady-state and time-resolved fluorescence, we measured a pronounced pH-dependent photoluminescence (PL) quenching for all QD-dopamine assemblies. Several parameters affect the PL loss. First, the quenching efficiency strongly depends on the number of dopamines per QD-conjugate. Second, the quenching efficiency is substantially increased in alkaline buffers. Third, this pH-dependent PL loss can be completely eliminated when oxygen-depleted buffers are used, indicating that oxygen plays a crucial role in the redox activity of dopamine. We attribute these findings to charge transfer interactions between QDs and mainly two forms of dopamine: the reduced catechol and oxidized quinone. As the pH of the dispersions is changed from acidic to basic, oxygen-catalyzed transformation progressively reduces the dopamine potential for oxidation and shifts the equilibrium toward increased concentration of quinones. Thus, in a conjugate, a QD can simultaneously interact with quinones (electron acceptors) and catechols (electron donors), producing pH-dependent PL quenching combined with shortening of the exciton lifetime. This also alters the recombination kinetics of the electron and hole of photoexcited QDs. Transient absorption measurements that probed intraband transitions supported those findings where a simultaneous pronounced change in the electron and hole relaxation rates was measured when the pH was changed from

  1. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

    PubMed Central

    Lee, Jong Hun; Khor, Tin Oo; Shu, Limin; Su, Zheng-Yuan; Fuentes, Francisco; Kong, Ah-Ng Tony

    2013-01-01

    Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-κB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2-mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2–Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including

  2. Combination of the c-Met Inhibitor Tivantinib and Zoledronic Acid Prevents Tumor Bone Engraftment and Inhibits Progression of Established Bone Metastases in a Breast Xenograft Model

    PubMed Central

    Previdi, Sara; Scolari, Federica; Chilà, Rosaria; Ricci, Francesca; Abbadessa, Giovanni; Broggini, Massimo

    2013-01-01

    Bone is the most common metastatic site for breast cancer. There is a significant need to understand the molecular mechanisms controlling the engraftment and growth of tumor cells in bone and to discover novel effective therapeutic strategies. The aim of this study was to assess the effects of tivantinib and Zoledronic Acid (ZA) in combination in a breast xenograft model of bone metastases. Cancer cells were intracardially implanted into immunodeficient mice and the effects of drugs alone or in combination on bone metastasis were evaluated by in vivo non-invasive optical and micro-CT imaging technologies. Drugs were administered either before (preventive regimen) or after (therapeutic regimen) bone metastases were detectable. In the preventive regimen, the combination of tivantinib plus ZA was much more effective than single agents in delaying bone metastatic tumor growth. When administered in the therapeutic schedule, the combination delayed metastatic progression and was effective in improving survival. These effects were not ascribed to a direct cytotoxic effect of the combined therapy on breast cancer cells in vitro. The results of this study provide the rationale for the design of new combinatorial strategies with tivantinib and ZA for the treatment of breast cancer bone metastases. PMID:24260160

  3. The effects of orally administered Bacillus coagulans and inulin on prevention and progression of rheumatoid arthritis in rats

    PubMed Central

    Abhari, Khadijeh; Shekarforoush, Seyed Shahram; Hosseinzadeh, Saeid; Nazifi, Saeid; Sajedianfard, Javad; Eskandari, Mohammad Hadi

    2016-01-01

    Background Probiotics have been considered as an approach to addressing the consequences of different inflammatory disorders. The spore-forming probiotic strain Bacillus coagulans has demonstrated anti-inflammatory and immune-modulating effects in both animals and humans. The prebiotic inulin also potentially affects the immune system as a result of the change in the composition or fermentation profile of the gastrointestinal microbiota. Objective In the present study, an in vivo model was conducted to investigate the possible influences of probiotic B. coagulans and prebiotic inulin, both in combination and/or separately, on the downregulation of immune responses and the progression of rheumatoid arthritis (RA), using arthritis-induced rat model. Design Forty-eight healthy male Wistar rats were randomly categorized into six experimental groups as follows: 1) control: normal healthy rats fed with standard diet, 2) disease control (RA): arthritis-induced rats fed with standard diet, 3) prebiotic (PRE): RA+ 5% w/w long-chain inulin, 4) probiotic (PRO): RA+ 109 spores/day B. coagulans by orogastric gavage, 5) synbiotic (SYN): RA+ 5% w/w long-chain inulin and 109 spores/day B. coagulans, and 6) treatment control: (INDO): RA+ 3 mg/kg/day indomethacin by orogastric gavage. Feeding with the listed diets started on day 0 and continued to the end of study. On day 14, rats were injected with complete Freund's adjuvant (CFA) to induce arthritis. Arthritis activity was evaluated by the biochemical parameters and paw thickness. Biochemical assay for fibrinogen (Fn), serum amyloid A (SAA), and TNF-α and alpha-1-acid glycoprotein (α1AGp) was performed on day 21, 28, and 35 (7, 14 and 21 days post RA induction), respectively. Results Pretreatment with PRE, PRO, and SYN diets significantly inhibits SAA and Fn production in arthritic rats (P < 0.001). A significant decrease in the production of pro-inflammatory cytokines, such as TNF-α, was seen in the PRE, PRO, and SYN groups (P

  4. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis.

    PubMed

    Seeman, Philip; Madras, Bertha

    2002-03-10

    How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2-0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.

  5. Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors.

    PubMed

    Yasunari, K; Kohno, M; Hasuma, T; Horio, T; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J

    1997-11-01

    Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine and specific D1-like agonists SKF 38,393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration and proliferation were studied. We observed that cells stimulated by PDGF-BB (5 ng/mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 (1 to 10 mumol/L), and this prevention was reversed by Sch 23,390 (1 to 10 mumol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mumol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89), but not blocked by its negative control, N-[2-(N-formyl)-p-chlorociannamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/mL)-mediated activation of phospholipase D, protein kinase C, and mitogen activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration and proliferation of VSMC, possibly through protein kinase A activation and suppression of activated phospholipase D, protein kinase C, and mitogen-activated protein kinase activity.

  6. Dopamine receptors – IUPHAR Review 13

    PubMed Central

    Beaulieu, Jean-Martin; Espinoza, Stefano; Gainetdinov, Raul R

    2015-01-01

    The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors. PMID:25671228

  7. Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology.

    PubMed

    Strömberg, Ingrid; Bickford, Paula; Gerhardt, Greg A

    2010-02-09

    Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease.

  8. Mesolimbic Dopamine Signals the Value of Work

    PubMed Central

    Hamid, Arif A.; Pettibone, Jeffrey R.; Mabrouk, Omar S.; Hetrick, Vaughn L.; Schmidt, Robert; Vander Weele, Caitlin M.; Kennedy, Robert T.; Aragona, Brandon J.; Berke, Joshua D.

    2015-01-01

    Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions. PMID:26595651

  9. A genetic link between discriminative fear coding by the lateral amygdala, dopamine, and fear generalization

    PubMed Central

    Jones, Graham L; Soden, Marta E; Knakal, Cerise R; Lee, Heather; Chung, Amanda S; Merriam, Elliott B; Zweifel, Larry S

    2015-01-01

    The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses. DOI: http://dx.doi.org/10.7554/eLife.08969.001 PMID:26402461

  10. [Analysis of the role of neurohumoral systems in action of dopaminomimetic dopamine on ion-regulating renal function].

    PubMed

    Landar', L N; Kuz'min, O B

    2013-01-01

    Dopamine causes in anesthetized rats expressed diuretic response that is accompanied by an increase in GRF and a significant enhance of sodium and potassium excretion. Pretreatment the animals in diclofenac sodium or contrical in doses, that inhibit respectively activity of renal PG-system and kallikrein-kinin system, don't prevent of renal effects of dopamine. Preliminary assignment a direct renin inhibitor aliskiren enhances the diuretic, natriuretic and kaliyuretic effects of the drug. It is concluded that renal PG-system and kallikrein-kinin system are not involved in the formation of renal effects of dopamine. Renal tissue RAS directly included in the mechanism of action of dopamine in the kidney, acting as a modulator, preventing excessive loss of water and electrolytes with urine.

  11. Progress in prevention of mother-to-child transmission of HIV infection in Ukraine: results from a birth cohort study

    PubMed Central

    2009-01-01

    Background Ukraine was the epicentre of the HIV epidemic in Eastern Europe, which has the most rapidly accelerating HIV epidemic world-wide today; national HIV prevalence is currently estimated at 1.6%. Our objective was to evaluate the uptake and effectiveness of interventions for prevention of mother-to-child transmission (PMTCT) over an eight year period within operational settings in Ukraine, within the context of an ongoing birth cohort study. Methods The European Collaborative Study (ECS) is an ongoing birth cohort study in which HIV-infected pregnant women identified before or during pregnancy or at delivery were enrolled and their infants prospectively followed. Three centres in Ukraine started enrolling in 2000, with a further three joining in September 2006. Results Of the 3356 women enrolled, 21% (689) reported current or past injecting drug use (IDU). Most women were diagnosed antenatally and of those, the proportion diagnosed in the first/second trimester increased from 47% in 2000/01 (83/178) to 73% (776/1060) in 2006/07 (p < 0.001); intrapartum diagnosis was associated with IDU (Adjusted odds ratio 4.38; 95%CI 3.19–6.02). The percentage of women not receiving any antiretroviral prophylaxis declined from 18% (36/205) in 2001 to 7% in 2007 (61/843) (p < 0.001). Use of sdNVP alone substantially declined after 2003, with a concomitant increase in zidovudine prophylaxis. Median antenatal zidovudine prophylaxis duration increased from 24 to 72 days between 2000 and 2007. Elective caesarean section (CS) rates were relatively stable over time and 34% overall. Mother-to-child transmission (MTCT) rates decreased from 15.2% in 2001 (95%CI 10.2–21.4) to 7.0% in 2006 (95%CI 2.6–14.6). In adjusted analysis, MTCT risk was reduced by 43% with elective CS versus vaginal delivery and by 75% with zidovudine versus no prophylaxis. Conclusion There have been substantial improvements in use of PMTCT interventions in Ukraine, including earlier diagnosis of HIV

  12. The Transfection of BDNF to Dopamine Neurons Potentiates the Effect of Dopamine D3 Receptor Agonist Recovering the Striatal Innervation, Dendritic Spines and Motor Behavior in an Aged Rat Model of Parkinson’s Disease

    PubMed Central

    Razgado-Hernandez, Luis F.; Espadas-Alvarez, Armando J.; Reyna-Velazquez, Patricia; Sierra-Sanchez, Arturo; Anaya-Martinez, Veronica; Jimenez-Estrada, Ismael; Bannon, Michael J.; Martinez-Fong, Daniel; Aceves-Ruiz, Jorge

    2015-01-01

    The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson’s disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring

  13. Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence.

    PubMed

    Boileau, Isabelle; McCluskey, Tina; Tong, Junchao; Furukawa, Yoshiaki; Houle, Sylvain; Kish, Stephen J

    2016-03-01

    We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [(11)C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [(11)C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [(11)C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [(11)C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support post-mortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.

  14. Direct inhibition of the N-methyl-D-aspartate receptor channel by dopamine and (+)-SKF38393.

    PubMed

    Castro, N G; de Mello, M C; de Mello, F G; Aracava, Y

    1999-04-01

    1. Dopamine is known to modulate glutamatergic synaptic transmission in the retina and in several brain regions by activating specific G-protein-coupled receptors. We have examined the possibility of a different type of mechanism for this modulation, one involving direct interaction of dopamine with ionotropic glutamate receptors. 2. Ionic currents induced by fast application of N-methyl-D-aspartate (NMDA) were recorded under whole-cell patch-clamp in cultured striatal, thalamic and hippocampal neurons of the rat and in retinal neurons of the chick. Dopamine at concentrations above 100 microM inhibited the NMDA response in all four neuron types, exhibiting an IC50 of 1.2 mM in hippocampal neurons. The time course of this inhibition was fast, developing in less than 100 ms. 3. The D1 receptor agonist (+)-SKF38393 mimicked the effect of dopamine, with an IC50 of 58.9 microM on the NMDA response, while the enantiomer (-)-SKF38393 was ineffective at 50 microM. However, the D1 antagonist R(+)-SCH23390 did not prevent the inhibitory effect of (+)-SKF38393. 4. The degree of inhibition by dopamine and (+)-SKF38393 depended on transmembrane voltage, increasing 2.7 times with a hyperpolarization of about 80 mV. The voltage-dependent block by dopamine was also observed in the presence of MgCl2 1 mM. 5. Single-channel recordings showed that the open times of NMDA-gated channels were shortened by (+)-SKF38393. 6. These data suggested that the site to which the drugs bound to produce the inhibitory effect was distinct from the classical D1-type dopamine receptor sites, possibly being located inside the NMDA channel pore. It is concluded that dopamine and (+)-SKF38393 are NMDA channel ligands.

  15. Direct inhibition of the N-methyl-D-aspartate receptor channel by dopamine and (+)-SKF38393

    PubMed Central

    Castro, Newton G; de Mello, Maria Christina F; de Mello, Fernando G; Aracava, Yasco

    1999-01-01

    Dopamine is known to modulate glutamatergic synaptic transmission in the retina and in several brain regions by activating specific G-protein-coupled receptors. We have examined the possibility of a different type of mechanism for this modulation, one involving direct interaction of dopamine with ionotropic glutamate receptors.Ionic currents induced by fast application of N-methyl-D-aspartate (NMDA) were recorded under whole-cell patch-clamp in cultured striatal, thalamic and hippocampal neurons of the rat and in retinal neurons of the chick. Dopamine at concentrations above 100 μM inhibited the NMDA response in all four neuron types, exhibiting an IC50 of 1.2 mM in hippocampal neurons. The time course of this inhibition was fast, developing in less than 100 ms.The D1 receptor agonist (+)-SKF38393 mimicked the effect of dopamine, with an IC50 of 58.9 μM on the NMDA response, while the enantiomer (−)-SKF38393 was ineffective at 50 μM. However, the D1 antagonist R(+)-SCH23390 did not prevent the inhibitory effect of (+)-SKF38393.The degree of inhibition by dopamine and (+)-SKF38393 depended on transmembrane voltage, increasing 2.7 times with a hyperpolarization of about 80 mV. The voltage-dependent block by dopamine was also observed in the presence of MgCl2 1 mM.Single-channel recordings showed that the open times of NMDA-gated channels were shortened by (+)-SKF38393.These data suggested that the site to which the drugs bound to produce the inhibitory effect was distinct from the classical D1-type dopamine receptor sites, possibly being located inside the NMDA channel pore. It is concluded that dopamine and (+)-SKF38393 are NMDA channel ligands. PMID:10372829

  16. Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers.

    PubMed

    Rademacher, Lena; Prinz, Susanne; Winz, Oliver; Henkel, Karsten; Dietrich, Claudia A; Schmaljohann, Jörn; Mohammadkhani Shali, Siamak; Schabram, Ina; Stoppe, Christian; Cumming, Paul; Hilgers, Ralf-Dieter; Kumakura, Yoshitaka; Coburn, Mark; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

    2016-08-01

    There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. Dopamine D2 Receptor antagonism suppresses tau aggregation and neurotoxicity

    PubMed Central

    McCormick, Allyson V.; Wheeler, Jeanna M.; Guthrie, Chris R.; Liachko, Nicole F.; Kraemer, Brian C.

    2012-01-01

    Background Tauopathies, including Alzheimer’s disease (AD) and frontotemporal dementia, are diseases characterized by the formation of pathological tau protein aggregates in the brain and progressive neurodegeneration. Presently no effective disease modifying treatments exist for tauopathies. Methods To identify drugs targeting tau neurotoxicity, we have used a C. elegans model of tauopathy to screen a drug library containing 1120 compounds approved for human use for the ability to suppress tau-induced behavioral effects. Results One compound, the typical antipsychotic azaperone, improved the motility of tau transgenic worms, reduced levels of insoluble tau, and was protective against neurodegeneration. We found that azaperone reduces insoluble tau in a human cell culture model of tau aggregation, and that other antipsychotic drugs (flupenthixol, perphenazine, and zotepine) also ameliorate the effects of tau expression in both models. Conclusions Reduction of dopamine signaling through the dopamine D2 receptor with the use of gene knockouts in C. elegans or RNAi knockdown in human cell culture have similar protective effects against tau toxicity. These results suggest dopamine D2 receptor antagonism holds promise as a potential neuroprotective strategy for targeting tau aggregation and neurotoxicity. PMID:23140663

  18. Beating a dead horse: dopamine and Parkinson disease.

    PubMed

    Ahlskog, J Eric

    2007-10-23

    Our collective thinking about Parkinson disease (PD) has been heavily influenced by the dramatic response to dopamine replacement therapy. For progress to continue, however, we need to take a broad view of this disorder, which includes recognition of the following. First, substantial evidence now indicates that dopamine oxidation is unlikely to substantially contribute to the pathogenesis of PD. Second, levodopa therapy is not associated with neurotoxicity. Third, the first neurons affected in PD are nondopaminergic; the substantia nigra and other dopaminergic nuclei are affected only later in the course. Thus, PD is much more than degeneration of the dopaminergic nigrostriatal system. Fourth, in the current era, most of the disability of advancing PD is from involvement of nondopaminergic systems, including levodopa-refractory motor symptoms, dementia, and dysautonomia. Motor complications associated with levodopa therapy can be problematic, but they can be controlled in most, using available medications and deep brain stimulation surgery. We have reached the point of diminishing therapeutic returns with drugs acting on dopamine systems; more dopaminergic medications will provide only modest incremental benefit over current therapies. Finally, the benefits from transplantation surgeries aimed at restoring dopaminergic neurotransmission will be limited because later-stage PD disability comes from nondopaminergic substrates. Scale.

  19. Are dopamine derivatives implicated in the pathogenesis of Parkinson's disease?

    PubMed

    Bisaglia, Marco; Filograna, Roberta; Beltramini, Mariano; Bubacco, Luigi

    2014-01-01

    Parkinson's disease (PD) is the most common motor system disorder affecting 1-2% of people over the age of sixty-five. Although PD is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease, representing 5-10% of all cases, has been very important in helping to partially delineate the molecular pathways that lead to this pathology. These mechanisms include impairment of the intracellular protein-degradation pathways, protein aggregation, mitochondria dysfunction, oxidative stress and neuroinflammation. Some of these features are also supported by post-mortem analyses. One of the main pathological hallmarks of PD is the preferential degeneration of dopaminergic neurons, which supports a direct role of dopamine itself in promoting the disorder. This review presents a comprehensive overview of the existing literature that links the aforementioned pathways to the oxidative chemistry of dopamine, ultimately leading to the formation of free radicals and reactive quinone species. We emphasize, in particular, how the reaction of dopamine-derived quinones with several cellular targets could foster the processes involved in the pathogenesis of PD and contribute to the progression of the disorder.

  20. The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals.

    PubMed

    Stavarache, Mihaela A; Musatov, Sergei; McGill, Marlon; Vernov, Mary; Kaplitt, Michael G

    2015-10-01

    Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.

  1. PET imaging of dopamine receptors in MPTP-induced parkinsonism

    SciTech Connect

    Larson, S.M.; DiChiro, G.; Burns, R.S.; Dannals, R.F.; Kopin, I.J.; Brooks, R.A.; Kessler, R.M.; Wagner, R.F.; Eckelman, W.C.; Margolin, R.A.

    1984-01-01

    MPTP(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in animals and man by selectively destroying dopaminergic neurons in the pars compacta of the substantia nigra. The postsynaptic neurons (and presumably the dopamine receptors) are intact. The authors have imaged dopamine receptors in a patient with MPTP induced parkinsonism, using /sup 11/CMS (3-N(/sup 11/C) methylspiperone. Seven and 9 mCi's, respectively, were injected at one week intervals while the patient was first off, and then on, L-dopa. As measured by NeuroPET (NIH), putamen to cerebellum concentration ratios rose progressively to 5.5:1, by 90 min. after injection. At this time the concentration of /sup 11/CMS was 10 picomole/cc (off L-dopa), and 14 picomole/cc (on L-dopa). The Duvoisin scale was used to assess the severity of the patient's parkinsonism immediately prior and at the end of PET imaging. On both occasions, despite the small mass amount of /sup 11/CMS injected, (1.1 g/kg), a transient worsening of symptoms was seen. The effect of L-Dopa was almost completely reversed by the /sup 11/CMS. In contrast, off L-Dopa the patients severe basal state was worsened only slightly. The PET scans suggested that dopamine receptors are not reduced in MPTP-induced parkinsonism. The findings were consistent with the hypotheses that PET may identify patients who will benefit from L-Dopa, and that expression of parkinsonian symptoms reflects desaturation of dopamine receptors in striatum.

  2. Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease

    PubMed Central

    Morrow, Bret A.; Roth, Robert H.; Redmond, D. Eugene; Elsworth, John D.

    2011-01-01

    Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to 4 treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal TH immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 hours after administration than the adults. As a possible explanation for the protection, striatal GDNF levels were elevated in young animals 1-week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: 1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, 2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal DA neurons, and 3) the increased striatal production of GDNF in young animals, but not in adults, in

  3. Rapid determination of dopamine in human plasma using a gold nanoparticle-based dual-mode sensing system.

    PubMed

    Zhang, Yali; Qi, Suijian; Liu, Zhonggang; Shi, Yupeng; Yue, Wanqing; Yi, Changqing

    2016-04-01

    Dopamine plays a very important role in biological systems and has a direct relationship with the ability of learning and cognition, human desires, feelings and mental state, as well as motor functions. Traditional methods for the detection of dopamine are complicated and time-consuming, therefore it is necessary to explore rapid and accurate detection of dopamine with high sensitivity and specificity. Herein we report a dual-mode system of colorimetric and fluorometric analyses based on gold nanoparticles (AuNPs) and aptamers specifically targeting dopamine. Aptamers modified with the fluorophore were used as dopamine specific recognition probe and the sensing mechanism is based on the color change of AuNPs and the fluorescence recovery of fluorophore conjugated on the aptamers in the presence of dopamine. The addition of aptamers into AuNPs colloid solution would prevent the AuNPs from aggregation in the high-salt solution. The close distance between AuNPs and fluorophore conjugated on the aptamers would lead to the quenching of fluorescence signal. In the presence of dopamine, the conformation of the aptamers and the inter-particle distance would be changed, leading to the aggregation of AuNPs, which subsequently results in color change from red to blue and fluorescence signal recovery. The dual-mode sensing system demonstrated high specificity towards dopamine with the detection limit as low as 78.7 nM. The sensing system reflects on its simplicity as no surface functionalization is required for the nanoparticles, leading to less laborious and more cost-effective synthesis. The reaction time is only 6 min, demonstrating a simple approach for rapid analysis of dopamine. More importantly, the sensing system allows the detection of dopamine in both aqueous solution and complicated biological sample with sensitive response, illustrating the feasibility and reliability for the potential applications in clinical and biomedical analysis in the future.

  4. Acquisition of an appetitive behavior prevents development of stress-induced neurochemical modifications in rat nucleus accumbens.

    PubMed

    Nanni, Giulio; Scheggi, Simona; Leggio, Benedetta; Grappi, Silvia; Masi, Flavio; Rauggi, Riccardo; De Montis, Maria Graziella

    2003-08-15

    In rats, exposure to chronic unavoidable stress produces a decrease in dopamine output in the nucleus accumbens shell that is accompanied by a decreased density of the dopamine transporter and an increased activity of the dopamine-D(1) receptor complex. These modifications have been hypothesized to be adaptive to decreased dopamine output in stressed rats. We investigated whether the learning of an appetitive behavior sustained by palatable food, which is associated with increased dopamine output in the nucleus accumbens shell as measured by microdialysis experiments, would affect the modifications induced by chronic stress exposure on dopamine transporter density and dopamine-D(1) receptor complex activity in the nucleus accumbens. Rats exposed to chronic unavoidable stress after acquisition of the appetitive behavior showed a higher dopamine extraneuronal release in the nucleus accumbens shell than that of stressed animals, and similar to that of control rats. Moreover, previous acquisition of the appetitive behavior prevented development of a stress-induced decrease in dopamine transporter density, measured by [(3)H]-WIN 35428 binding, a stress-induced increase in dopamine-D(1) receptor density, measured by binding of [(3)H]-SCH 23390, and SKF 38393-stimulated adenylyl cyclase activity in the nucleus accumbens. These results support the hypothesis that changes induced in pre- and postsynaptic dopaminergic transmission by chronic stress exposure are related to decreased dopamine output. Copyright 2003 Wiley-Liss, Inc.

  5. Fluoxetine at anorectic doses does not have properties of a dopamine uptake inhibitor.

    PubMed

    Fuller, R W; Hemrick-Luecke, S K; Snoddy, H D

    1994-01-01

    Although fluoxetine is a highly selective inhibitor of serotonin uptake in vitro and in vivo, some investigators have suggested that dopamine uptake inhibition may contribute to anorectic actions of fluoxetine. The present experiments were done to determine fluoxetine's effects in some animal protocols in which dopamine uptake inhibitors have characteristic actions. Mazindol prevented the depletion of striatal dopamine and its metabolites by amphetamine in iprindole-pretreated rats, but fluoxetine had no effect. Mazindol prevented the depletion of striatal dopamine and its metabolites by 6-hydroxydopamine injected intracerebroventricularly into rats, but fluoxetine had no effect. Mazindol enhanced the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain after spiperone injection, but fluoxetine did not cause that effect. Fluoxetine did not mimic amfonelic acid in antagonizing the retention of alpha-methyl-m-tyramine invant striatum after the injection of alpha-methyl-m-tyrosine. These results show that fluoxetine, at doses that are effective in blocking the serotonin uptake carrier and causing anorexia, does not block the dopamine uptake carrier.

  6. Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior.

    PubMed

    du Hoffmann, Johann; Nicola, Saleem M

    2016-01-01

    Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety.

  7. Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior

    PubMed Central

    du Hoffmann, Johann; Nicola, Saleem M.

    2016-01-01

    Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety. PMID:27471453

  8. Synapsins Differentially Control Dopamine and Serotonin Release

    PubMed Central

    Kile, Brian M.; Guillot, Thomas S.; Venton, B. Jill; Wetsel, William C.; Augustine, George J.; Wightman, R. Mark

    2010-01-01

    Synapsins are a family of synaptic vesicle proteins that are important for neurotransmitter release. Here we have used triple knockout (TKO) mice lacking all three synapsin genes to determine the roles of synapsins in the release of two monoamine neurotransmitters, dopamine and serotonin. Serotonin release evoked by electrical stimulation was identical in substantia nigra pars reticulata slices prepared from TKO and wild-type mice. In contrast, release of dopamine in response to electrical stimulation was approximately doubled in striatum of TKO mice, both in vivo and in striatal slices, in comparison to wild-type controls. This was due to loss of synapsin III, because deletion of synapsin III alone was sufficient to increase dopamine release. Deletion of synapsins also increased the sensitivity of dopamine release to extracellular calcium ions. Although cocaine did not affect the release of serotonin from nigral tissue, this drug did enhance dopamine release. Cocaine-induced facilitation of dopamine release was a function of external calcium, an effect that was reduced in TKO mice. We conclude that synapsins play different roles in the control of release of dopamine and serotonin, with release of dopamine being negatively regulated by synapsins, specifically synapsin III, while serotonin release appears to be relatively independent of synapsins. These results provide further support for the concept that synapsin function in presynaptic terminals varies according to the neurotransmitter being released. PMID:20660258

  9. Synapsins differentially control dopamine and serotonin release.

    PubMed

    Kile, Brian M; Guillot, Thomas S; Venton, B Jill; Wetsel, William C; Augustine, George J; Wightman, R Mark

    2010-07-21

    Synapsins are a family of synaptic vesicle proteins that are important for neurotransmitter release. Here we have used triple knock-out (TKO) mice lacking all three synapsin genes to determine the roles of synapsins in the release of two monoamine neurotransmitters, dopamine and serotonin. Serotonin release evoked by electrical stimulation was identical in substantia nigra pars reticulata slices prepared from TKO and wild-type mice. In contrast, release of dopamine in response to electrical stimulation was approximately doubled in striatum of TKO mice, both in vivo and in striatal slices, in comparison to wild-type controls. This was due to loss of synapsin III, because deletion of synapsin III alone was sufficient to increase dopamine release. Deletion of synapsins also increased the sensitivity of dopamine release to extracellular calcium ions. Although cocaine did not affect the release of serotonin from nigral tissue, this drug did enhance dopamine release. Cocaine-induced facilitation of dopamine release was a function of external calcium, an effect that was reduced in TKO mice. We conclude that synapsins play different roles in the control of release of dopamine and serotonin, with release of dopamine being negatively regulated by synapsins, specifically synapsin III, while serotonin release appears to be relatively independent of synapsins. These results provide further support for the concept that synapsin function in presynaptic terminals varies according to the neurotransmitter being released.

  10. Going for broke: dopamine influences risky choice.

    PubMed

    Moschak, Travis M; Carelli, Regina M

    2014-10-01

    Dopamine neurons track reward by increasing or decreasing their firing rate when a reward is present or absent. In this issue of Neuron, Stopper et al. (2014) demonstrate that artificially eliminating these dopamine bursts or dips can alter risky decision-making.

  11. Metabolism of dopamine by the nasal mucosa.

    PubMed

    Chemuturi, Nagendra V; Donovan, Maureen D

    2006-11-01

    The nasal route of administration offers several advantages over oral and intravenous administration, including the ability to avoid hepatic first pass metabolism. Dopamine deficiency has been associated with several neurological disorders; it has been shown to have good systemic bioavailability and significant uptake into the CNS following intranasal administration. The purpose of these studies was to investigate the limiting role of mucosal metabolism of dopamine during nasal absorption. In vitro transport and initial rate studies were carried out using nasal mucosal explants to study dopamine permeability and metabolism. Dihydroxyphenylacetic acid (DOPAC) was the only metabolite detected. Monoamine oxidase (MAO), the enzyme responsible for DOPAC formation, was localized to the submucosal region of the nasal explants. The amount of DOPAC formed during the transport studies was less than 0.5% of the initial amount of dopamine placed into the system. Iproniazid, an MAO inhibitor, blocked DOPAC formation but had no effect on dopamine transport. The limited extent of dopamine metabolism compared to its mucosal transport demonstrates that nasal dopamine transport is not significantly reduced by mucosal metabolism and suggests that the nasal route may be promising for the efficient delivery of dopamine to the CNS.

  12. Normative data of dopaminergic neurotransmission functions in substantia nigra measured with MRI and PET: Neuromelanin, dopamine synthesis, dopamine transporters, and dopamine D2 receptors.

    PubMed

    Ito, Hiroshi; Kawaguchi, Hiroshi; Kodaka, Fumitoshi; Takuwa, Hiroyuki; Ikoma, Yoko; Shimada, Hitoshi; Kimura, Yasuyuki; Seki, Chie; Kubo, Hitoshi; Ishii, Shiro; Takano, Harumasa; Suhara, Tetsuya

    2017-09-01

    The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[β-(11)C]DOPA, [(18)F]FE-PE2I and [(11)C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 recepto