Cocaine- and amphetamine-regulated transcript peptide (CART) in the telencephalon of the catfish, Clarias gariepinus: distribution and response to fasting, 2-deoxy-D-glucose, glucose, insulin, and leptin treatments.

PubMed

Subhedar, Nishikant; Barsagade, Vikas G; Singru, Praful S; Thim, Lars; Clausen, Jes Thorn

2011-05-01

The cocaine- and amphetamine-regulated transcript peptide (CART)-containing system in the forebrain of Clarias gariepinus was studied with immunocytochemistry. While the immunoreactivity was prominently seen in the neurons of the entopeduncular nucleus (EN) located in the ventral telencephalon, CART-immunoreactive fibers were widely distributed in the dorsal and ventral telencephalon. In view of the established role of CART in energy metabolism, we investigated the response of the CART immunoreactive system to positive and negative nutritional conditions. Neurons of the EN and fibers in the different areas of the telencephalon showed significant reduction in CART immunoreactivity following 48 hours food deprivation, or 2 hours following intracranial administration of 2-deoxy-D-glucose (2DG, 100 ng/g body weight, a metabolic antagonist of glucose). However, intracranial injection of glucose (100 ng/g body weight) resulted in a distinct increase in CART immunoreactivity in these components. In mammals, insulin and leptin have been recognized as adiposity agents that convey peripheral energy status-related information to brain. Intracranial administration of insulin (3 mU/fish) and leptin (10 ng/g body weight) significantly increased CART immunoreactivity in the EN neurons and in the fiber network within 2 hours. Superfusion of the EN-containing tissue fragments in the medium enriched in glucose, insulin, or leptin evoked a significant increase in CART immunoreactivity in the EN neurons, but 2DG reduced the immunoreactivity. We suggest that CART-containing neurons of the EN, and fibers in the telencephalon, may process the energy status-related information and contribute to satiety. Copyright © 2011 Wiley-Liss, Inc.

Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

PubMed

Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

2015-04-01

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pre and postprandial changes in orexigenic and anorexigenic factors in channel catfish Ictalurus punctatus

USDA-ARS?s Scientific Manuscript database

We examined pre- and postprandial changes in the expression of plasma ghrelin (GHRL) and mRNAs encoding GRLN, cocaine and amphetamine regulated transcript (CART), neuropeptide Y (NPY), and cholecystokinin (CCK) in channel catfish. Fish were either offered feed (Fed) or fasted (Unfed). Feeding incr...

Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats.

PubMed

Dhillo, W S; Small, C J; Stanley, S A; Jethwa, P H; Seal, L J; Murphy, K G; Ghatei, M A; Bloom, S R

2002-09-01

A number of neuropeptides implicated in the hypothalamic regulation of appetite are synthesized in the arcuate nucleus (Arc). Neuropeptide Y (NPY) and agouti-related protein (Agrp) are orexigenic. The pro-opiomelanocortin (POMC) product alpha-melanocyte-stimulating hormone (alpha-MSH) is anorectic. Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) decreases food intake. However, recent results show that CART is orexigenic when injected into discrete hypothalamic nuclei. There is almost complete coexpression of NPY and Agrp mRNA in Arc neurones, and the majority of CART-containing neurones in the Arc also contain POMC mRNA. We investigated possible interactions between these neuropeptides in vitro using a rat hypothalamic explant system. Administration of 1, 10 and 100 nm of NPY to hypothalamic explants significantly increased release of Agrp(83-132)-immunoreactivity (IR). NPY (10 and 100 nm) significantly increased the release of CART(55-102)-IR and alpha-MSH-IR from hypothalamic explants. Agrp(83-132) (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. Agrp(83-132) (10 and 100 nm) significantly decreased the release of CART(55-102)-IR from hypothalamic explants. Administration of 1, 10 and 100 nm CART(55-102) to hypothalamic explants resulted in a significant increase in NPY-IR release. Administration of 10 nm CART(55-102) to hypothalamic explants significantly increased the release of Agrp(83-132)-IR. NDP-MSH (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. NDP-MSH (10 and 100 nm) significantly increased the release of Agrp(83-132)-IR from hypothalamic explants. These data suggest that orexigenic neuropeptides in the arcuate nucleus stimulate the release of each other, perhaps reinforcing orexigenic behaviour via a positive-feedback loop. Our results are also in keeping with the possibility that the melanocortin-3 receptor in the arcuate nucleus may influence the release of arcuate neuropeptides.

Differential expression of cocaine- and amphetamine-regulated transcript and agouti related-protein in chronically food-restricted sheep.

PubMed

Henry, B A; Rao, A; Ikenasio, B A; Mountjoy, K G; Tilbrook, A J; Clarke, I J

2001-11-09

Recently, much attention has focused on the role of the melanocortin system in the regulation of energy homeostasis, especially the satiety effects of the pro-opiomelanocortin (POMC)-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH). We have found that POMC mRNA levels are similar in fat and thin sheep and the current study sought to further characterize the effects of nutritional status on the melanocortin system. To this end, we studied the expression of agouti-related peptide (AGRP) (an endogenous antagonist of alpha-MSH) and cocaine- and amphetamine-regulated transcript (CART), which is co-localized within POMC cells of the arcuate nucleus (ARC) in rodents. Twelve ovariectomized ewes were randomly divided into two groups and fed a maintenance (n=6) or restricted diet (n=6). At the time of experimentation, the animals had significantly (P<0.0001) different bodyweights (53.4+/-2.2 kg, ad libitum vs. 30.4+/-1.2 kg, food-restricted), which was largely due to altered body fat deposits. In situ hybridization was used to study the expression of POMC, AGRP and CART. The expression of POMC in the ARC was similar in ad libitum and food-restricted animals but the expression of AGRP was profoundly increased in the food-restricted group. The expression of CART was abundant throughout the hypothalamus but was not found in the ARC. In food-restricted animals, the expression of CART was lower in the retrochiasmatic nucleus (P<0.01), paraventricular nucleus (P<0.001), the dorsomedial nucleus and the lateral hypothalamic area (P<0.05), but was higher (P<0.01) in the posterior hypothalamic area. Thus, long-term changes in nutritional status have profound effects on the expression of AGRP and CART in the hypothalamus.

Distribution of cocaine- and amphetamine-regulated transcript in the hippocampal formation of the guinea pig and domestic pig.

PubMed

Kolenkiewicz, M; Robak, A; Równiak, M; Bogus-Nowakowska, K; Całka, J; Majewski, M

2009-02-01

This study provides a detailed description concerning the distribution of cocaineand amphetamine-regulated transcript (CART) subunits - CART(61-102) and rhCART(28-116) - in the hippocampal formation (HF) of the guinea pig and domestic pig, focussing on the dentate gyrus (DG) and hippocampus proper (HP). Although in both studied species CART-immunoreactive (CART-IR) neuronal somata and processes were present generally in the same layers, some species-specific differences were still found. In the granular layer (GL) of both species, the ovalshaped neurons and some thick varicose fibres were encountered. In the guinea pig there was an immunoreactive "band of dots", probably representing crosssectioned terminals within the DG molecular layer (MOL), whereas in the domestic pig, some varicose fibres were detected, thus suggesting a different orientation of, at least, some nerve terminals. Furthermore, some CART-positive cells and fibres were observed in the hilus (HL) of the guinea pig, whereas in the analogical part of the domestic pig only nerve terminals were labelled. In both species, in the pyramidal layer (PL) of the hippocampus proper, CART-IR triangular somata were observed in the CA3 sector, as well as some positive processes in MOL; however, a few immunoreactive perikarya were found only in the CA1 sector of the guinea pig. As regards the localization patterns of two isoforms of CART in the guinea pig, both peptide fragments were present simultaneously in each of the labelled neurons or fibres, whereas in the domestic pig three types of fibres may be distinguished within the area of the DG. In the hilus and MOL of the dentate gyrus, there were fibres expressing both isoforms of CART in their whole length (fibres of the first type). Fibres of the second type (in GL) coexpressed both peptides only on their short segments, and the last ones (in MOL) expressed solely rhCART(28-116). These results indicate that the distribution of the two CART isoforms are specifically related, thus the relationship between the two CART isoforms may imply different metabolic profiles of CART-expressing neurons.

Changes in expression of appetite-regulating hormones in the cunner (Tautogolabrus adspersus) during short-term fasting and winter torpor.

PubMed

Babichuk, Nicole A; Volkoff, Hélène

2013-08-15

Feeding in vertebrates is controlled by a number of appetite stimulating (orexigenic, e.g., orexin and neuropeptide Y, NPY) and appetite suppressing (anorexigenic, e.g., cholecystokinin, CCK and cocaine- and amphetamine-regulated transcript, CART) hormones. Cunners (Tautogolabrus adspersus) survive the winter in shallow coastal waters by entering a torpor-like state, during which they forgo feeding. In order to better understand the mechanisms regulating appetite/fasting in these fish, quantitative real-time PCR was used to measure transcript expression levels of four appetite-regulating hormones: NPY, CART, orexin and CCK in the forebrain (hypothalamus and telencephalon) and CCK in the gut of fed, short-term summer fasted, and natural winter torpor cunners. Summer fasting induced a decrease in hypothalamic orexin levels and telencephalon NPY, CART and CCK mRNA levels. All brain hormone mRNA levels decreased during natural torpor as compared to fed summer fish. In the gut, CCK expression levels decreased during summer fasting. These results indicate that, in cunner, orexin, NPY, CART and CCK may play a role in appetite regulation and might mediate different physiological responses to short-term summer fasting and torpor-induced long-term fasting. © 2013.

Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+ /calmodulin-dependent protein kinase II.

PubMed

Xiong, Lixia; Meng, Qing; Sun, Xi; Lu, Xiangtong; Fu, Qiang; Peng, Qinghua; Yang, Jianhua; Oh, Ki-Wan; Hu, Zhenzhen

2018-01-04

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca 2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. This study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca 2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-over-expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca 2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-over-expressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-over-expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. © 2018 International Society for Neurochemistry.

Nucleus accumbens cocaine-amphetamine regulated transcript mediates food intake during novelty conflict

PubMed Central

Burghardt, PR; Krolewski, DM; Dykhuis, KE; Ching, J; Pinawin, AM; Britton, SL; Koch, LG; Watson, SJ; Akil, H.

2016-01-01

Obesity is a persistent and pervasive problem, particularly in industrialized nations. It has come to be appreciated that the metabolic health of an individual can influence brain function and subsequent behavioral patterns. To examine the relationship between metabolic phenotype and central systems that regulate behavior, we tested rats with divergent metabolic phenotypes (Low Capacity Runner: LCR vs. High Capacity Runner: HCR) for behavioral responses to the conflict between hunger and environmental novelty using the novelty suppressed feeding (NSF) paradigm. Additionally, we measured expression of mRNA, for peptides involved in energy management, in response to fasting. Following a 24-h fast, LCR rats showed lower latencies to begin eating in a novel environment compared to HCR rats. A 48-h fast equilibrated the latency to begin eating in the novel environment. A 24-h fast differentially affected expression of cocaine-amphetamine regulated transcript (CART) mRNA in the nucleus accumbens (NAc), where 24-h of fasting reduced CART mRNA in LCR rats. Bilateral microinjections of CART 55–102 peptide into the NAc increased the latency to begin eating in the NSF paradigm following a 24-h fast in LCR rats. These results indicate that metabolic phenotype influences how animals cope with the conflict between hunger and novelty, and that these differences are at least partially mediated by CART signaling in the NAc. For individuals with poor metabolic health who have to navigate food-rich and stressful environments, changes in central systems that mediate conflicting drives may feed into the rates of obesity and exacerbate the difficulty individuals have in maintaining weight loss. PMID:26926827

Enhanced Upregulation of CRH mRNA Expression in the Nucleus Accumbens of Male Rats after a Second Injection of Methamphetamine Given Thirty Days Later

PubMed Central

Cadet, Jean Lud; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T.; Krasnova, Irina N.; Lehrmann, Elin; Becker, Kevin G.; Jayanthi, Subramaniam

2014-01-01

Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P<0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh), oxytocin (Oxt), and vasopressin (Avp) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down-regulated) transcripts measured one month later (MS group). These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug. PMID:24475032

Cocaine- and amphetamine-regulated transcript peptide and calcium binding proteins immunoreactivity in the deep layers of the superior colliculus of the guinea pig: Implications for multisensory and visuomotor processing.

PubMed

Najdzion, Janusz

2018-03-01

The superior colliculus (SC) of mammals is a midbrain center, that can be subdivided into the superficial (SCs) and deep layers (SCd). In contrast to the visual SCs, the SCd are involved in multisensory and motor processing. This study investigated the pattern of distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (CaBPs) i.e. calbindin (CB), calretinin (CR) and parvalbumin (PV) in the SCd of the guinea pig. CART labeling was seen almost exclusively in the neuropil and fibers, which differed in regard to morphology and location. CART-positive neurons were very rare and restricted to a narrow area of the SCd. The most intense CART immunoreactivity was observed in the most dorsally located sublayer of the SCd, which is anatomically and functionally connected with the SCs. CART immunoreactivity in the remaining SCd was less intensive, but still relatively high. This characteristic pattern of immunoreactivity indicates that CART as a putative neurotransmitter or neuromodulator may play an important role in processing of visual information, while its involvement in the auditory and visuomotor processing is less significant, but still possible. CaBPs-positive neurons were morphologically diverse and widely distributed throughout all SCd. From studied CaBPs, CR showed a markedly different distribution compared to CB and PV. Overall, the patterns of distribution of CB and PV were similar in the entire SCd. Consequently, the complementarity of these patterns in the guinea pig was very weak. Double immunostaining revealed that CART did not colocalize with either CaBPs, which suggested that these neurochemical substances might not coexist in the multisensory and visuomotor parts of the SC. Copyright © 2017 Elsevier B.V. All rights reserved.

CART in the brain of vertebrates: circuits, functions and evolution.

PubMed

Subhedar, Nishikant K; Nakhate, Kartik T; Upadhya, Manoj A; Kokare, Dadasaheb M

2014-04-01

Cocaine- and amphetamine-regulated transcript peptide (CART) with its wide distribution in the brain of mammals has been the focus of considerable research in recent years. Last two decades have witnessed a steady rise in the information on the genes that encode this neuropeptide and regulation of its transcription and translation. CART is highly enriched in the hypothalamic nuclei and its relevance to energy homeostasis and neuroendocrine control has been understood in great details. However, the occurrence of this peptide in a range of diverse circuitries for sensory, motor, vegetative, limbic and higher cortical areas has been confounding. Evidence that CART peptide may have role in addiction, pain, reward, learning and memory, cognition, sleep, reproduction and development, modulation of behavior and regulation of autonomic nervous system are accumulating, but an integration has been missing. A steady stream of papers has been pointing at the therapeutic potentials of CART. The current review is an attempt at piecing together the fragments of available information, and seeks meaning out of the CART elements in their anatomical niche. We try to put together the CART containing neuronal circuitries that have been conclusively demonstrated as well as those which have been proposed, but need confirmation. With a view to finding out the evolutionary antecedents, we visit the CART systems in sub-mammalian vertebrates and seek the answer why the system is shaped the way it is. We enquire into the conservation of the CART system and appreciate its functional diversity across the phyla. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

PubMed

Rakovska, Angelina; Baranyi, Maria; Windisch, Katalin; Petkova-Kirova, Polina; Gagov, Hristo; Kalfin, Reni

2017-09-01

CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [ 3 H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal levels of DOPET. At the same concentration, 0.1μM, CART (55-102) peptide did not have any effect on the release of noradrenaline. In the presence of CART (55-102) peptide, 0.1μM, the effect of cocaine, 30μM, on the basal dopamine release was inhibited and the effect on the basal DOPAC release substantially increased. To our knowledge, our findings are the first to show direct neurochemical evidence that CART (55-102) peptide plays a neuromodulatory role on the dopaminergic reward system by decreasing dopamine in the mouse nucleus accumbens and by attenuating cocaine-induced effects on dopamine release. Copyright © 2017 Elsevier Inc. All rights reserved.

The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans.

PubMed

Jensen, P B; Kristensen, P; Clausen, J T; Judge, M E; Hastrup, S; Thim, L; Wulff, B S; Foged, C; Jensen, J; Holst, J J; Madsen, O D

1999-03-26

The hypothalamic satiety peptide CART (cocaine and amphetamine regulated transcript) is expressed at high levels in anorectic rat glucagonomas but not in hypoglycemic insulinomas. However, a non-anorectic metastasis derived from the glucagonoma retained high CART expression levels and produced circulating CART levels comparable to that of the anorectic tumors. Moreover, distinct glucagonoma lines derived by stable HES-1 transfection of the insulinoma caused severe anorexia but retained low circulating levels of CART comparable to that of insulinoma bearing or control rats. Islet tumor associated anorexia and circulating CART levels are thus not correlated, and in line with this peripheral administration of CART (5-50 mg/kg) produced no effect on feeding behavior. In the rat two alternatively spliced forms of CART mRNA exist and quantitative PCR revealed expression of both forms in the hypothalamus, in the different islet tumors, and in the islets of Langerhans. Immunocytochemistry as well as in situ hybridization localized CART expression to the somatostatin producing islet D cell. A potential endocrine/paracrine role of islet CART remains to be clarified.

MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

PubMed

Burgos, Jonathan R; Iresjö, Britt-Marie; Smedh, Ulrika

2016-04-01

The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.

Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent.

PubMed

Gerrits, Han; Bakker, Nicole Ec; van de Ven-de Laat, Cindy Jm; Bourgondien, Freek Gm; Peddemors, Carolien; Litjens, Ralph Hgm; Kok, Han J; Vogel, Gerard Mt; Krajnc-Franken, Magda Am; Gossen, Jan A

2011-12-01

Cocaine- and amphetamine-regulated transcript (CART) has emerged as a neurotransmitter and hormone that has been implicated in many processes including food intake, maintenance of body weight, and reward, but also in the regulation of bone mass. CART-deficient mice are characterized by an osteoporotic phenotype, whereas female transgenic mice overexpressing CART display an increase in bone mass. Here we describe experiments that show that peripheral subcutaneous sustained release of different CART peptide isoforms for a period up to 60 days increased bone mass by 80% in intact mice. CART peptides increased trabecular bone mass, but not cortical bone mass, and the increase was caused by reduced osteoclast activity in combination with normal osteoblast activity. The observed effect on bone was gender-specific, because male mice did not respond to treatment with CART peptides. In addition, male transgenic CART overexpressing mice did not display increased bone mass. Ovariectomy (OVX) completely abolished the increase of bone mass by CART peptides, both in CART peptide-treated wild-type mice and in CART transgenic mice. The effect of CART peptide treatment on trabecular bone was not mediated by 17β-estradiol (E(2)) because supplementation of OVX mice with E(2) could not rescue the effect of CART peptides on bone. Together, these results indicate that sustained release of CART peptides increases bone mass in a gender-specific way via a yet unknown mechanism that requires the presence of the ovary. Copyright © 2011 American Society for Bone and Mineral Research.

Evaluation of CART peptide level in rat plasma and CSF: Possible role as a biomarker in opioid addiction.

PubMed

Bakhtazad, Atefeh; Vousooghi, Nasim; Garmabi, Behzad; Zarrindast, Mohammad Reza

2016-10-01

It has been shown previously that cocaine- and amphetamine-regulated transcript (CART) peptide has a modulatory role and homeostatic regulatory effect in motivation to and reward of the drugs of abuse specially psychostimulants. Recent data also showed that in addition to psychostimulants, CART is critically involved in the different stages of opioid addiction. Here we have evaluated the fluctuations in the level of CART peptide in plasma and CSF in different phases of opioid addiction to find out whether CART can serve as a suitable marker in opioid addiction studies. Male rats were randomly distributed in groups of control, acute low-dose (10mg/kg) morphine, acute high-dose morphine (80mg/kg), chronic escalating doses of morphine, withdrawal syndrome precipitated by administration of naloxone (1mg/kg), and abstinent after long-term drug-free maintenance of addicted animals. The level of CART peptide in CSF and plasma samples was measured by enzyme immunoassay. CART peptide concentration in the CSF and plasma was significantly elevated in acute high-dose morphine and withdrawal state animals and down-regulated in addicted rats. In abstinent group, CART peptide level was up-regulated in plasma but not in CSF samples. As the observed results are in agreement with data regarding the CART mRNA and protein expression in the brain reward pathway in opioid addiction phases, it may be suggested that evaluation of CART peptide level in CSF or plasma could be a suitable marker which reflects the rises and falls of the peptide concentration in brain in the development of opioid addiction. Copyright © 2016 Elsevier Inc. All rights reserved.

Characterization of the Two CART Genes (CART1 and CART2) in Chickens (Gallus gallus)

PubMed Central

Huang, Long; Li, Juan; Wang, Yajun

2015-01-01

Cocaine- and amphetamine-regulated transcript (CART) peptide is implicated in the control of avian energy balance, however, the structure and expression of CART gene(s) remains largely unknown in birds. Here, we cloned and characterized two CART genes (named cCART1 and cCART2) in chickens. The cloned cCART1 is predicted to generate two bioactive peptides, cCART1(42-89) and cCART1(49-89), which share high amino acid sequence identity (94-98%) with their mammalian counterparts, while the novel cCART2 may produce a bioactive peptide cCART2(51-91) with 59% identity to cCART1. Interestingly, quantitative RT-PCR revealed that cCART1 is predominantly expressed in the anterior pituitary and less abundantly in the hypothalamus. In accordance with this finding, cCART1 peptide was easily detected in the anterior pituitary by Western blot, and its secretion from chick pituitaries incubated in vitro was enhanced by ionomycin and forskolin treatment, indicating that cCART1 is a novel peptide hormone produced by the anterior pituitary. Moreover, cCART1 mRNA expression in both the pituitary and hypothalamus is down-regulated by 48-h fasting, suggesting its expression is affected by energy status. Unlike cCART1, cCART2 is only weakly expressed in most tissues examined by RT-PCR, implying a less significant role of cCART2 in chickens. As in chickens, 2 or more CART genes, likely generated by gene and genome duplication event(s), were also identified in other non-mammalian vertebrate species including coelacanth. Collectively, the identification and characterization of CART genes in birds helps to uncover the roles of CART peptide(s) in vertebrates and provides clues to the evolutionary history of vertebrate CART genes. PMID:25992897

Association of the Cocaine- and Amphetamine-Regulated Transcript Prepropeptide Gene (CARTPT) rs2239670 Variant with Obesity among Kampar Health Clinic Patrons, Malaysia.

PubMed

Lisa, Yeo; Sook-, Ha Fan; Yee-, How Say

2012-01-01

Cocaine- and amphetamine-regulated transcript (CART) is a hypothalamic anorectic neuropeptide that controls feeding behaviour and body weight. The study objective was to investigate the association of the CART prepropeptide gene (CARTPT) rs2239670 variant with obesity and its related anthropometric indicators among patients of a Malaysian health clinic in Kampar, Perak, Malaysia. A total of 300 Malay/Peninsular Bumiputera, Chinese, and Indian subjects (115 males, 185 females; 163 non-obese, 137 obese) were recruited by convenience sampling, and anthropometric measurements, blood pressures, and pulse rate were taken. Genotyping was performed using AvaII polymerase chain reaction-restriction fragment length polymorphism. Genotyping revealed 203 (67.7%), 90 (30.0%), and 7 (2.3%) subjects with the GG, GA, and AA genotypes, respectively, with a minor allele (A) frequency of 0.17. No significant difference in the CARTPT rs2239670 genotype and allele distribution was found between obese and non-obese subjects, and logistic regression showed no association between the mutated genotypes (GA, AA) and allele (A) with obesity, even after adjusting for age, gender, and ethnicity. Furthermore, the measurements did not differ significantly between the genotypes and alleles. No significant difference in the genotype and allele distribution was found among genders, but they were significantly different among ethnicities (P = 0.030 and P = 0.019, respectively). CARTPT rs2239670 is not a predictor for obesity among the Malaysian subjects in this study.

Temperature dependence of the control of energy homeostasis requires CART signaling.

PubMed

Lau, Jackie; Shi, Yan-Chuan; Herzog, Herbert

2016-10-01

Cocaine- and amphetamine-regulated transcript (CART) is a key neuropeptide with predominant expression in the hypothalamus central to the regulation of diverse biological processes, including food intake and energy expenditure. While there is considerable information on CART's role in the control of feeding, little is known about its thermoregulatory potential. Here we show the consequences of lack of CART signaling on major parameters of energy homeostasis in CART -/- mice under standard ambient housing (RT, 22°C), which is considered a mild cold exposure for mice, and thermoneutral conditions (TN, 30°C). WT mice kept at RT showed an increase in food intake, energy expenditure, BAT UCP-1 expression, and physical activity compared with TN condition, reflecting the augmented energy demand for thermogenesis at RT. On the molecular level, RT housing led to upregulated mRNA expression of TH, CRH, and TRH at the PVN, while NPY, AgRP and CART mRNA levels in the Arc were downregulated. CART -/- mice displayed elevated adiposity and diminished lean mass across both RT and TN. At RT, CART -/- mice showed unchanged food consumption yet greater body weight gain. In addition, an increase in energy expenditure and heightened BAT thermogenesis marked by UCP-1 protein expression was observed in the CART -/- mice. In contrast, TN-housed CART -/- mice exhibited lower weight gain than WT mice accompanied with pronounced reduction in basal feeding. These findings were correlated with reduced BAT temperature, but unchanged energy expenditure and UCP-1 levels. Interestingly, the respiratory exchange ratio for CART -/- mice, which shifted from lower at RT to higher at TN with respect to WT controls, indicates a transition of relative fuel source preference from fat to carbohydrate in the absence of CART signaling. Taken together, these results demonstrate that CART is a critical regulator of energy expenditure, energy partitioning and utilization dependent on the thermal environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Leptin regulation of bone resorption by the sympathetic nervous system and CART.

PubMed

Elefteriou, Florent; Ahn, Jong Deok; Takeda, Shu; Starbuck, Michael; Yang, Xiangli; Liu, Xiuyun; Kondo, Hisataka; Richards, William G; Bannon, Tony W; Noda, Masaki; Clement, Karine; Vaisse, Christian; Karsenty, Gerard

2005-03-24

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

The Ontogeny and Brain Distribution Dynamics of the Appetite Regulators NPY, CART and pOX in Larval Atlantic Cod (Gadus morhua L.)

PubMed Central

Le, Hoang T. M. D.; Angotzi, Anna Rita; Ebbesson, Lars O. E.; Karlsen, Ørjan

2016-01-01

Similar to many marine teleost species, Atlantic cod undergo remarkable physiological changes during the early life stages with concurrent and profound changes in feeding biology and ecology. In contrast to the digestive system, very little is known about the ontogeny and the localization of the centers that control appetite and feed ingestion in the developing brain of fish. We examined the expression patterns of three appetite regulating factors (orexigenic: neuropeptide Y, NPY; prepro-orexin, pOX and anorexigenic: cocaine- and amphetamine-regulated transcript, CART) in discrete brain regions of developing Atlantic cod using chromogenic and double fluorescent in situ hybridization. Differential temporal and spatial expression patterns for each appetite regulator were found from first feeding (4 days post hatch; dph) to juvenile stage (76 dph). Neurons expressing NPY mRNA were detected in the telencephalon (highest expression), diencephalon, and optic tectum from 4 dph onward. CART mRNA expression had a wider distribution along the anterior-posterior brain axis, including both telencephalon and diencephalon from 4 dph. From 46 dph, CART transcripts were also detected in the olfactory bulb, region of the nucleus of medial longitudinal fascicle, optic tectum and midbrain tegmentum. At 4 and 20 dph, pOX mRNA expression was exclusively found in the preoptic region, but extended to the hypothalamus at 46 and 76 dph. Co-expression of both CART and pOX genes were also observed in several hypothalamic neurons throughout larval development. Our results show that both orexigenic and anorexigenic factors are present in the telencephalon, diencephalon and mesencephalon in cod larvae. The telencephalon mostly contains key factors of hunger control (NPY), while the diencephalon, and particularly the hypothalamus may have a more complex role in modulating the multifunctional control of appetite in this species. As the larvae develop, the overall progression in temporal and spatial complexity of NPY, CART and pOX mRNAs expression might be correlated to the maturation of appetite control regulation. These observations suggest that teleost larvae continue to develop the regulatory networks underlying appetite control after onset of exogenous feeding. PMID:27100086

The Ontogeny and Brain Distribution Dynamics of the Appetite Regulators NPY, CART and pOX in Larval Atlantic Cod (Gadus morhua L.).

PubMed

Le, Hoang T M D; Angotzi, Anna Rita; Ebbesson, Lars O E; Karlsen, Ørjan; Rønnestad, Ivar

2016-01-01

Similar to many marine teleost species, Atlantic cod undergo remarkable physiological changes during the early life stages with concurrent and profound changes in feeding biology and ecology. In contrast to the digestive system, very little is known about the ontogeny and the localization of the centers that control appetite and feed ingestion in the developing brain of fish. We examined the expression patterns of three appetite regulating factors (orexigenic: neuropeptide Y, NPY; prepro-orexin, pOX and anorexigenic: cocaine- and amphetamine-regulated transcript, CART) in discrete brain regions of developing Atlantic cod using chromogenic and double fluorescent in situ hybridization. Differential temporal and spatial expression patterns for each appetite regulator were found from first feeding (4 days post hatch; dph) to juvenile stage (76 dph). Neurons expressing NPY mRNA were detected in the telencephalon (highest expression), diencephalon, and optic tectum from 4 dph onward. CART mRNA expression had a wider distribution along the anterior-posterior brain axis, including both telencephalon and diencephalon from 4 dph. From 46 dph, CART transcripts were also detected in the olfactory bulb, region of the nucleus of medial longitudinal fascicle, optic tectum and midbrain tegmentum. At 4 and 20 dph, pOX mRNA expression was exclusively found in the preoptic region, but extended to the hypothalamus at 46 and 76 dph. Co-expression of both CART and pOX genes were also observed in several hypothalamic neurons throughout larval development. Our results show that both orexigenic and anorexigenic factors are present in the telencephalon, diencephalon and mesencephalon in cod larvae. The telencephalon mostly contains key factors of hunger control (NPY), while the diencephalon, and particularly the hypothalamus may have a more complex role in modulating the multifunctional control of appetite in this species. As the larvae develop, the overall progression in temporal and spatial complexity of NPY, CART and pOX mRNAs expression might be correlated to the maturation of appetite control regulation. These observations suggest that teleost larvae continue to develop the regulatory networks underlying appetite control after onset of exogenous feeding.

Evidence of a local negative role for cocaine and amphetamine regulated transcript (CART), inhibins and low molecular weight insulin like growth factor binding proteins in regulation of granulosa cell estradiol production during follicular waves in cattle

PubMed Central

Kobayashi, Yasuhiro; Jimenez-Krassel, Fermin; Ireland, James J; Smith, George W

2006-01-01

The ability of ovarian follicles to produce large amounts of estradiol is a hallmark of follicle health status. Estradiol producing capacity is lost in ovarian follicles before morphological signs of atresia. A prominent wave like pattern of growth of antral follicles is characteristic of monotocous species such as cattle, horses and humans. While our knowledge of the role of pituitary gonadotropins in support of antral follicle growth and development is well established, the intrinsic factors that suppress estradiol production and may help promote atresia during follicular waves are not well understood. Numerous growth factors and cytokines have been reported to suppress granulosa cell estradiol production in vitro, but the association of expression of many such factors in vivo with follicle health status and their physiological significance are not clear. The purpose of this review is to discuss the in vivo and in vitro evidence supporting a local physiological role for cocaine and amphetamine regulated transcript, inhibins and low molecular weight insulin like growth factor binding proteins in negative regulation of granulosa cell estradiol production, with emphasis on evidence from the bovine model system. PMID:16611367

Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

PubMed

Venancio, Jade Cabestre; Margatho, Lisandra Oliveira; Rorato, Rodrigo; Rosales, Roberta Ribeiro Costa; Debarba, Lucas Kniess; Coletti, Ricardo; Antunes-Rodrigues, Jose; Elias, Carol F; Elias, Lucila Leico K

2017-11-01

Leptin is a permissive factor for puberty initiation, participating as a metabolic cue in the activation of the kisspeptin (Kiss1)-gonadotropin-releasing hormone neuronal circuitry; however, it has no direct effect on Kiss1 neurons. Leptin acts on hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons, participating in the regulation of energy homeostasis. We investigated the influence of a short-term high-fat diet (HFD) on the effect of leptin on puberty timing. Kiss1-hrGFP female mice received a HFD or regular diet (RD) after weaning at postnatal day (PN)21 and were studied at PN28 and PN32. The HFD increased body weight and plasma leptin concentrations and decreased the age at vaginal opening (HFD, 32 ± 0.53 days; RD, 38 ± 0.67 days). Similar colocalization of neurokinin B and dynorphin in Kiss1-hrGFP neurons of the arcuate nucleus (ARC) was observed between the HFD and RD groups. The HFD increased CART expression in the ARC and Kiss1 messenger RNA expression in the anteroventral periventricular (AVPV)/anterior periventricular (Pe). The HFD also increased the number of ARC CART neurons expressing leptin-induced phosphorylated STAT3 (signal transducer and activator of transcription 3) at PN32. Close apposition of CART fibers to Kiss1-hrGFP neurons was observed in the ARC of both RD- and HFD-fed mice. In conclusion, these data reinforce the notion that a HFD increases kisspeptin expression in the AVPV/Pe and advances puberty initiation. Furthermore, we have demonstrated that the HFD-induced earlier puberty is associated with an increase in CART expression in the ARC. Therefore, these data indicate that CART neurons in the ARC can mediate the effect of leptin on Kiss1 neurons in early puberty induced by a HFD. Copyright © 2017 Endocrine Society.

Quantitative Evaluation of CART-Containing Cells in Urinary Bladder of Rats with Renovascular Hypertension

PubMed Central

Janiuk, I.; Kasacka, I.

2015-01-01

Recent biological advances make it possible to discover new peptides associated with hypertension. The cocaine- and amphetamine-regulated transcript (CART) is a known factor in appetite and feeding behaviour. Various lines of evidence suggest that this peptide participates not only in control of feeding behaviour but also in the regulation of the cardiovascular and sympathetic systems and blood pressure. The role of CART in blood pressure regulation led us to undertake a study aimed at analysing quantitative changes in CART-containing cells in urinary bladders (UB) of rats with renovascular hypertension. We used the Goldblatt model of arterial hypertension (two-kidney, one clip) to evaluate quantitative changes. This model provides researchers with a commonly used tool to analyse the renin-angiotensin system of blood pressure control and, eventually, to develop drugs for the treatment of chronic hypertension. The study was performed on sections of urinary bladders of rats after 3-, 14-, 28-, 42 and 91 days from hypertension induction. Immunohistochemical identification of CART cells was performed on paraffin for the UBs of all the study animals. CART was detected in the endocrine cells, especially numerous in the submucosa and muscularis layers, with a few found in the transitional epithelium and only occasionally in serosa. Hypertension significantly increased the number of CART-positive cells in the rat UBs. After 3 and 42 days following the procedure, statistically significantly higher numbers of CART-positive cells were identified in comparison with the control animals. The differences between the hypertensive rats and the control animals concerned not only the number density of CART-immunoreactive cells but also their localization. After a 6-week period, each of the rats subjected to the renal artery clipping procedure developed stable hypertension. CART appeared in numerous transitional epithelium cells. As this study provides novel findings, the question appears about the type of connection between hypertension and the functioning and activity of CART in the urinary tract (UT). The study gives rise to the assumption that high blood pressure can be a factor that intensifies CART secretion. In conclusion, the endocrine system of the urinary tract is modified by renovascular hypertension. This may affect the production of hormones and biologically active substances and contribute to the development of possible hypertension complications. In order to fully comprehend the role of the CART peptide in blood pressure regulation, further analyses are necessary. PMID:26150151

Quantitative evaluation of CART-containing cells in urinary bladder of rats with renovascular hypertension.

PubMed

Janiuk, I; Kasacka, I

2015-04-13

Recent biological advances make it possible to discover new peptides associated with hypertension. The cocaine- and amphetamine-regulated transcript (CART) is a known factor in appetite and feeding behaviour. Various lines of evidence suggest that this peptide participates not only in control of feeding behaviour but also in the regulation of the cardiovascular and sympathetic systems and blood pressure. The role of CART in blood pressure regulation led us to undertake a study aimed at analysing quantitative changes in CART-containing cells in urinary bladders (UB) of rats with renovascular hypertension. We used the Goldblatt model of arterial hypertension (two-kidney, one clip) to evaluate quantitative changes. This model provides researchers with a commonly used tool to analyse the renin-angiotensin system of blood pressure control and, eventually, to develop drugs for the treatment of chronic hypertension. The study was performed on sections of urinary bladders of rats after 3-, 14-, 28-, 42 and 91 days from hypertension induction. Immunohistochemical identification of CART cells was performed on paraffin for the UBs of all the study animals. CART was detected in the endocrine cells, especially numerous in the submucosa and muscularis layers, with a few found in the transitional epithelium and only occasionally in serosa. Hypertension significantly increased the number of CART-positive cells in the rat UBs. After 3 and 42 days following the procedure, statistically significantly higher numbers of CART-positive cells were identified in comparison with the control animals. The differences between the hypertensive rats and the control animals concerned not only the number density of CART-immunoreactive cells but also their localization. After a 6-week period, each of the rats subjected to the renal artery clipping procedure developed stable hypertension. CART appeared in numerous transitional epithelium cells. As this study provides novel findings, the question appears about the type of connection between hypertension and the functioning and activity of CART in the urinary tract (UT). The study gives rise to the assumption that high blood pressure can be a factor that intensifies CART secretion. In conclusion, the endocrine system of the urinary tract is modified by renovascular hypertension. This may affect the production of hormones and biologically active substances and contribute to the development of possible hypertension complications. In order to fully comprehend the role of the CART peptide in blood pressure regulation, further analyses are necessary.

Mediation of oxidative stress in hypothalamic ghrelin-associated appetite control in rats treated with phenylpropanolamine.

PubMed

Yu, C-H; Chu, S-C; Chen, P-N; Hsieh, Y-S; Kuo, D-Y

2017-04-01

Phenylpropanolamine (PPA)-induced appetite control is associated with oxidative stress in the hypothalamus. This study explored whether hypothalamic antioxidants participated in hypothalamic ghrelin system-associated appetite control in PPA-treated rats. Rats were given PPA daily for 4 days, and changes in food intake and the expression of neuropeptide Y (NPY), the cocaine- and amphetamine-regulated transcript (CART), superoxide dismutase, catalase, ghrelin, acyl ghrelin (AG), ghrelin O-acyltransferase (GOAT) and the ghrelin receptor (GHSR1a) were examined and compared. Results showed that both food intake and the expression of NPY and ghrelin/AG/GOAT/GHSR1a decreased in response to PPA treatment with maximum decrease on Day 2 of the treatment. In contrast, the expression of antioxidants and CART increased, with the maximum increase on Day 2, with the expression opposite to that of NPY and ghrelin. A cerebral infusion of either a GHSR1a antagonist or reactive oxygen species scavenger modulated feeding behavior and NPY, CART, antioxidants and ghrelin system expression, showing the involvement of ghrelin signaling and oxidative stress in regulating PPA-mediated appetite control. We suggest that hypothalamic ghrelin signaling system, with the help of antioxidants, may participate in NPY/CART-mediated appetite control in PPA-treated rats. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

New analogs of the CART peptide with anorexigenic potency: the importance of individual disulfide bridges.

PubMed

Blechová, Miroslava; Nagelová, Veronika; Záková, Lenka; Demianová, Zuzana; Zelezná, Blanka; Maletínská, Lenka

2013-01-01

The CART (cocaine- and amphetamine-regulated transcript) peptide is an anorexigenic neuropeptide that acts in the hypothalamus. The receptor and the mechanism of action of this peptide are still unknown. In our previous study, we showed that the CART peptide binds specifically to PC12 rat pheochromocytoma cells in both the native and differentiated into neuronal phenotype. Two biologically active forms, CART(55-102) and CART(61-102), with equal biological activity, contain three disulfide bridges. To clarify the importance of each of these disulfide bridges in maintaining the biological activity of CART(61-102), an Ala scan at particular S-S bridges forming cysteines was performed, and analogs with only one or two disulfide bridges were synthesized. In this study, a stabilized CART(61-102) analog with norleucine instead of methionine at position 67 was also prepared and was found to bind to PC12 cells with an anorexigenic potency similar to that of CART(61-102). The binding study revealed that out of all analogs tested, [Ala(68,86)]CART(61-102), which contains two disulfide bridges (positions 74-94 and 88-101), preserved a high affinity to both native PC12 cells and those that had been differentiated into neurons. In food intake and behavioral tests with mice after intracerebroventricular administration, this analog showed strong and long-lasting anorexigenic potency. Therefore, the disulfide bridge between cysteines 68 and 86 in CART(61-102) can be omitted without a loss of biological activity, but the preservation of two other disulfide bridges and the full-length peptide are essential for biological activity. Copyright © 2012 Elsevier Inc. All rights reserved.

Energy Balance Regulating Neuropeptides Are Expressed through Pregnancy and Regulated by Interleukin-6 Deficiency in Mouse Placenta.

PubMed

Pazos, Patricia; Lima, Luis; Diéguez, Carlos; García, María C

2014-01-01

The placenta produces a number of signaling molecules including metabolic and reproductive hormones as well as several inflammatory mediators. Among them, Interleukin-6 (IL-6), a well-known immune and metabolic regulator, acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. IL-6 interacts with key hypothalamic neuropeptidergic systems controlling energy homeostasis such as those producing the orexigenic/anabolic: neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorectic/catabolic neuropeptides: proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). Human and rat placenta have been identified as source of these neuropeptides, but their expression and regulation in murine placental tissues remain unknown. Therefore, placental mRNA levels of IL-6, NPY, AgRP, POMC, and CART at different pregnancy stages (gestational days 13, 15, and 18) were analyzed by real time PCR, as were the effect of IL-6 deficiency (IL-6 knockout mice) on their placental expression. Our results showed that placenta-derived neuropeptides were regulated by gestational age and IL-6 throughout the second half of mouse pregnancy. These data suggest that IL-6 may participate in the fine tune control of energy balance during pregnancy by extending its action as a metabolic signal to the main organ at the fetomaternal interface: the placenta.

Energy Balance Regulating Neuropeptides Are Expressed through Pregnancy and Regulated by Interleukin-6 Deficiency in Mouse Placenta

PubMed Central

Pazos, Patricia; Lima, Luis; Diéguez, Carlos; García, María C.

2014-01-01

The placenta produces a number of signaling molecules including metabolic and reproductive hormones as well as several inflammatory mediators. Among them, Interleukin-6 (IL-6), a well-known immune and metabolic regulator, acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. IL-6 interacts with key hypothalamic neuropeptidergic systems controlling energy homeostasis such as those producing the orexigenic/anabolic: neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorectic/catabolic neuropeptides: proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). Human and rat placenta have been identified as source of these neuropeptides, but their expression and regulation in murine placental tissues remain unknown. Therefore, placental mRNA levels of IL-6, NPY, AgRP, POMC, and CART at different pregnancy stages (gestational days 13, 15, and 18) were analyzed by real time PCR, as were the effect of IL-6 deficiency (IL-6 knockout mice) on their placental expression. Our results showed that placenta-derived neuropeptides were regulated by gestational age and IL-6 throughout the second half of mouse pregnancy. These data suggest that IL-6 may participate in the fine tune control of energy balance during pregnancy by extending its action as a metabolic signal to the main organ at the fetomaternal interface: the placenta. PMID:24744782

Glucocorticoids decrease body weight and food intake and inhibit appetite regulatory peptide expression in the hypothalamus of rats

PubMed Central

LIU, XIAO-YAN; SHI, JIAN-HUA; DU, WEN-HUA; FAN, YAN-PING; HU, XIAO-LEI; ZHANG, CHEN-CHEN; XU, HUAN-BAI; MIAO, YAN-JUN; ZHOU, HAI-YAN; XIANG, PING; CHEN, FENG-LING

2011-01-01

The aim of the present study was to investigate the effects of glucocorticoids (GCs) on appetite and gene expression of the hypothalamic appetite regulatory peptides, neuropeptide Y (NPY), agouti-related protein (AGRP) and cocaine and amphetamine-regulated transcript (CART), in non-obese and obese rats. Both non-obese and obese rats were randomly assigned to three groups: normal saline, low- and high-dose GC groups (NSG, LDG and HDG, respectively), which received an intraperitoneal injection with normal saline (0.2 ml/100 g) or hydrocortisone sodium succinate at 5 and 15 mg/kg, respectively, for 20 days. The expression levels of NPY, AGRP and CART mRNA in the hypothalamus were measured by real-time quantitative PCR. Non-obese and obese rats were found to undergo weight loss after GC injection, and a higher degree of weight loss was observed in the HDG rats. The average and cumulative food intakes in the obese and non-obese rats injected with high-dose GC were lower compared to that in the NSG (p<0.05). mRNA expression levels of the orexigenic neuropeptides, NPY and AGRP, and the anorexigenic neuropeptide, CART, were significantly lower in the HDG than levels in the NSG for both the obese and non-obese rats (p<0.05). GC treatment decreased appetite and body weight, induced apparent glucolipid metabolic disturbances and hyperinsulinemia, while down-regulated mRNA expression levels of the orexigenic neuropeptides, NPY and AGRP, and anorexigenic neuropeptide, CART, in the hypothalamus in the rats. The mechanism which induces this neuropeptide expression requires further study. PMID:22977608

Immunohistochemical localization of cocaine- and amphetamine-regulated transcript peptide (CARTp) in the brain of the pigeon (Columba livia) and zebra finch (Taeniopygia guttata).

PubMed

Gutierrez-Ibanez, Cristian; Iwaniuk, Andrew N; Jensen, Megan; Graham, David J; Pogány, Ákos; Mongomery, Benjamin C; Stafford, James L; Luksch, Harald; Wylie, Douglas R

2016-12-15

Cocaine- and amphetamine-regulated transcript peptides (CARTp) are neuropeptides that act as neurotransmitters in the brain of vertebrates. The expression of CARTp has been characterized in teleosts, amphibians, and several mammalian species, but comparative data in reptiles and birds are nonexistent. In this study, we show the distribution of immunoreactivity against CART peptides (CARTp-ir) in the brains of two bird species: the pigeon (Columba livia) and zebra finch (Taeniopygia guttata). We found CARTp-ir cells and terminals in the brains of both, but no major differences between the two species. As in mammals, teleost fish, and amphibians, CARTp-ir terminals and cells were abundant in subpallial regions, particularly the striatum and nucleus accumbens. We also found CARTp-ir cells and terminals in the hypothalamus, and a large number of CARTp-ir terminals in the substantia nigra, ventral tegmental area, periaqueductal gray, parabrachial nucleus, and dorsal vagal complex. However, in contrast to other vertebrates, CARTp-ir was not found in the olfactory bulb. In addition there was almost no CARTp-ir in the pallium or the hippocampal formation, and little CARTp-ir in the cerebellum. The conserved expression of CARTp in the subpallium, hypothalamus, and dorsal vagal complex of birds suggests that some of the functions of CARTp, such as regulation of food intake and interactions with the social control network and mesolimbic reward system, are conserved among vertebrates. J. Comp. Neurol. 524:3747-3773, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Hypothalamic Integration of Metabolic, Endocrine, and Circadian Signals in Fish: Involvement in the Control of Food Intake

PubMed Central

Delgado, María J.; Cerdá-Reverter, José M.; Soengas, José L.

2017-01-01

The regulation of food intake in fish is a complex process carried out through several different mechanisms in the central nervous system (CNS) with hypothalamus being the main regulatory center. As in mammals, a complex hypothalamic circuit including two populations of neurons: one co-expressing neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and the second one population co-expressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) is involved in the integration of information relating to food intake control. The production and release of these peptides control food intake, and the production results from the integration of information of different nature such as levels of nutrients and hormones as well as circadian signals. The present review summarizes the knowledge and recent findings about the presence and functioning of these mechanisms in fish and their differences vs. the known mammalian model. PMID:28694769

Fluoxetine Induces Proliferation and Inhibits Differentiation of Hypothalamic Neuroprogenitor Cells In Vitro

PubMed Central

Sousa-Ferreira, Lígia; Aveleira, Célia; Botelho, Mariana; Álvaro, Ana Rita; Pereira de Almeida, Luís; Cavadas, Cláudia

2014-01-01

A significant number of children undergo maternal exposure to antidepressants and they often present low birth weight. Therefore, it is important to understand how selective serotonin reuptake inhibitors (SSRIs) affect the development of the hypothalamus, the key center for metabolism regulation. In this study we investigated the proliferative actions of fluoxetine in fetal hypothalamic neuroprogenitor cells and demonstrate that fluoxetine induces the proliferation of these cells, as shown by increased neurospheres size and number of proliferative cells (Ki-67+ cells). Moreover, fluoxetine inhibits the differentiation of hypothalamic neuroprogenitor cells, as demonstrated by decreased number of mature neurons (Neu-N+ cells) and increased number of undifferentiated cells (SOX-2+ cells). Additionally, fluoxetine-induced proliferation and maintenance of hypothalamic neuroprogenitor cells leads to changes in the mRNA levels of appetite regulator neuropeptides, including Neuropeptide Y (NPY) and Cocaine-and-Amphetamine-Regulated-Transcript (CART). This study provides the first evidence that SSRIs affect the development of hypothalamic neuroprogenitor cells in vitro with consequent alterations on appetite neuropeptides. PMID:24598761

Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice

PubMed Central

Wu, Yuwei; Tu, Qisheng; Valverde, Paloma; Zhang, Jin; Murray, Dana; Dong, Lily Q.; Cheng, Jessica; Jiang, Hua; Rios, Maribel; Morgan, Elise; Tang, Zhihui

2014-01-01

Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN-KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC. PMID:24780611

Distribution and female reproductive state differences in orexigenic and anorexigenic neurons in the brain of the mouth brooding African cichlid fish, Astatotilapia burtoni.

PubMed

Porter, Danielle T; Roberts, David A; Maruska, Karen P

2017-10-01

Integration of reproduction and metabolism is necessary for species survival. While the neural circuits controlling energy homeostasis are well-characterized, the signals controlling the relay of nutritional information to the reproductive axis are less understood. The cichlid fish Astatotilapia burtoni is ideal for studying the neural regulation of feeding and reproduction because females cycle between a feeding gravid state and a period of forced starvation while they brood developing young inside their mouths. To test the hypothesis that candidate neuropeptide-containing neurons known to be involved in feeding and energy homeostasis in mammals show conserved distribution patterns, we performed immunohistochemistry and in situ hybridization to localize appetite-stimulating (neuropeptide Y, NPY; agouti-related protein, AGRP) and appetite-inhibiting (cocaine and amphetamine-regulated transcript, CART; pro-opiomelanocortin, pomc1a) neurons in the brain. NPY, AGRP, CART, and pomc1a somata showed distribution patterns similar to other teleosts, which included localization to the lateral tuberal nucleus (NLT), the putative homolog of the mammalian arcuate nucleus. Gravid females also had larger NPY and AGRP neurons in the NLT compared to brooding females, but brooding females had larger pomc1a neurons compared to gravid females. Hypothalamic agrp mRNA levels were also higher in gravid compared to brooding females. Thus, larger appetite-stimulating neurons (NPY, AGRP) likely promote feeding while females are gravid, while larger pomc1a neurons may act as a signal to inhibit food intake during mouth brooding. Collectively, our data suggest a potential role for NPY, AGRP, POMC, and CART in regulating energetic status in A. burtoni females during varying metabolic and reproductive demands. © 2017 Wiley Periodicals, Inc.

Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice.

PubMed

Wu, Yuwei; Tu, Qisheng; Valverde, Paloma; Zhang, Jin; Murray, Dana; Dong, Lily Q; Cheng, Jessica; Jiang, Hua; Rios, Maribel; Morgan, Elise; Tang, Zhihui; Chen, Jake

2014-06-15

Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN-KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC. Copyright © 2014 the American Physiological Society.

Neuropeptidergic Signaling Partitions Arousal Behaviors in Zebrafish

PubMed Central

Schoppik, David; Shi, Veronica J.; Zimmerman, Steven; Coleman, Haley A.; Greenwood, Joel; Soucy, Edward R.

2014-01-01

Animals modulate their arousal state to ensure that their sensory responsiveness and locomotor activity match environmental demands. Neuropeptides can regulate arousal, but studies of their roles in vertebrates have been constrained by the vast array of neuropeptides and their pleiotropic effects. To overcome these limitations, we systematically dissected the neuropeptidergic modulation of arousal in larval zebrafish. We quantified spontaneous locomotor activity and responsiveness to sensory stimuli after genetically induced expression of seven evolutionarily conserved neuropeptides, including adenylate cyclase activating polypeptide 1b (adcyap1b), cocaine-related and amphetamine-related transcript (cart), cholecystokinin (cck), calcitonin gene-related peptide (cgrp), galanin, hypocretin, and nociceptin. Our study reveals that arousal behaviors are dissociable: neuropeptide expression uncoupled spontaneous activity from sensory responsiveness, and uncovered modality-specific effects upon sensory responsiveness. Principal components analysis and phenotypic clustering revealed both shared and divergent features of neuropeptidergic functions: hypocretin and cgrp stimulated spontaneous locomotor activity, whereas galanin and nociceptin attenuated these behaviors. In contrast, cart and adcyap1b enhanced sensory responsiveness yet had minimal impacts on spontaneous activity, and cck expression induced the opposite effects. Furthermore, hypocretin and nociceptin induced modality-specific differences in responsiveness to changes in illumination. Our study provides the first systematic and high-throughput analysis of neuropeptidergic modulation of arousal, demonstrates that arousal can be partitioned into independent behavioral components, and reveals novel and conserved functions of neuropeptides in regulating arousal. PMID:24573274

Differential expression of CART in ewes with differing ovulation rates.

PubMed

Juengel, Jennifer L; French, Michelle C; Quirke, Laurel D; Kauff, Alexia; Smith, George W; Johnstone, Peter D

2017-04-01

We hypothesised that cocaine- and amphetamine-regulated transcript ( CARTPT ) would be differentially expressed in ewes with differing ovulation rates. Expression of mRNA for CARTPT , as well as LHCGR , FSHR , CYP19A1 and CYP17A1 was determined in antral follicles ≥1 mm in diameter collected during the follicular phase in ewes heterozygous for the Booroola and Inverdale genes (I+B+; average ovulation rate 4) and ++ contemporaries (++; average ovulation rate 1.8). In ++ ewes ( n  = 6), CARTPT was expressed in small follicles (1 to <3 mm diameter), where 18.8 ± 2.5% follicles expressed CARTPT CART peptide was also detected in follicular fluid of some follicles of ++ ewes. In I+B+ ewes, 5/6 ewes did not have any follicles that expressed CARTPT , and no CART peptide was detected in any follicle examined. Expression pattern of CYP19A1 differed between I+B+ and ++ ewes with an increased percentage of small and medium follicles (3 to <4.5 mm diameter) but decreased percentage of large follicles (≥4.5 mm diameter) expressing CYP19A1 in the I+B+ ewes. Many of the large follicles from the I+B+ ewes appeared non-functional and expression of LHCGR , FSHR , CYP17A1 and CYP19A1 was less than that observed in ++ ewes. Expression of FSHR and CYP17A1 was not different between groups in small and medium follicles, but LHCGR expression was approximately double in I+B+ ewes compared to that in ++ ewes. Thus, ewes with high ovulation rates had a distinct pattern of expression of CARTPT mRNA and protein compared to ewes with normal ovulation rates, providing evidence for CART being important in the regulation of ovulation rate. © 2017 Society for Reproduction and Fertility.

Putative roles of neuropeptides in vagal afferent signaling

PubMed Central

de Lartigue, Guillaume

2014-01-01

The vagus nerve is a major pathway by which information is communicated between the brain and peripheral organs. Sensory neurons of the vagus are located in the nodose ganglia. These vagal afferent neurons innervate the heart, the lung and the gastrointestinal tract, and convey information about peripheral signals to the brain important in the control of cardiovascular tone, respiratory tone, and satiation, respectively. Glutamate is thought to be the primary neurotransmitter involved in conveying all of this information to the brain. It remains unclear how a single neurotransmitter can regulate such an extensive list of physiological functions from a wide range of visceral sites. Many neurotransmitters have been identified in vagal afferent neurons and have been suggested to modulate the physiological functions of glutamate. Specifically, the anorectic peptide transmitters, cocaine and amphetamine regulated transcript (CART) and the orexigenic peptide transmitters, melanin concentrating hormone (MCH) are differentially regulated in vagal afferent neurons and have opposing effects on food intake. Using these two peptides as a model, this review will discuss the potential role of peptide transmitters in providing a more precise and refined modulatory control of the broad physiological functions of glutamate, especially in relation to the control of feeding. PMID:24650553

Promoter Targeting RNAs: Unexpected Contributors to the Control of HIV-1 Transcription.

PubMed

Suzuki, Kazuo; Ahlenstiel, Chantelle; Marks, Katherine; Kelleher, Anthony D

2015-01-27

In spite of prolonged and intensive treatment with combined antiretroviral therapy (cART), which efficiently suppresses plasma viremia, the integrated provirus of HIV-1 persists in resting memory CD4(+) T cells as latent infection. Treatment with cART does not substantially reduce the burden of latent infection. Once cART is ceased, HIV-1 replication recrudesces from these reservoirs in the overwhelming majority of patients. There is increasing evidence supporting a role for noncoding RNAs (ncRNA), including microRNAs (miRNAs), antisense (as)RNAs, and short interfering (si)RNA in the regulation of HIV-1 transcription. This appears to be mediated by interaction with the HIV-1 promoter region. Viral miRNAs have the potential to act as positive or negative regulators of HIV transcription. Moreover, inhibition of virally encoded long-asRNA can induce positive transcriptional regulation, while antisense strands of siRNA targeting the NF-κB region suppress viral transcription. An in-depth understanding of the interaction between ncRNAs and the HIV-1 U3 promoter region may lead to new approaches for the control of HIV reservoirs. This review focuses on promoter associated ncRNAs, with particular emphasis on their role in determining whether HIV-1 establishes active or latent infection.

Promoter Targeting RNAs: Unexpected Contributors to the Control of HIV-1 Transcription

PubMed Central

Suzuki, Kazuo; Ahlenstiel, Chantelle; Marks, Katherine; Kelleher, Anthony D

2015-01-01

In spite of prolonged and intensive treatment with combined antiretroviral therapy (cART), which efficiently suppresses plasma viremia, the integrated provirus of HIV-1 persists in resting memory CD4+ T cells as latent infection. Treatment with cART does not substantially reduce the burden of latent infection. Once cART is ceased, HIV-1 replication recrudesces from these reservoirs in the overwhelming majority of patients. There is increasing evidence supporting a role for noncoding RNAs (ncRNA), including microRNAs (miRNAs), antisense (as)RNAs, and short interfering (si)RNA in the regulation of HIV-1 transcription. This appears to be mediated by interaction with the HIV-1 promoter region. Viral miRNAs have the potential to act as positive or negative regulators of HIV transcription. Moreover, inhibition of virally encoded long-asRNA can induce positive transcriptional regulation, while antisense strands of siRNA targeting the NF-κB region suppress viral transcription. An in-depth understanding of the interaction between ncRNAs and the HIV-1 U3 promoter region may lead to new approaches for the control of HIV reservoirs. This review focuses on promoter associated ncRNAs, with particular emphasis on their role in determining whether HIV-1 establishes active or latent infection. PMID:25625613

Association of cocaine- and amphetamine-related transcript, leptin and leptin receptor gene polymorphisms with anthropometric obesity phenotype indicators in South African learners.

PubMed

Yako, Y Y; Fanampe, B L; Hassan, M S; Erasmus, R T; van der Merwe, L; van Rensburg, S J; Matsha, T E

2011-01-01

Obesity has increased rapidly in South African children and adolescents. Genes involved in appetite regulation have been extensively studied worldwide, but their role in the obesity phenotype in South African Black and mixed-ancestry school adolescents is unknown. Seven common polymorphisms in LEP, GHRL, CART and LEPR were analysed for genotype and haplotype association with anthropometric obesity phenotype indicators in South African Black and mixed-ancestry adolescent school learners. The CART c.517A→G polymorphism was significantly associated with obesity susceptibility. The LEPR Lys(109)Arg G allele was associated with an average reduction of 2.36 kg/m(2) in body mass index (BMI), 5.66 cm in waist circumference (WC) and 1.61 cm in mid-upper-arm circumference (MUAC). This was confirmed by haplotype analysis. Additionally, a haplotype of the LEP polymorphisms significantly increased BMI, MUAC and hip circumference, while LEPR haplotypes were associated with differences in MUAC. Our findings suggest that c.517A→G and Lys(109)Arg contribute to the variation in anthropometric obesity phenotype indicators observed among Black African and mixed-ancestry South African learners. Furthermore, haplotypes of LEP, LEPR and GHRL polymorphisms were associated with varying measurements of weight, BMI and WC. Further studies are required to confirm our results in a larger and homogeneous study population group. Copyright © 2011 S. Karger AG, Basel.

The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

PubMed

Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

2012-12-11

In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this 'paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT(4) receptors (5-HTR(4)) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR(1B) self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR(4) in the absence of 5-HTR(1B), associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR(4) overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR(4) knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR(4). Additionally, inactivating NAc-5-HTR(4) suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR(4)/CART pathway establishes a 'tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules.

The nucleus accumbens 5-HTR4-CART pathway ties anorexia to hyperactivity

PubMed Central

Jean, A; Laurent, L; Bockaert, J; Charnay, Y; Dusticier, N; Nieoullon, A; Barrot, M; Neve, R; Compan, V

2012-01-01

In mental diseases, the brain does not systematically adjust motor activity to feeding. Probably, the most outlined example is the association between hyperactivity and anorexia in Anorexia nervosa. The neural underpinnings of this ‘paradox', however, are poorly elucidated. Although anorexia and hyperactivity prevail over self-preservation, both symptoms rarely exist independently, suggesting commonalities in neural pathways, most likely in the reward system. We previously discovered an addictive molecular facet of anorexia, involving production, in the nucleus accumbens (NAc), of the same transcripts stimulated in response to cocaine and amphetamine (CART) upon stimulation of the 5-HT4 receptors (5-HTR4) or MDMA (ecstasy). Here, we tested whether this pathway predisposes not only to anorexia but also to hyperactivity. Following food restriction, mice are expected to overeat. However, selecting hyperactive and addiction-related animal models, we observed that mice lacking 5-HTR1B self-imposed food restriction after deprivation and still displayed anorexia and hyperactivity after ecstasy. Decryption of the mechanisms showed a gain-of-function of 5-HTR4 in the absence of 5-HTR1B, associated with CART surplus in the NAc and not in other brain areas. NAc-5-HTR4 overexpression upregulated NAc-CART, provoked anorexia and hyperactivity. NAc-5-HTR4 knockdown or blockade reduced ecstasy-induced hyperactivity. Finally, NAc-CART knockdown suppressed hyperactivity upon stimulation of the NAc-5-HTR4. Additionally, inactivating NAc-5-HTR4 suppressed ecstasy's preference, strengthening the rewarding facet of anorexia. In conclusion, the NAc-5-HTR4/CART pathway establishes a ‘tight-junction' between anorexia and hyperactivity, suggesting the existence of a primary functional unit susceptible to limit overeating associated with resting following homeostasis rules. PMID:23233022

Effects of random food deprivation and refeeding on energy metabolism, behavior and hypothalamic neuropeptide expression in Apodemus chevrieri.

PubMed

Wan-Long, Zhu; Zheng-Kun, Wang

2016-11-01

Maintaining adaptive control of behavior and physiology is the main strategy used by animals in responding to changes of food resources. To investigate the effects of random food deprivation (FD) and refeeding on energy metabolism and behavior in Apodemus chevrieri, we acclimated adult males to FD for 4weeks, then refed them ad libitum for 4weeks (FD-Re group). During the period of FD, animals were fed ad libitum for 4 randomly assigned days each week, and deprived of food the other 3days. A control group was fed ad libitum for 8weeks. At 4 and 8weeks we measured body mass, thermogenesis, serum leptin levels, body composition, gastrointestinal tract morphology, behavior and hypothalamic neuropeptide expression. At 4weeks, food intake, gastrointestinal mass, neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expressions increased and thermogenesis, leptin levels, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressions decreased in FD compared with controls. FD also showed more resting behavior and less activity than the controls on ad libitum day. There were no differences between FD-Re and controls at 8weeks, indicating significant plasticity. These results suggested that animals can compensate for unpredictable reduction in food availability by increasing food intake and reducing energy expended through thermogenesis and activity. Leptin levels, NPY, AgRP, POMC, and CART mRNA levels may also regulate energy metabolism. Significant plasticity in energy metabolism and behavior was shown by A. chevrieri over a short timescale, allowing them to adapt to food shortages in nutritionally unpredictable environments. Copyright © 2016 Elsevier Inc. All rights reserved.

Induction of NPY/AgRP orexigenic peptide expression in rat hypothalamus is an early event in fasting: relationship with circulating leptin, insulin and glucose.

PubMed

Palou, Mariona; Sánchez, Juana; Rodríguez, Ana M; Priego, Teresa; Picó, Catalina; Palou, Andreu

2009-01-01

Hypothalamus is crucial in the control of energy intake and expenditure in mammals, presenting two interconnected populations of neurons producing orexigenic NPY/AgRP (neuropeptide Y; agouti related peptide) and anorexigenic POMC/CART (pro-opiomelanocortin; cocaine and amphetamine regulated transcript) neuropeptides. We aimed to shed more light on the response and sensitivity in the production of these neuropeptides to face nutritional changes, particularly food deprivation, and on the signals that regulate them. Male Wistar rats were fasted for 0, 4, 8 and 24h and refed for 3h after 8h fasting. mRNA levels of gastric and adipose tissue (retroperitoneal, mesenteric and inguinal) leptin, and of hypothalamic NPY, AgRP, POMC, CART, leptin receptor, SOCS3 (suppressor of cytokine signaling 3) and insulin receptor were analyzed. Gastric and circulating leptin, and circulating insulin, glucose and ghrelin were also determined. The only neuropeptide mRNAs that responded (increasing) to the short-term periods of fasting used were those of NPY (transiently) and AgRP, and these changes were accompanied by an increase in leptin receptor mRNA levels and by a decrease in adipose and gastric leptin expression and in the circulating levels of leptin, insulin and glucose, but without changes in circulating ghrelin. The elevation in AgRP and leptin receptor mRNA levels and the drop in circulating leptin were not reverted with refeeding. It is suggested that the induction of expression of the orexigenic molecules in NPY/AgRP neurons is an early event upon fasting, related with changes in leptin, insulin and glucose levels, but with the role of leptin signaling in particular. 2009 S. Karger AG, Basel.

Hypothalamic neuropeptides, not leptin sensitivity, contributes to the hyperphagia in lactating Brandt's voles, Lasiopodomys brandtii.

PubMed

Cui, Jian-Guo; Tang, Gang-Bing; Wang, De-Hua

2011-07-01

Both pregnancy and lactation are associated with hyperphagia, and circulating leptin levels are elevated during pregnancy but decreased during lactation in Brandt's voles, Lasiopodomys brandtii. Previous findings suggest that impaired leptin sensitivity contributes to hyperphagia during pregnancy. The present study aimed to examine whether the decreased circulating leptin level and/or hypothalamic leptin sensitivity contributed to the hyperphagia during lactation in Brandt's voles. The serum leptin level and mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling-3 (SOCS-3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 17 of lactation and day 27 (1 week after weaning) in Brandt's voles. Compared with controls, hypothalamic Ob-Rb and SOCS-3 mRNA expression was not significantly changed during lactation. The serum leptin level was significantly lower in lactating females than in the non-reproductive group. Hypothalamic NPY and AgRP mRNA expression significantly increased whereas POMC mRNA expression was significantly decreased during lactation compared with controls. However, there were no significant changes in hypothalamic CART mRNA expression. Food intake was positively correlated with NPY and AgRP mRNA expression but negatively correlated with POMC mRNA expression during lactation. These data suggest that hyperphagia during lactation was associated with low leptin levels, but not impaired leptin sensitivity, and that the hypothalamic neuropeptides NPY, AgRP and POMC are involved in mediating the role of leptin in food intake regulation in lactating Brandt's voles.

Hypoxemia-induced leptin secretion: a mechanism for the control of food intake in diseased fish.

PubMed

MacDonald, Lauren E; Alderman, Sarah L; Kramer, Sarah; Woo, Patrick T K; Bernier, Nicholas J

2014-06-01

Leptin is a potent anorexigen, but little is known about the physiological conditions under which this cytokine regulates food intake in fish. In this study, we characterized the relationships between food intake, O2-carrying capacity, liver leptin-A1 (lep-a1) gene expression, and plasma leptin-A1 in rainbow trout infected with a pathogenic hemoflagellate, Cryptobia salmositica. As lep gene expression is hypoxia-sensitive and Cryptobia-infected fish are anemic, we hypothesized that Cryptobia-induced anorexia is mediated by leptin. A 14-week time course experiment revealed that Cryptobia-infected fish experience a transient 75% reduction in food intake, a sharp initial drop in hematocrit and hemoglobin levels followed by a partial recovery, a transient 17-fold increase in lep-a1 gene expression, and a sustained increase in plasma leptin-A1 levels. In the hypothalamus, peak anorexia was associated with decreases in mRNA levels of neuropeptide Y (npy) and cocaine- and amphetamine-regulated transcript (cart), and increases in agouti-related protein (agrp) and pro-opiomelanocortin A2 (pomc). In contrast, in non-infected fish pair-fed to infected animals, lep-a1 gene expression and plasma levels did not differ from those of non-infected satiated fish. Pair-fed fish were also characterized by increases in hypothalamic npy and agrp, no changes in pomc-a2, and a reduction in cart mRNA expression. Finally, peak infection was characterized by a significant positive correlation between O2-carrying capacity and food intake. These findings show that hypoxemia, and not feed restriction, stimulates leptin-A1 secretion in Cryptobia-infected rainbow trout and suggest that leptin contributes to anorexia by inhibiting hypothalamic npy and stimulating pomc-a2. © 2014 Society for Endocrinology.

The Central Nervous System and Bone Metabolism: An Evolving Story.

PubMed

Dimitri, Paul; Rosen, Cliff

2017-05-01

Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research

PubMed Central

Churchill, Melissa J.; Cowley, Daniel J.; Wesselingh, Steve L.; Gorry, Paul R.; Gray, Lachlan R.

2014-01-01

Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders (HAND) in up to 50% of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4+ T-cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbor persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence, and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognized and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS. PMID:25060300

P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain.

PubMed

Iioka, Takashi; Furukawa, Keizo; Yamaguchi, Akira; Shindo, Hiroyuki; Yamashita, Shunichi; Tsukazaki, Tomoo

2003-08-01

The paired-like homeoprotein, Cart1, is involved in skeletal development. We describe here that the general coactivator p300/CBP controls the transcription activity of Cart1 through acetylation of a lysine residue that is highly conserved in other homeoproteins. Acetylation of this residue increases the interaction between p300/CBP and Cart1 and enhances its transcriptional activation. Cart1 encodes a paired-like homeoprotein expressed selectively in chondrocyte lineage during embryonic development. Although its target gene remains unknown, gene disruption studies have revealed that Cart1 plays an important role for craniofacial bone formation as well as limb development by cooperating with another homeoprotein, Alx4. In this report, we study the functional involvement of p300/CBP, coactivators with intrinsic histone acetyltransferase (HAT) activity, in the transcriptional control of Cart1. To study the transcription activity of Cart1, a reporter construct containing a putative Cart1 binding site was transiently transfected with the expression vectors of each protein. The interaction between p300/CBP and Cart1 was investigated by glutathione S-transferase (GST) pull-down, yeast two-hybrid, and immunoprecipitation assays. In vitro acetylation assay was performed with the recombinant p300-HAT domain and Cart1 in the presence of acetyl-CoA. p300 and CBP stimulate Cart1-dependent transcription activity, and this transactivation is inhibited by E1A and Tax, oncoproteins that suppress the activity of p300/CBP. Cart1 binds to p300 in vivo and in vitro, and this requires the homeodomain of Cart 1 and N-terminal 139 amino acids of p300. Confocal microscopy analysis shows that Cart1 recruits overexpressed and endogenous p300 to a Cart1-specific subnuclear compartment. Cart1 is acetylated in vivo and sodium butyrate and trichostatin A, histone deacetylase inhibitors, markedly enhance the transcription activity of Cart1. Deletion and mutagenesis analysis identifies the 131st lysine that locates immediately adjacent to the homeodomain as a target of p300-HAT, and a point mutation to this residue attenuates the binding affinity to p300 as well as p300-dependent transcription activity. Together, these results indicate that p300/CBP acts as a cotransactivator to Cart1 through a direct interaction and specific lysine acetylation. In addition, because 131st lysine is highly conserved in other types of homeoprotein, this lysine may be a common target for HAT of p300/CBP for these proteins.

Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse.

PubMed

Haskell-Luevano, Carrie; Schaub, Jay W; Andreasen, Amy; Haskell, Kim R; Moore, Marcus C; Koerper, Lorraine M; Rouzaud, Francois; Baker, Henry V; Millard, William J; Walter, Glenn; Litherland, S A; Xiang, Zhimin

2009-02-01

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.

The gene expression of the hypothalamic feeding-regulating peptides in cisplatin-induced anorexic rats.

PubMed

Yoshimura, Mitsuhiro; Matsuura, Takanori; Ohkubo, Junichi; Ohno, Motoko; Maruyama, Takashi; Ishikura, Toru; Hashimoto, Hirofumi; Kakuma, Tetsuya; Yoshimatsu, Hironobu; Terawaki, Kiyoshi; Uezono, Yasuhito; Ueta, Yoichi

2013-08-01

Cisplatin has been widely used; however, various disadvantageous side effects afflict patients. Rikkunshito (RKT), a traditional Japanese herbal medicine, has been widely prescribed in Japan to improve anorexia; but the mechanisms are unknown. Here we studied whether RKT could improve anorexia induced by cisplatin and changes in feeding-regulating peptides in the hypothalamus in rats. Adult male rats were divided into 4 groups: water+saline (WS), water+cisplatin (WC), RKT+saline (RS), and RKT+cisplatin (RC) groups. Water or RKT (1g/kg) was intragastrically administered for 4 days, from day -1 to day 2, and saline or cisplatin (6mg/kg) was intraperitoneally (i.p.) administered at day 0. After i.p. administration, cumulative food intake, water intake, urine volume and body weight were measured. The rats were then decapitated, followed by removal of the brain, and feeding-regulating peptides in the hypothalamus were measured by in situ hybridization histochemistry. In the three-day measurements, there were no significant changes in cumulative water intake and urine volume. The body weight and cumulative food intake in WC significantly decreased compared to WS, whereas these were not observed in RC. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the arcuate nucleus (ARC) in WC significantly increased, and neuropeptide Y (NPY) in the ARC decreased compared to WS, whereas those in RS and RC were comparable to WS. These results suggest that RKT may have therapeutic potential for anorexia induced by cisplatin. Copyright © 2013. Published by Elsevier Inc.

Amphetamine manipulates monoamine oxidase-A level and behavior using theranostic aptamers of transcription factors AP-1/NF-kB.

PubMed

Liu, Christina H; Ren, Jiaqian; Liu, Philip K

2016-02-03

Monoamine oxidase (MAO) enzymes play a critical role in controlling the catabolism of monoamine neurotransmitters and biogenic trace amines and behavior in humans. However, the mechanisms that regulate MAO are unclear. Several transcription factor proteins are proposed to modulate the transcription of MAO gene, but evidence supporting these hypotheses is controversial. We aimed to investigate the mechanism of gene transcription regulator proteins on amphetamine-induced behavior. We applied aptamers containing a DNA binding sequence, as well as a random sequence (without target) to study the modulation of amphetamine-induced MAO levels and hyperactivity in living mice. We pretreated in adult male C57black6 mice (Taconic Farm, Germantown, NY) (n ≥ 3 litters at a time), 2 to 3 months of age (23 ± 2 gm body weight) with double-stranded (ds) DNA aptamers with sequence specific to activator protein-1 (5ECdsAP1), nuclear factor-kappa beta (5ECdsNF-kB), special protein-1 (5ECdsSP-1) or cyclicAMP responsive element binding (5ECdsCreB) protein binding regions, 5ECdsRan [a random sequence without target], single-stranded AP-1 (5ECssAP-1) (8 nmol DNA per kg) or saline (5 μl, intracerebroventricular [icv] injection) control before amphetamine administration (4 mg/kg, i.p.). We then measured and analyzed locomotor activities and the level of MAO-A and MAO-B activity. In the pathological condition of amphetamine exposure, we showed here that pretreatment with 5ECdsAP1 and 5ECdsNF-kB reversed the decrease of MAO-A activity (p < 0.05, t test), but not activity of the B isomer (MAO-B), in the ventral tegmental area (VTA) and substantia nigra (SN) of C57black6 mice. The change in MAO-A level coincided with a reversed amphetamine-induced restless behavior of mice. Pretreatments with saline, 5ECdsCreB, 5ECdsSP-1, 5ECdsRan or 5ECssAP-1 had no effect. Our data lead us to conclude that elevation of AP-1 or NF-kB indirectly decreases MAO-A protein levels which, in turn, diminishes MAO-A ability in the VTA of the mesolimbic dopaminergic pathway that has been implicated in cells under stress especially in the SN and VTA. This study has implications for design for the treatment of drug exposure and perhaps Parkinson's dementia.

Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections.

PubMed

Kay, Jeremy N; De la Huerta, Irina; Kim, In-Jung; Zhang, Yifeng; Yamagata, Masahito; Chu, Monica W; Meister, Markus; Sanes, Joshua R

2011-05-25

The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXVα1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations.

Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model.

PubMed

Diane, Abdoulaye; Kupreeva, Maria; Borthwick, Faye; Proctor, Spencer D; Pierce, W David; Vine, Donna F

2015-09-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow diet ad libitum or an energy-restricted diet combined with or without voluntary exercise (4  h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (P<0.01). Energy restriction induced an increase in exercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART. © 2015 Society for Endocrinology.

The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum.

PubMed

Szymanska, Kamila; Makowska, Krystyna; Gonkowski, Slawomir

2018-03-20

Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT-used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms.

The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system.

PubMed

Schéle, Erik; Grahnemo, Louise; Anesten, Fredrik; Hallén, Anna; Bäckhed, Fredrik; Jansson, John-Olov

2013-10-01

The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood. To investigate whether the gut microbiota affects hypothalamic and brainstem body fat-regulating circuits, we compared gene expression of food intake-regulating neuropeptides between germ-free and conventionally raised (CONV-R) mice. We found that CONV-R mice had decreased expression of the antiobesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in the brainstem. Moreover, in both the hypothalamus and the brainstem, CONV-R mice had decreased expression of the antiobesity neuropeptide brain-derived neurotrophic factor (Bdnf). CONV-R mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the antiobesity peptides proopiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart) in the hypothalamus. The latter changes in neuropeptide expression could be secondary to elevated fat mass in CONV-R mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in CONV-R mice compared with germ-free mice. The hypothalamic expression of leptin resistance-associated suppressor of cytokine signaling 3 (Socs-3) was increased in CONV-R mice. In conclusion, the gut microbiota reduces the expression of 2 genes coding for body fat-suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat-inducing gut microbiota is associated with hypothalamic signs of Socs-3-mediated leptin resistance, which may be linked to failed compensatory body fat reduction.

Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action

PubMed Central

Laque, Amanda; Zhang, Yan; Gettys, Sarah; Nguyen, Tu-Anh; Bui, Kelly; Morrison, Christopher D.

2013-01-01

Leptin acts centrally via leptin receptor (LepRb)-expressing neurons to regulate food intake, energy expenditure, and other physiological functions. LepRb neurons are found throughout the brain, and several distinct populations contribute to energy homeostasis control. However, the function of most LepRb populations remains unknown, and their contribution to regulate energy homeostasis has not been studied. Galanin has been hypothesized to interact with the leptin signaling system, but literature investigating colocalization of LepRb and galanin has been inconsistent, which is likely due to technical difficulties to visualize both. We used reporter mice with green fluorescent protein expression from the galanin locus to recapitulate the colocalization of galanin and leptin-induced p-STAT3 as a marker for LepRb expression. Here, we report the existence of two populations of galanin-expressing LepRb neurons (Gal-LepRb neurons): in the hypothalamus overspanning the perifornical area and adjacent dorsomedial and lateral hypothalamus [collectively named extended perifornical area (exPFA)] and in the brainstem (nucleus of the solitary tract). Surprisingly, despite the known orexigenic galanin action, leptin induces galanin mRNA expression and stimulates LepRb neurons in the exPFA, thus conflicting with the expected anorexigenic leptin action. However, we confirmed that intra-exPFA leptin injections were indeed sufficient to mediate anorexic responses. Interestingly, LepRb and galanin-expressing neurons are distinct from orexin or melanin-concentrating hormone (MCH)-expressing neurons, but exPFA galanin neurons colocalized with the anorexigenic neuropeptides neurotensin and cocaine- and amphetamine-regulated transcript (CART). Based on galanin's known inhibitory function, we speculate that in exPFA Gal-LepRb neurons galanin acts inhibitory rather than orexigenic. PMID:23482448

Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation

PubMed Central

McGee-Lawrence, Meghan; Buckendahl, Patricia; Carpenter, Caren; Henriksen, Kim; Vaughan, Michael; Donahue, Seth

2015-01-01

ABSTRACT Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. PMID:26157160

Molecular ontogenesis of digestive capability and associated endocrine control in Atlantic cod (Gadus morhua) larvae.

PubMed

Kortner, Trond M; Overrein, Ingrid; Oie, Gunvor; Kjørsvik, Elin; Bardal, Tora; Wold, Per-Arvid; Arukwe, Augustine

2011-10-01

We have profiled the expression of twelve genes, in order to provide an overview on the molecular ontogeny of digestive capability with the associated endocrine control during Atlantic cod (Gadus morhua) larval development. Enzyme activity levels for the key digestive enzyme, trypsin, was also measured. Specifically, transcripts for trypsin, amylase, lipolytic enzymes: bile salt activated lipase (BAL), phospholipase A2 (PLA2) and Acyl CoA dehydrogenase (ACADM), regulatory peptides: neuropeptide Y (NPY), orexin (OX) cholecystokinin (CCK) and cocaine and amphetamine-related transcript (CART), the somatotropic factors: growth hormone (GH), preprosomatostatin 1 (PPSS1) and thyroid hormone receptors (TRα and TRβ) were analyzed using quatitative (real-time) polymerase chain reaction (qPCR). Trypsin and BAL mRNA levels peaked at approximately day 17 and 25 post-hatch, respectively, and thereafter displayed a decreasing pattern until metamorphosis. GH mRNA levels decreased moderately from 3 to 33dph, and thereafter, an increase was observed until 46dph. TRα mRNA levels showed a fluctuating pattern peaking at day 39 post-hatch. TRβ mRNA levels were too low to obtain quantitative measurements. Amylase mRNA slightly increased from day 3 to 17 post-hatch, and thereafter showed a steady decrease until day 60. Interestingly, PLA2 mRNA expression showed a consistent increase throughout the study period, indicating an increasingly important role during larval development. Overall, data from this study indicate that cod larvae show differential developmental mode of expression patterns for key genes and endocrine factors that regulate digestive capability, growth and development. These data are discussed in relation to larval trypsin enzyme activity and previous reports for other teleost species. Copyright © 2011 Elsevier Inc. All rights reserved.

The TRH neuron: a hypothalamic integrator of energy metabolism.

PubMed

Lechan, Ronald M; Fekete, Csaba

2006-01-01

Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy homeostasis not only through effects on thyroid function orchestrated through hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN), but also through central effects on feeding behavior, thermogenesis, locomotor activation and autonomic regulation. Hypophysiotropic TRH neurons are located in the medial and periventricular parvocellular subdivisions of the PVN and receive direct monosynaptic projections from two, separate, populations of leptin-responsive neurons in the hypothalamic arcuate nucleus containing either alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine- and amphetamine-regulated transcript (CART), peptides that promote weight loss and increase energy expenditure, or neuropeptide Y (NPY) and agouti-related protein (AGRP), peptides that promote weight gain and reduce energy expenditure. During fasting, the reduction in TRH mRNA in hypophysiotropic neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase in NPY/AGRP gene expression in arcuate nucleus neurons contributes to the fall in circulating thyroid hormone levels, presumably by increasing the sensitivity of the TRH gene to negative feedback inhibition by thyroid hormone. Endotoxin administration, however, has the paradoxical effect of increasing circulating levels of leptin and melanocortin signaling and CART gene expression in arcuate nucleus neurons, but inhibiting TRH gene expression in hypophysiotropic neurons. This may be explained by an overriding inhibitory effect of endotoxin to increase type 2 iodothyroine deiodinase (D2) in a population of specialized glial cells, tanycytes, located in the base and infralateral walls of the third ventricle. By increasing the conversion of T4 into T3, tanycytes may increase local tissue concenetrations of thyroid hormone, and thereby induce a state of local tissue hyperthyroidism in the region of hypophysisotrophic TRH neurons. Other regions of the brain may also serve as metabolic sensors for hypophysiostropic TRH neurons including the ventrolateral medulla and dorsomedial nucleus of the hypothalamus that have direct monosynaptic projections to the PVN. TRH also exerts a number of effects within the central nervous system that may contribute to the regulation of energy homeostasis. Included are an increase in core body temperature mediated through neurons in the anterior hypothalamic-preoptic area that coordinate a variety of autonomic responses; arousal and locomotor activation through cholinergic and dopaminergic mechanisms on the septum and nucleus accumbens, respectively; and regulation of the cephalic phase of digestion. While the latter responses are largely mediated through cholinergic mechanisms via TRH neurons in the brainstem medullary raphe and dorsal motor nucleus of the vagus, effects of TRH on autonomic loci in the hypothalamic PVN may also be important. Contrary to the actions of T3 to increase appetite, TRH has central effects to reduce food intake in normal, fasting and stressed animals. The precise locus where TRH mediates this response is unknown. However, evidence that an anatomically separate population of nonhypophysiotropic TRH neurons in the anterior parvocellular subdivision of the PVN is integrated into the leptin regulatory control system by the same arcuate nucleus neuronal populations that innervate hypophysiotropic TRH neurons, raises the possibility that anterior parvocellular TRH neurons may be involved, possibly through interactions with the limbic nervous system.

[Roles of biologically active peptide in regulation of feeding behavior and energy homeostasis].

PubMed

Sakurai, Takeshi

2003-09-01

The mechanisms for regulating food intake involve a complicated interplay between peripheral systems (including gastrointestinal peptide secretion, leptin, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. Many hypothalamic neuropeptides are involved in the regulation of energy homeostasis and feeding behavior, including melanocortins, Agouti-related peptide, neuropeptide-Y, cocaine, and amphetamine-regulated transcript, orexin, and melanine concentrating hormone (MCH) as well as monamines (serotonin, dopamine, norepinephrine). Many of these systems are regulated by peripheral metabolic cues including plasma leptin levels. This review summarizes roles of neuropeptides in the regulatory mechanism of feeding and energy homeostasis.

The Influence of Prolonged Acetylsalicylic Acid Supplementation-Induced Gastritis on the Neurochemistry of the Sympathetic Neurons Supplying Prepyloric Region of the Porcine Stomach.

PubMed

Palus, Katarzyna; Całka, Jarosław

2015-01-01

This experiment was designed to establish the localization and neurochemical phenotyping of sympathetic neurons supplying prepyloric area of the porcine stomach in a physiological state and during acetylsalicylic acid (ASA) induced gastritis. In order to localize the sympathetic perikarya the stomachs of both control and acetylsalicylic acid treated (ASA group) animals were injected with neuronal retrograde tracer Fast Blue (FB). Seven days post FB injection, animals were divided into a control and ASA supplementation group. The ASA group was given 100 mg/kg of b.w. ASA orally for 21 days. On the 28th day all pigs were euthanized with gradual overdose of anesthetic. Then fourteen-micrometer-thick cryostat sections were processed for routine double-labeling immunofluorescence, using primary antisera directed towards tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), neuropeptide Y (NPY), galanin (GAL), neuronal nitric oxide synthase (nNOS), leu 5-enkephalin (LENK), cocaine- and amphetamine- regulated transcript peptide (CART), calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP). The data obtained in this study indicate that postganglionic sympathetic nerve fibers supplying prepyloric area of the porcine stomach originate from the coeliac-cranial mesenteric ganglion complex (CCMG). In control animals, the FB-labelled neurons expressed TH (94.85 ± 1.01%), DβH (97.10 ± 0.97%), NPY (46.88 ± 2.53%) and GAL (8.40 ± 0.53%). In ASA group, TH- and DβH- positive nerve cells were reduced (85.78 ± 2.65% and 88.82 ± 1.63% respectively). Moreover, ASA- induced gastritis resulted in increased expression of NPY (76.59 ± 3.02%) and GAL (26.45 ± 2.75%) as well as the novo-synthesis of nNOS (6.13 ± 1.11%) and LENK (4.77 ± 0.42%) in traced CCMG neurons. Additionally, a network of CART-, CGRP-, SP-, VIP-, LENK-, nNOS- immunoreactive (IR) nerve fibers encircling the FB-positive perikarya were observed in both intact and ASA-treated animals. The results of this study indicate involvement of these neuropeptides in the development or presumably counteraction of gastric inflammation.

SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation.

PubMed

Pan, Zhen-Guo; An, Xu-Sheng

2018-04-06

SARM1 (Sterile alpha and armadillo motif-containing protein 1) is the recently identified TIR domain-containing cytosolic protein, which is involved in toll-like receptors (TLRs) signaling transduction. In the present study, the role of SARM1 in high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) progression was explored. We found that SARM1 was expressed highly in fatty liver. And SARM1-knockout (KO) reduced steatohepatitis and metabolic disorders induced by HFD. SARM1-deletion decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in HFD-fed mice. Additionally, inflammatory response caused by HFD was alleviated by SARM1-deletion through inactivating TLR4/7/9 and nuclear factor kappa B (NF-κB) pathways. Of note, SARM1-deletion also reduced the expressions of inflammation-associated molecules in hypothalamus of HFD-fed mice. Furthermore, HFD administration led to oxidative stress in liver of mice, while being decreased in SARM1-KO mice. Moreover, SARM1-ablation improved lipid dyslipidemia by suppressing the mRNA levels of genes, linked to glycolysis, lipogenesis and transcriptional regulation. Insulin resistance was also attenuated by SARM1-deficiency through enhancing the activation of liver Akt/glycogen synthase kinase-3β (GSK3β) and insulin receptor substrate-1 (IRS1)/FOXO1 pathways in HFD-fed mice. Also, SARM1-knockout improved neuropeptide Y (NPY), Pro-Opiomelanocortins (POMC), Agouti-related Protein (AGRP) and Cocaine-and-Amphetamine Responsive Transcript 1 (CART1) expressions in hypothalamus of mice after HFD administration. In vitro, we found that the reduction of inflammatory response, oxidative stress and dyslipidemia induced by SARM1-knockout in primary hepatocytes after fructose stimulation was largely attributed to its suppression to TLR4/7/9. Together, the findings demonstrated that SARM1 might be an effective target for developing effective therapeutic strategies against NAFLD. Copyright © 2018. Published by Elsevier Inc.

Barriers and facilitators to antiretroviral therapy adherence among Peruvian adolescents living with HIV: A qualitative study

PubMed Central

Wong, Milagros; Muñoz, Maribel; Valle, Emiliano; Leon, Segundo R.; Díaz Perez, Dayana; Kolevic, Lenka; Franke, Molly

2018-01-01

AIDS deaths among adolescents are increasing globally. This qualitative study investigated the barriers and facilitators to cART adherence among Peruvian adolescents living with HIV. Guided by a social ecological model, we analyzed transcripts from 24 psychosocial support groups for HIV-positive adolescents aged 13–17 years and 15 individual, in-depth interviews with cART providers and caregivers to identify the barriers and facilitators to cART adherence at the individual, family/caregiver and hospital levels. Most barriers and facilitators to cART adherence clustered at the individual and family/caregiver levels, centering on support provided to adolescents; history of declining health due to suboptimal cART adherence; side effects from antiretroviral drugs; and cART misinformation. Interventions to support adolescent HIV cART adherence should begin at the individual and family/caregiver levels and include an educational component. No adolescent living with HIV should die from AIDS in an era of accessible cART. PMID:29447226

Alterations of neurochemical expression of the coeliac-superior mesenteric ganglion complex (CSMG) neurons supplying the prepyloric region of the porcine stomach following partial stomach resection.

PubMed

Palus, Katarzyna; Całka, Jarosław

2016-03-01

The purpose of the present study was to determine the response of the porcine coeliac-superior mesenteric ganglion complex (CSMG) neurons projecting to the prepyloric area of the porcine stomach to peripheral neuronal damage following partial stomach resection. To identify the sympathetic neurons innervating the studied area of stomach, the neuronal retrograde tracer Fast Blue (FB) was applied to control and partial stomach resection (RES) groups. On the 22nd day after FB injection, following laparotomy, the partial resection of the previously FB-injected stomach prepyloric area was performed in animals of RES group. On the 28th day, all animals were re-anaesthetized and euthanized. The CSMG complex was then collected and processed for double-labeling immunofluorescence. In control animals, retrograde-labelled perikarya were immunoreactive to tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), neuropeptide Y (NPY) and galanin (GAL). Partial stomach resection decreased the numbers of FB-positive neurons immunopositive for TH and DβH. However, the strong increase of NPY and GAL expression, as well as de novo-synthesis of neuronal nitric oxide synthase (nNOS) and leu5-Enkephalin (LENK) was noted in studied neurons. Furthermore, FB-positive neurons in all pigs were surrounded by a network of cocaine- and amphetamine-regulated transcript peptide (CART)-, calcitonin gene-related peptide (CGRP)-, and substance P (SP)-, vasoactive intestinal peptide (VIP)-, LENK- and nNOS- immunoreactive nerve fibers. This may suggest neuroprotective contribution of these neurotransmitters in traumatic responses of sympathetic neurons to peripheral axonal damage. Copyright © 2015 Elsevier B.V. All rights reserved.

CART PEPTIDE IN THE NUCLEUS ACCUMBENS REGULATES PSYCHOSTIMULANTS: CORRELATIONS BETWEEN PSYCHOSTIMULANT AND CART PEPTIDE EFFECTS

PubMed Central

JOB, MARTIN O.; KUHAR, MICHAEL J.

2017-01-01

In this study, we reexamined the effect of CART peptide on psychostimulant (PS)-induced locomotor activity (LMA) in individual rats. The Methods utilized were as previously published. The PS-induced LMA was defined as the distance traveled after PS administration (intraperitoneal), and the CART peptide effect was defined as the change in the PS-induced activity after bilateral intra-NAc administration of CART peptide. The experiments included both male and female Sprague-Dawley rats, and varying the CART peptide dose and the PS dose. While the average effect of CART peptide was to inhibit PS-induced LMA, the effect of CART peptide on individual PS treated animals was not always inhibitory and sometimes even produced an increase or no change in PS-induced LMA. Upon further analysis, we observed a linear correlation, reported for the first time, between the magnitude of PS-induced LMA and the CART peptide effect. Because CART peptide inhibits PS-induced LMA when it is large, and increases PS-induced LMA when it is small, the peptide can be considered a homeostatic regulator of dopamine (DA)-induced LMA, which supports our earlier homeostatic hypothesis. PMID:28215744

Glucostatic regulation of (+)-(/sup 3/H)amphetamine binding in the hypothalamus: correlation with Na/sup +/, K/sup +/-ATPase activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Angel, I.; Hauger, R.L.; Luu, M.D.

1985-09-01

Preincubation of rat hypothalamic slices in glucose-free Krebs-Ringer buffer (37/sup 0/C) resulted in a time-dependent decrease in specific (+)-(/sup 3/H)amphetamine binding in the crude synaptosomal fraction prepared from these slices. The addition of D-glucose resulted in a dose- and time-dependent stimulation of (+)-(/sup 3/H)amphetamine binding, whereas incubations with L-glucose, 2-deoxy-D-glucose, or 3-O-methyl-D-glucose failed to increase the number of (+)-(/sup 3/H)amphetamine binding sites. Ouabain potently inhibited the glucose-induced stimulation of (+)-(/sup 3/H)amphetamine binding, suggesting the involvement of Na/sup +/, K/sup +/-ATPase. Preincubation of hypothalamic slices with glucose also resulted in an increase in Na/sup +/,K/sup +/-ATPase activity and the number ofmore » specific high-affinity binding sites for (/sup 3/H)ouabain, and a good correlation was observed between the glucose-stimulated increase in (+)-(/sup 3/H)amphetamine and (/sup 3/H)ouabain binding. These data suggest that the (+)-(/sup 3/H)amphetamine binding site in hypothalamus, previously linked to the anorectic actions of various phenylethylamines, is regulated both in vitro and in vivo by physiological concentrations of glucose. Glucose and amphetamine appear to interact at common sites in the hypothalamus to stimulate Na/sup +/,K/sup +/-ATPase activity, and the latter may be involved in the glucostatic regulation of appetite.« less

A genome-wide association study identifies multiple loci for variation in human ear morphology.

PubMed

Adhikari, Kaustubh; Reales, Guillermo; Smith, Andrew J P; Konka, Esra; Palmen, Jutta; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Calderón, Rosario; Rosique, Javier; Cheeseman, Michael; Bhutta, Mahmood F; Humphries, Steve E; Gonzalez-José, Rolando; Headon, Denis; Balding, David; Ruiz-Linares, Andrés

2015-06-24

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1.

Polymorphisms and haplotypes in the bovine neuropeptide Y, growth hormone receptor, ghrelin, insulin-like growth factor 2, and uncoupling proteins 2 and 3 genes and their associations with measures of growth, performance, feed efficiency, and carcass merit in beef cattle.

PubMed

Sherman, E L; Nkrumah, J D; Murdoch, B M; Li, C; Wang, Z; Fu, A; Moore, S S

2008-01-01

Genes that regulate metabolism and energy partitioning have the potential to influence economically important traits in farm animals, as do polymorphisms within these genes. In the current study, SNP in the bovine neuropeptide Y (NPY), growth hormone receptor (GHR), ghrelin (GHRL), uncoupling proteins 2 and 3 (UCP2 and UCP3), IGF2, corticotrophin-releasing hormone (CRH), cocaine and amphetamine regulated transcript (CART), melanocortin-4 receptor (MC4R), proopiomelanocortin (POMC), and GH genes were evaluated for associations with growth, feed efficiency, and carcass merit in beef steers. In total, 24 SNP were evaluated for associations with these traits and haplotypes were constructed within each gene when 2 or more SNP showed significant associations. An A/G SNP located in intron 4 of the GHR gene had the largest effects on BW of the animals (dominance effect P < 0.01) and feed efficiency (allele substitution effect P < 0.05). Another A/G SNP located in the promoter region of GHR had similar effects but the haplotypes of these 2 SNP reduced the effects of the SNP located in intron 4. Three SNP in the NPY gene showed associations to marbling (P < 0.001) as well as with ADG, BW, and feed conversion ratio (FCR; P < 0.05). The combination of these 3 SNP into haplotypes generally improved the association or had a similar scale of association as each single SNP. Only 1 SNP in UCP3, an A/G SNP in intron 3, was associated with ADG (P = 0.025), partial efficiency of growth, and FCR (P < 0.01). Three SNP in UCP2 gene were in almost complete linkage disequilibrium and showed associations with lean meat yield, yield grade, DMI, and BW (P < 0.05). Haplo-types between the SNP in UCP3 and UCP2 generally reduced the associations seen individually in each SNP. An A/G SNP in the GHRL gene tended to show effects on residual feed intake, FCR, and partial efficiency of growth (P < 0.10). The IGF2 SNP most strongly affected LM area (P < 0.01), back fat, ADG, and FCR (P < 0.05). The SNP in the CART, MC4R, POMC, GH, and CRH genes did not show associations at P < 0.05 with any of the traits. Although most of the SNP that showed associations do not cause amino acid changes, these SNP could be linked to other yet to be detected causative mutations or nearby QTL. It will be very important to verify these results in other cattle populations.

Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

PubMed

Trinko, Joseph R; Land, Benjamin B; Solecki, Wojciech B; Wickham, Robert J; Tellez, Luis A; Maldonado-Aviles, Jaime; de Araujo, Ivan E; Addy, Nii A; DiLeone, Ralph J

2016-01-01

The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

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

Addiction-Related Gene Regulation: Risks of Exposure to Cognitive Enhancers vs. Other Psychostimulants

PubMed Central

Steiner, Heinz; Van Waes, Vincent

2012-01-01

The psychostimulants methylphenidate (Ritalin, Concerta), amphetamine (Adderall), and modafinil (Provigil) are widely used in the treatment of medical conditions such as attention-deficit hyperactivity disorder and narcolepsy and, increasingly, as “cognitive enhancers” by healthy people. The long-term neuronal effects of these drugs, however, are poorly understood. A substantial amount of research over the past 2 decades has investigated the effects of psychostimulants such as cocaine and amphetamines on gene regulation in the brain because these molecular changes are considered critical for psychostimulant addiction. This work has determined in some detail the neurochemical and cellular mechanisms that mediate psychostimulant-induced gene regulation and has also identified the neuronal systems altered by these drugs. Among the most affected brain systems are corticostriatal circuits, which are part of cortico-basal ganglia-cortical loops that mediate motivated behavior. The neurotransmitters critical for such gene regulation are dopamine in interaction with glutamate, while other neurotransmitters (e.g., serotonin) play modulatory roles. This review presents (1) an overview of the main findings on cocaine- and amphetamine-induced gene regulation in corticostriatal circuits in an effort to provide a cellular framework for (2) an assessment of the molecular changes produced by methylphenidate, medical amphetamine (Adderall), and modafinil. The findings lead to the conclusion that protracted exposure to these cognitive enhancers can induce gene regulation effects in corticostriatal circuits that are qualitatively similar to those of cocaine and other amphetamines. These neuronal changes may contribute to the addiction liability of the psychostimulant cognitive enhancers. PMID:23085425

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

PubMed Central

Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice.

PubMed

Mines, Marjelo A; Jope, Richard S

2012-07-01

Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3α and GSK3β. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with β-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3. Copyright © 2012 Elsevier Inc. All rights reserved.

PKC phosphorylates residues in the N-terminal of the DA transporter to regulate amphetamine-induced DA efflux.

PubMed

Wang, Qiang; Bubula, Nancy; Brown, Jason; Wang, Yunliang; Kondev, Veronika; Vezina, Paul

2016-05-27

The DA transporter (DAT), a phosphoprotein, controls extracellular dopamine (DA) levels in the central nervous system through transport or reverse transport (efflux). Multiple lines of evidence support the claim that PKC significantly contributes to amphetamine-induced DA efflux. Other signaling pathways, involving CaMKII and ERK, have also been shown to regulate DAT mediated efflux. Here we assessed the contribution of putative PKC residues (S4, S7, S13) in the N-terminal of the DAT to amphetamine-induced DA efflux by transfecting DATs containing different serine to alanine (S-A) point mutations into DA pre-loaded HEK-293 cells and incubating these cells in amphetamine (2μM). The effects of a S-A mutation at the non-PKC residue S12 and a threonine to alanine (T-A) mutation at the ERK T53 residue were also assessed for comparison. WT-DATs were used as controls. In an initial experiment, we confirmed that inhibiting PKC with Go6976 (130nM) significantly reduced amphetamine-induced DA efflux. In subsequent experiments, cells transfected with the S4A, S12A, S13A, T53A and S4,7,13A mutants showed a reduction in amphetamine-induced DA efflux similar to that observed with Go6976. Interestingly, cells transfected with the S7A mutant, identified by some as a PKC-PKA residue, showed unperturbed WT-DAT levels of amphetamine-induced DA efflux. These results indicate that phosphorylation by PKC of select residues in the DAT N-terminal can regulate amphetamine-induced efflux. PKC can act either independently or in concert with other kinases such as ERK to produce this effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Schoolchildren's Consumption of Competitive Foods and Beverages, Excluding a la Carte

ERIC Educational Resources Information Center

Kakarala, Madhuri; Keast, Debra R.; Hoerr, Sharon

2010-01-01

Background: Competitive foods/beverages are those in school vending machines, school stores, snack bars, special sales, and items sold a la carte in the school cafeteria that compete with United States Department of Agriculture (USDA) meal program offerings. Grouping a la carte items with less nutritious items allowed in less regulated venues may…

Adolescent social defeat increases adult amphetamine conditioned place preference and alters D2 dopamine receptor expression

PubMed Central

Burke, Andrew R.; Watt, Michael J.; Forster, Gina L.

2011-01-01

Components of the brain’s dopaminergic system, such as dopamine receptors, undergo final maturation in adolescence. Exposure to social stress during human adolescence contributes to substance abuse behaviors. We utilized a rat model of adolescent social stress to investigate the neural mechanisms underlying this correlation. Rats exposed to repeated social defeat in adolescence (P35–P39) exhibited increased conditioned place preference (CPP) for amphetamine (1 mg/kg) in adulthood (P70). In contrast, rats experiencing foot-shock during the same developmental period exhibited amphetamine CPP levels similar to non-stressed controls. Our previous experiments suggested adolescent defeat alters dopamine activity in the mesocorticolimbic system. Furthermore, dopamine receptors have been implicated in the expression of amphetamine CPP. Therefore, we hypothesized that alteration to dopamine receptor expression in the mesocorticolimbic system may be associated with to heightened amphetamine CPP of adult rats exposed to adolescence defeat. We measured D1 and D2 dopamine receptor protein content in the medial prefrontal cortex, nucleus accumbens (NAc) and dorsal striatum following either adolescent social defeat or foot-shock stress and then adult amphetamine CPP. In controls, amphetamine CPP training reduced D2 receptor protein content in the NAc core. However, this down-regulation of NAc core D2 receptors was blocked by exposure to social defeat but not foot-shock stress in adolescence. These results suggest social defeat stress in adolescence alters the manner in which later amphetamine exposure down-regulates D2 receptors. Furthermore, persistent alterations to adult D2 receptor expression and amphetamine responses may depend on the type of stress experienced in adolescence. PMID:21933700

32 CFR 636.29 - Go-carts, minibikes, and all terrain vehicles (ATV's).

Code of Federal Regulations, 2010 CFR

2010-07-01

... (SPECIFIC INSTALLATIONS) Fort Stewart, Georgia § 636.29 Go-carts, minibikes, and all terrain vehicles (ATV's... applicable Georgia State Law and Fort Stewart traffic laws and regulations contained in this part. (b) “Go...

Nitric Oxide Exerts Basal and Insulin-Dependent Anorexigenic Actions in POMC Hypothalamic Neurons

PubMed Central

Wellhauser, Leigh; Chalmers, Jennifer A.

2016-01-01

The arcuate nucleus of the hypothalamus represents a key center for the control of appetite and feeding through the regulation of 2 key neuronal populations, notably agouti-related peptide/neuropeptide Y and proopimelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons. Altered regulation of these neuronal networks, in particular the dysfunction of POMC neurons upon high-fat consumption, is a major pathogenic mechanism involved in the development of obesity and type 2 diabetes mellitus. Efforts are underway to preserve the integrity or enhance the functionality of POMC neurons in order to prevent or treat these metabolic diseases. Here, we report for the first time that the nitric oxide (NO−) donor, sodium nitroprusside (SNP) mediates anorexigenic actions in both hypothalamic tissue and hypothalamic-derived cell models by mediating the up-regulation of POMC levels. SNP increased POMC mRNA in a dose-dependent manner and enhanced α-melanocortin-secreting hormone production and secretion in mHypoA-POMC/GFP-2 cells. SNP also enhanced insulin-driven POMC expression likely by inhibiting the deacetylase activity of sirtuin 1. Furthermore, SNP enhanced insulin-dependent POMC expression, likely by reducing the transcriptional repression of Foxo1 on the POMC gene. Prolonged SNP exposure prevented the development of insulin resistance. Taken together, the NO− donor SNP enhances the anorexigenic potential of POMC neurons by promoting its transcriptional expression independent and in cooperation with insulin. Thus, increasing cellular NO− levels represents a hormone-independent method of promoting anorexigenic output from the existing POMC neuronal populations and may be advantageous in the fight against these prevalent disorders. PMID:26930171

Etiologies of pediatric craniofacial injuries: a comparison of injuries involving all-terrain vehicles and golf carts.

PubMed

White, Lauren C; McKinnon, Brian J; Hughes, C Anthony

2013-03-01

To determine incidence and etiologies of craniofacial injuries in the pediatric population through comparison of injuries caused by all-terrain vehicles and golf cart trauma. Case series with chart review. Level 1 trauma center. Retrospective review of pediatric traumas at a tertiary academic medical center from 2003 to 2012 identified 196 patients whose injuries resulted from accidents involving either all-terrain vehicles or golf carts. Data was collected and variables such as age, gender, driver vs. passenger, location of accident, Glasgow coma scale, Injury severity scale, Abbreviated injury scale, and presence or absence of helmet use were examined. 196 pediatric patients were identified: 68 patients had injuries resulting from golf cart accidents, and 128 patients from ATV accidents. 66.4% of ATV-related traumas were male, compared to 52.9% of golf cart-related traumas. Ages of injured patients were similar between the two modalities with average age of ATV traumas 10.8 (±4.0) years and golf cart traumas 10.0 (±4.6) years. Caucasians were most commonly involved in both ATV (79.7%) and golf cart traumas (85.3%). 58.6% of all ATV related trauma and 69.1% of all golf cart trauma resulted in craniofacial injuries. The most common craniofacial injury was a closed head injury with brief loss of consciousness, occurring in 46.1% of the ATV traumas and 54.4% of the golf cart traumas. Temporal bone fractures were the second most common type of craniofacial injury, occurring in 5.5% of ATV accidents and 7.4% of the golf cart traumas. Length of hospital stay and, cases requiring surgery and severity scores were similar between both populations. Intensive care admissions and injury severity scores approached but not reach statistical significance (0.096 and 0.083, respectively). The only statistically significant differences between the two modalities were helmet use (P=0.00018%) and days requiring ventilator assistance (P=0.025). ATVs and golf carts are often exempt from the safety features and regulations required of motor vehicles, and ATV and golf cart accidents represent a significant portion of pediatric traumas. This study found that ATV and golf cart accidents contribute significantly to craniofacial trauma requiring hospitalization, with resultant morbidity and mortality. Further investigation of these injuries and their prevention in the pediatric population is needed before efforts to promote effective safety regulations for such vehicles in the future can be addressed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chronic Mild Cold Conditioning Modulates the Expression of Hypothalamic Neuropeptide and Intermediary Metabolic-Related Genes and Improves Growth Performances in Young Chicks.

PubMed

Nguyen, Phuong; Greene, Elizabeth; Ishola, Peter; Huff, Geraldine; Donoghue, Annie; Bottje, Walter; Dridi, Sami

2015-01-01

Low environmental temperatures are among the most challenging stressors in poultry industries. Although landmark studies using acute severe cold exposure have been conducted, still the molecular mechanisms underlying cold-stress responses in birds are not completely defined. In the present study we determine the effect of chronic mild cold conditioning (CMCC) on growth performances and on the expression of key metabolic-related genes in three metabolically important tissues: brain (main site for feed intake control), liver (main site for lipogenesis) and muscle (main site for thermogenesis). 80 one-day old male broiler chicks were divided into two weight-matched groups and maintained in two different temperature floor pen rooms (40 birds/room). The temperature of control room was 32°C, while the cold room temperature started at 26.7°C and gradually reduced every day (1°C/day) to reach 19.7°C at the seventh day of the experiment. At day 7, growth performances were recorded (from all birds) and blood samples and tissues were collected (n = 10). The rest of birds were maintained at the same standard environmental condition for two more weeks and growth performances were measured. Although feed intake remained unchanged, body weight gain was significantly increased in CMCC compared to the control chicks resulting in a significant low feed conversion ratio (FCR). Circulating cholesterol and creatine kinase levels were higher in CMCC chicks compared to the control group (P<0.05). CMCC significantly decreased the expression of both the hypothalamic orexigenic neuropeptide Y (NPY) and anorexigenic cocaine and amphetamine regulated transcript (CART) in chick brain which may explain the similar feed intake between the two groups. Compared to the control condition, CMCC increased the mRNA abundance of AMPKα1/α2 and decreased mTOR gene expression (P<0.05), the master energy and nutrient sensors, respectively. It also significantly decreased the expression of fatty acid synthase (FAS) gene in chick brain compared to the control. Although their roles are still unknown in avian species, adiponectin (Adpn) and its related receptors (AdipoR1 and 2) were down regulated in the brain of CMCC compared to control chicks (P<0.05). In the liver, CMCC significantly down regulated the expression of lipogenic genes namely FAS, acetyl-CoA carboxylase alpha (ACCα) and malic enzyme (ME) and their related transcription factors sterol regulatory element binding protein 1/2 (SREBP-1 and 2). Hepatic mTOR mRNA levels and phosphorylated mTOR at Ser2448 were down regulated (P<0.05), however phosphorylated ACCαSer79 (inactivation) was up regulated (P<0.05) in CMCC compared to control chicks, indicating that CMCC switch hepatic catabolism on and inhibits hepatic lipogenesis. In the muscle however, CMCC significantly up regulated the expression of carnitine palmitoyltransferase 1 (CPT-1) gene and the mRNA and phosphorylated protein levels of mTOR compared to the control chicks, indicating that CMCC enhanced muscle fatty acid β-oxidation. In conclusion, this is the first report indicating that CMCC may regulate AMPK-mTOR expression in a tissue specific manner and identifying AMPK-mTOR as a potential molecular signature that controls cellular fatty acid utilization (inhibition of hepatic lipogenesis and induction of muscle fatty acid β-oxidation) to enhance growth performance during mild cold acclimation.

Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens.

PubMed

Lindefors, N; Hurd, Y L; O'Connor, W T; Brené, S; Persson, H; Ungerstedt, U

1992-01-01

In situ hybridization histochemistry and in vivo microdialysis were combined to study the effect of amphetamine on the expression of choline acetyltransferase and glutamate decarboxylase67 mRNA and in vivo release of acetylcholine and GABA in rat medial nucleus accumbens. Differential effects on acetylcholine and GABA neurons by a single challenge injection of amphetamine (1.5 mg/kg, s.c.) were apparent in saline-pretreated and amphetamine-pretreated (same dose, twice daily for the previous seven days) rats. Extracellular acetylcholine levels were increased up to 50% over a prolonged period following both single and repeated amphetamine. In contrast, extracellular concentrations of GABA were gradually decreased to half the control values, but only in rats receiving repeated amphetamine. Although the increase of acetylcholine release was not associated with any change in choline acetyltransferase mRNA levels, the number of neurons expressing high levels of glutamate decarboxylase67 mRNA was decreased (28%) following repeated injections. Thus we suggest that amphetamine decreases extracellular GABA levels by a slow mechanism, associated with the decreased expression of glutamate decarboxylase67 mRNA in a subpopulation of densely labeled neurons in the medial nucleus accumbens. The delayed response by GABA to amphetamine may reflect supersensitivity in the activity of postsynaptic gamma-aminobutyric acid-containing neurons in nucleus accumbens as a consequence of the repeated amphetamine treatment.

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

PubMed

Bray, Brenna; Scholl, Jamie L; Tu, Wenyu; Watt, Michael J; Renner, Kenneth J; Forster, Gina L

2016-08-01

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal. Copyright © 2016 Elsevier B.V. All rights reserved.

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation.

PubMed

Vicente-Rodríguez, Marta; Rojo Gonzalez, Loreto; Gramage, Esther; Fernández-Calle, Rosalía; Chen, Ying; Pérez-García, Carmen; Ferrer-Alcón, Marcel; Uribarri, María; Bailey, Alexis; Herradón, Gonzalo

2016-11-01

It was previously shown that mice with genetic deletion of the neurotrophic factor pleiotrophin (PTN-/-) show enhanced amphetamine neurotoxicity and impair extinction of amphetamine conditioned place preference (CPP), suggesting a modulatory role of PTN in amphetamine neurotoxicity and reward. We have now studied the effects of amphetamine (10mg/kg, 4 times, every 2h) in the striatum of mice with transgenic PTN overexpression (PTN-Tg) in the brain and in wild type (WT) mice. Amphetamine caused an enhanced loss of striatal dopaminergic terminals, together with a highly significant aggravation of amphetamine-induced increase in the number of GFAP-positive astrocytes, in the striatum of PTN-Tg mice compared to WT mice. Given the known contribution of D1 and D2 dopamine receptors to the neurotoxic effects of amphetamine, we also performed quantitative receptor autoradiography of both receptors in the brains of PTN-Tg and WT mice. D1 and D2 receptors binding in the striatum and other regions of interest was not altered by genotype or treatment. Finally, we found that amphetamine CPP was significantly reduced in PTN-Tg mice. The data demonstrate that PTN overexpression in the brain blocks the conditioning effects of amphetamine and enhances the characteristic striatal dopaminergic denervation caused by this drug. These results indicate for the first time deleterious effects of PTN in vivo by mechanisms that are probably independent of changes in the expression of D1 and D2 dopamine receptors. The data also suggest that PTN-induced neuroinflammation could be involved in the enhanced neurotoxic effects of amphetamine in the striatum of PTN-Tg mice. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer.

PubMed

Rose, Rebecca; Lamers, Susanna L; Nolan, David J; Maidji, Ekaterina; Faria, N R; Pybus, Oliver G; Dollar, James J; Maruniak, Samuel A; McAvoy, Andrew C; Salemi, Marco; Stoddart, Cheryl A; Singer, Elyse J; McGrath, Michael S

2016-10-15

While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV(+) cART-treated (cART(+)) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART(+) and cART-naive (cART(-)) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA(+) cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV(+) cART(+) individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Previous Exposure to Δ9-Tetrahydrocannibinol Enhances Locomotor Responding to but Not Self-Administration of AmphetamineS⃞

PubMed Central

Cortright, James J.; Lorrain, Daniel S.; Beeler, Jeff A.; Tang, Wei-Jen

2011-01-01

Previous exposure to amphetamine leads to enhanced locomotor and nucleus accumbens (NAcc) dopamine (DA) responding to the drug as well as enhanced amphetamine self-administration. Here, we investigated the effects of exposure to Δ9-tetrahydrocannibinol (Δ9-THC) on behavioral and biochemical responding to amphetamine. Rats in different groups received five exposure injections of vehicle or one of five doses of Δ9-THC (0.4, 0.75, 1.5, 3.0, and 6.0 mg/kg i.p.) and were tested 2 days and 2 weeks later. Exposure to all but the lowest and highest doses of Δ9-THC enhanced the locomotor response to amphetamine (0.75 mg/kg i.p.), but all failed to enhance NAcc DA overflow in response to the drug. Moreover, exposure to 3.0 mg/kg i.p. Δ9-THC increased forskolin-evoked adenylyl cyclase activity in the NAcc and rats' locomotor response to the direct DA receptor agonist apomorphine (1.0 mg/kg s.c.), suggesting that Δ9-THC sensitized locomotor responding to amphetamine by up-regulating postsynaptic DA receptor signaling in the NAcc. Finally, amphetamine self-administration (200 μg/kg/infusion i.v.) was enhanced in amphetamine (5 × 1.5 mg/kg i.p.)-exposed rats, but not in rats exposed to Δ9-THC (5 × 3.0 mg/kg i.p.). Previous exposure to this dose of Δ9-THC modestly increased apomorphine SA (0.5 mg/kg/infusion i.v.). Thus, unlike amphetamine exposure, exposure to Δ9-THC does not enhance the subsequent NAcc DA response to amphetamine or promote amphetamine self-administration. Although Δ9-THC leads to alterations in postsynaptic DA receptor signaling in the NAcc and these can affect the generation of locomotion, these neuroadaptations do not seem to be linked to the expression of enhanced amphetamine self-administration. PMID:21389094

Accuracy of sign interpreting and real-time captioning of science videos for the delivery of instruction to deaf students

NASA Astrophysics Data System (ADS)

Sadler, Karen L.

2009-04-01

The purpose of this study was to quantitatively examine the impact of third-party support service providers on the quality of science information available to deaf students in regular science classrooms. Three different videotapes that were developed by NASA for high school science classrooms were selected for the study, allowing for different concepts and vocabulary to be examined. The focus was on the accuracy of translation as measured by the number of key science words included in the transcripts (captions) or videos (interpreted). Data were collected via transcripts completed by CART (computer assisted real-time captionists) or through videos of sign language interpreters. All participants were required to listen to and translate these NASA educational videos with no prior experience with this information so as not to influence their delivery. CART personnel using captions were found to be significantly more accurate in the delivery of science words as compared to the sign language interpreters in this study.

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer

PubMed Central

Rose, Rebecca; Lamers, Susanna L.; Nolan, David J.; Maidji, Ekaterina; Faria, N. R.; Pybus, Oliver G.; Dollar, James J.; Maruniak, Samuel A.; McAvoy, Andrew C.; Salemi, Marco; Stoddart, Cheryl A.; Singer, Elyse J.

2016-01-01

ABSTRACT While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV+ cART-treated (cART+) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART+ and cART-naive (cART−) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA+ cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. IMPORTANCE Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV+ cART+ individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies. PMID:27466425

76 FR 37062 - Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-24

..., computer assisted real-time transcription (CART), and sign language interpreters will be available at the... Washington, DC, Monday through Wednesday, July 11-13, 2011, at the times and location noted below. DATES: The... Governments; and Terry Moakley, Association of Travel Instruction). 1:30-3 p.m.--Board Meeting (guest speaker...

Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment

PubMed Central

Cooper, Jason D.; Tomasik, Jakub; Bahn, Sabine; Aerts, Joeri L.; Osterhaus, Albert D. M. E.; Gruters, Rob A.; Andeweg, Arno C.

2018-01-01

Objectives To characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level. Design An autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls. Methods Plasma marker (‘analyte’) levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression. Results Plasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands. Conclusions Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection. PMID:29389978

Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment.

PubMed

van den Ham, Henk-Jan; Cooper, Jason D; Tomasik, Jakub; Bahn, Sabine; Aerts, Joeri L; Osterhaus, Albert D M E; Gruters, Rob A; Andeweg, Arno C

2018-01-01

To characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level. An autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls. Plasma marker ('analyte') levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression. Plasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands. Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection.

Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants.

PubMed

Gross, Joshua D; Kaski, Shane W; Schroer, Adam B; Wix, Kimberley A; Siderovski, David P; Setola, Vincent

2018-02-01

Regulators of G protein signaling are proteins that accelerate the termination of effector stimulation after G protein-coupled receptor activation. Many regulators of G protein signaling proteins are highly expressed in the brain and therefore considered potential drug discovery targets for central nervous system pathologies; for example, here we show that RGS12 is highly expressed in microdissected mouse ventral striatum. Given a role for the ventral striatum in psychostimulant-induced locomotor activity, we tested whether Rgs12 genetic ablation affected behavioral responses to amphetamine and cocaine. RGS12 loss significantly decreased hyperlocomotion to lower doses of both amphetamine and cocaine; however, other outcomes of administration (sensitization and conditioned place preference) were unaffected, suggesting that RGS12 does not function in support of the rewarding properties of these psychostimulants. To test whether observed response changes upon RGS12 loss were caused by changes to dopamine transporter expression and/or function, we prepared crude membranes from the brains of wild-type and RGS12-null mice and measured dopamine transporter-selective [ 3 H]WIN 35428 binding, revealing an increase in dopamine transporter levels in the ventral-but not dorsal-striatum of RGS12-null mice. To address dopamine transporter function, we prepared striatal synaptosomes and measured [ 3 H]dopamine uptake. Consistent with increased [ 3 H]WIN 35428 binding, dopamine transporter-specific [ 3 H]dopamine uptake in RGS12-null ventral striatal synaptosomes was found to be increased. Decreased amphetamine-induced locomotor activity and increased [ 3 H]WIN 35428 binding were recapitulated with an independent RGS12-null mouse strain. Thus, we propose that RGS12 regulates dopamine transporter expression and function in the ventral striatum, affecting amphetamine- and cocaine-induced increases in dopamine levels that specifically elicit acute hyperlocomotor responses.

Amphetamine regulation of mesolimbic dopamine/cholecystokinin neurotransmission.

PubMed

Hurd, Y L; Lindefors, N; Brodin, E; Brené, S; Persson, H; Ungerstedt, U; Hökfelt, T

1992-04-24

The effects of acute and repeated amphetamine administration on mesolimbic dopamine (DA) neurons was assessed by studying DA and cholecystokinin (CCK) release in the nucleus accumbens (Acc), as well as effects on mRNA genes regulating DA and CCK synthesis in ventral tegmental area (VTA) cells in rats. Amphetamine (1.5 mg/kg) markedly increased extracellular levels of DA in the medial Acc (assessed by in vivo microdialysis) in drug-naive animals, about twice the amount released in animals repeatedly administered the drug for the previous 7 days (twice daily). CCK overflow was found to mirror the DA responses in that the very transient elevation of CCK monitored in drug-naive animals was attenuated in those with prior amphetamine use. The attenuation of both DA and CCK overflow in the medial Acc was found to be associated with a decrease in the number of CCK mRNA-positive VTA neurons (assessed by in situ hybridization histochemistry). Although the number of cells expressing CCK mRNA were decreased, the gene expression in those positive CCK and tyrosine hydroxylase mRNA cells in the VTA was significantly increased. The CCK mRNA neurons in the VTA were positively identified as those projecting to the medial Acc by the local perfusion of Fluoro-gold retrograde tracer via microdialysis probes located in the Acc.

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

PubMed Central

Wang, Wengang; Darvas, Martin; Storey, Granville P.; Bamford, Ian J.; Gibbs, Jeffrey T.; Palmiter, Richard D.

2013-01-01

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. PMID:23785153

Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells

PubMed Central

Berger, Carolina; Sommermeyer, Daniel; Hudecek, Michael; Berger, Michael; Balakrishnan, Ashwini; Paszkiewicz, Paulina J.; Kosasih, Paula L.; Rader, Christoph; Riddell, Stanley R.

2014-01-01

Genetic engineering of T cells for adoptive transfer by introducing a tumor-targeting chimeric antigen receptor (CAR) is a new approach to cancer immunotherapy. A challenge for the field is to define cell surface molecules that are both preferentially expressed on tumor cells and can be safely targeted with T cells. The orphan tyrosine kinase receptor ROR1 is a candidate target for T-cell therapy with CAR-modified T cells (CAR-T cells) since it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival. The cell surface isoform of ROR1 is expressed in embryogenesis but absent in adult tissues except for B-cell precursors, and low levels of transcripts in adipocytes, pancreas, and lung. ROR1 is highly conserved between humans and macaques and has a similar pattern of tissue expression. To determine if low-level ROR1-expression on normal cells would result in toxicity or adversely affect CAR-T cell survival and/or function, we adoptively transferred autologous ROR1 CAR-T cells into nonhuman primates. ROR1 CAR-T cells did not cause overt toxicity to normal organs and accumulated in bone marrow and lymph node sites where ROR1-positive B cells were present. The findings support the clinical evaluation of ROR1 CAR-T cells for ROR1+ malignancies and demonstrate the utility of nonhuman primates for evaluating the safety of immunotherapy with engineered T cells specific for tumor-associated molecules that are homologous between humans and nonhuman primates. PMID:25355068

Repeated Exposure to D-Amphetamine Decreases Global Protein Synthesis and Regulates the Translation of a Subset of mRNAs in the Striatum

PubMed Central

Biever, Anne; Boubaker-Vitre, Jihane; Cutando, Laura; Gracia-Rubio, Irene; Costa-Mattioli, Mauro; Puighermanal, Emma; Valjent, Emmanuel

2017-01-01

Repeated psychostimulant exposure induces persistent gene expression modifications that contribute to enduring changes in striatal GABAergic spiny projecting neurons (SPNs). However, it remains unclear whether changes in the control of mRNA translation are required for the establishment of these durable modifications. Here we report that repeated exposure to D-amphetamine decreases global striatal mRNA translation. This effect is paralleled by an enhanced phosphorylation of the translation factors, eIF2α and eEF2, and by the concomitant increased translation of a subset of mRNAs, among which the mRNA encoding for the activity regulated cytoskeleton-associated protein, also known as activity regulated gene 3.1 (Arc/Arg3.1). The enrichment of Arc/Arg3.1 mRNA in the polysomal fraction is accompanied by a robust increase of Arc/Arg3.1 protein levels within the striatum. Immunofluorescence analysis revealed that this increase occurred preferentially in D1R-expressing SPNs localized in striosome compartments. Our results suggest that the decreased global protein synthesis following repeated exposure to D-amphetamine favors the translation of a specific subset of mRNAs in the striatum. PMID:28119566

Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice.

PubMed

Mines, Marjelo A; Beurel, Eleonore; Jope, Richard S

2013-01-05

Abnormalities in dopaminergic activity have been implicated in psychiatric diseases, such as attention deficit hyperactivity disorder (ADHD), and are treated with therapeutic stimulants, commonly methylphenidate or amphetamine. Amphetamine administration increases glycogen synthase kinase-3 (GSK3) activation, which is necessary for certain acute behavioral responses to amphetamine, including increased locomotor activity and impaired sensorimotor gating. Here, we tested if modulating GSK3 by administration of the GSK3 inhibitor lithium or expression of constitutively active GSK3 altered behavioral responses to methylphenidate administered to mice acutely or daily for 8 days. Methylphenidate or amphetamine was administered to mice intraperitoneally for 1 or 8 days. Open-field activity and pre-pulse inhibition (PPI) were measured. In contrast to lithium's blockade of acute amphetamine-induced locomotor hyperactivity, lithium treatment did not significantly reduce methylphenidate-induced locomotor hyperactivity in wild-type mice after acute or 8 days of repeated methylphenidate administration. Lithium treatment significantly increased the impairment in PPI caused by methylphenidate, but significantly reduced the amphetamine-induced PPI deficit. In GSK3 knockin mice, expression of constitutively active GSK3β, but not GSK3α, significantly increased locomotor hyperactivity after acute methylphenidate treatment, and significantly impaired PPI, preventing further methylphenidate-induced impairment of PPI that was evident in wild-type mice and GSK3α knockin mice. Lithium does not counteract locomotor activity and PPI responses to methylphenidate as it does these responses to amphetamine, indicating that different mechanisms mediate these behavioral responses to methylphenidate and amphetamine. Only active GSK3β, not GSK3α, modulates behavioral responses to MPH, indicating selectivity in the actions of GSK3 isoforms. Copyright © 2012 Elsevier B.V. All rights reserved.

Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy.

PubMed

Nasi, Milena; De Biasi, Sara; Bianchini, Elena; Digaetano, Margherita; Pinti, Marcello; Gibellini, Lara; Pecorini, Simone; Carnevale, Gianluca; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina; Cossarizza, Andrea

2015-09-24

Few studies have investigated the importance of different components of the inflammasome system and of innate mitochondrial sensing (IMS) pathways in HIV infection and its treatment. We analysed the expression of several components of the inflammasome and of the IMS in HIV-positive patients taking successful combination antiretroviral therapy (cART). We enrolled 20 HIV-positive patients under cART, who achieved viral suppression since at least 10 months and 20 age and sex-matched healthy donors. By RT-PCR, using peripheral blood mononuclear cells (PBMCs), we quantified the mRNA expression of 16 genes involved in inflammasome activation and regulation (AIM2, NAIP, PYCARD, CASP1, CASP5, NLRP6, NLRP1, NLRP3, TXNIP, BCL2, NLRC4, PANX1, P2RX7, IL-18, IL-1β, SUGT1) and eight genes involved in IMS (MFN2, MFN1, cGAS, RIG-I, MAVS, NLRX1, RAB32, STING). Compared with controls, HIV-positive patients showed significantly lower mRNA levels of the mitochondrial protein NLRX1, which plays a key role in regulating apoptotic cell death; main PBMC subpopulations behave in a similar manner. No differences were observed in the expression of inflammasome components, which however showed complex correlations. The decreased level of NLRX1 in HIV infection could suggest that the virus is able to downregulate mechanisms linked to triggering of cell death in several immune cell types. The fact that HIV-positive patients did not show altered expression of inflammasome components, nor of most genes involved in IMS, suggests that the infection and/or the chronic immune activation does not influence the transcriptional machinery of innate mechanisms able to trigger inflammation at different levels.

Analysis of amphetamine and methamphetamine in municipal wastewater influent and effluent using weak cation-exchange SPE and LC-MS/MS.

PubMed

Boles, Tammy H; Wells, Martha J M

2016-12-01

Amphetamine and methamphetamine are emerging contaminants-those for which no regulations currently require monitoring or public reporting of their presence in our water supply. In this research, a protocol for weak cation-exchange (WCX) SPE coupled with LC-MS/MS was developed for determination of emerging contaminants amphetamine and methamphetamine in a complex wastewater matrix. Gradient LC parameters were adjusted to yield baseline separation of methamphetamine from other contaminants. Methamphetamine-D5 was used as the internal standard (IS) to compensate for sample loss during SPE and for signal loss during MS (matrix effects). Recoveries were 102.1 ± 7.9% and 99.4 ± 4.0% for amphetamine and methamphetamine, respectively, using WCX sorbent. Notably, methamphetamine was determined to be present in wastewater influent at each sampling date tested. Amphetamine was present in wastewater influent on two of four sampling dates. Amphetamine concentrations ranged from undetectable to 86.4 ng/L in influent, but it was undetectable in wastewater effluent. Methamphetamine was detected in influent at concentrations ranging from 27.0-60.3 ng/L. Methamphetamine concentration was reduced but incompletely removed at this facility. Although absent in one post-UV effluent sample, concentrations of methamphetamine ranged from 10.8-14.8 ng/L. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Detection and classification of medication errors at Joan XXIII University Hospital].

PubMed

Jornet Montaña, S; Canadell Vilarrasa, L; Calabuig Mũoz, M; Riera Sendra, G; Vuelta Arce, M; Bardají Ruiz, A; Gallart Mora, M J

2004-01-01

Medication errors are multifactorial and multidisciplinary, and may originate in processes such as drug prescription, transcription, dispensation, preparation and administration. The goal of this work was to measure the incidence of detectable medication errors that arise within a unit dose drug distribution and control system, from drug prescription to drug administration, by means of an observational method confined to the Pharmacy Department, as well as a voluntary, anonymous report system. The acceptance of this voluntary report system's implementation was also assessed. A prospective descriptive study was conducted. Data collection was performed at the Pharmacy Department from a review of prescribed medical orders, a review of pharmaceutical transcriptions, a review of dispensed medication and a review of medication returned in unit dose medication carts. A voluntary, anonymous report system centralized in the Pharmacy Department was also set up to detect medication errors. Prescription errors were the most frequent (1.12%), closely followed by dispensation errors (1.04%). Transcription errors (0.42%) and administration errors (0.69%) had the lowest overall incidence. Voluntary report involved only 4.25% of all detected errors, whereas unit dose medication cart review contributed the most to error detection. Recognizing the incidence and types of medication errors that occur in a health-care setting allows us to analyze their causes and effect changes in different stages of the process in order to ensure maximal patient safety.

Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

PubMed Central

Parnaudeau, Sébastien; Dongelmans, Marie-louise; Turiault, Marc; Ambroggi, Frédéric; Delbes, Anne-Sophie; Cansell, Céline; Luquet, Serge; Piazza, Pier-Vincenzo; Tronche, François; Barik, Jacques

2014-01-01

The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice. PMID:24574986

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

PubMed Central

Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina; Weber, Gerrit; Liu, Hao; Kim, Eugene S.; Ittmann, Michael M.; Marchetti, Dario; Dotti, Gianpietro

2015-01-01

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors1–3 than in lymphoid malignancies4, 5. Although active tumor-mediated immunosuppression may play a role in limiting efficacy6, functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors. PMID:25849134

Considerations pertaining to cell collection and administration of industry-manufactured autologous CAR-T cells, in relation to French healthcare organization and regulations.

PubMed

Chabannon, Christian; Larghero, Jérôme

2018-05-01

Access to treatment with CAR-T Cells at European hospitals in general and at French hospitals in particular remains limited, when compared with the situation that prevails in the USA or in certain Asian countries. Multiple reasons explain why European investigators lag behind their US or Chinese colleagues in this clinical research area. Some of these reasons are related to the European and French regulatory landscapes that hamper the design and rapid implementation of organizational solutions needed for safe and efficient administration of CAR-T Cells. We here identify some of these pressing issues and propose some possible paths to move forward. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The odor of Osmanthus fragrans attenuates food intake

PubMed Central

Yamamoto, Takashi; Inui, Tadashi; Tsuji, Tadataka

2013-01-01

Odors have been shown to exert an influence on various physiological and behavioral activities. However, little is known whether or not odor stimulation directly affects the levels of feeding-related neuropeptides. Here we show that the neural transmission by Osmanthus fragrans (OSM) decreased the mRNA expression of orexigenic neuropeptides, such as agouti-related protein, neuropeptide Y, melanin-concentrating hormone and prepro-orexin, while increased anorexigenic neuropeptides, such as cocaine- and amphetamine-regulated transcript and proopiomelanocortin in rats. The decreased number of orexin-immunoreactive neurons in the hypothalamus coincided well with the OSM-induced decreases in the expression of prepro-orexin mRNA. This study demonstrates that the OSM odor, which is known to have a mild sedative effect, decreases the motivation to eat, food intake and body weight, accompanied by sluggish masticatory movements. The data suggest that these effects are due to suppression of orexigenic neuropeptides and activation of anorexigenic neuropeptides in the hypothalamus. PMID:23519146

Ablation of Neurons Expressing Melanin-Concentrating Hormone (MCH) in Adult Mice Improves Glucose Tolerance Independent of MCH Signaling

PubMed Central

Whiddon, Benjamin B.; Palmiter, Richard D.

2013-01-01

Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on tudies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine–amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous PmchDTR/+ mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH. PMID:23365238

Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling.

PubMed

Whiddon, Benjamin B; Palmiter, Richard D

2013-01-30

Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on studies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine-amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous Pmch(DTR/+) mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH.

Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

PubMed Central

Johnston, Caitlin E.; Herschel, Daniel; Lasek, Amy W.; Hammer, Ronald P.; Nikulina, Ella M.

2014-01-01

Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse. PMID:25446676

Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice

PubMed Central

Wiskerke, Joost; Stoop, Nicky; Schetters, Dustin; Schoffelmeer, Anton N. M.; Pattij, Tommy

2011-01-01

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior. PMID:22016780

Occupational conditions and the risk of the use of amphetamines by truck drivers.

PubMed

de Oliveira, Lúcio Garcia; de Souza, Letícia Maria de Araújo; Barroso, Lúcia Pereira; Gouvêa, Marcela Júlio César; de Almeida, Carlos Vinícius Dias; Muñoz, Daniel Romero; Leyton, Vilma

2015-01-01

OBJECTIVE To test whether the occupational conditions of professional truck drivers are associated with amphetamine use after demographic characteristics and ones regarding mental health and drug use are controlled for.METHODS Cross-sectional study, with a non-probabilistic sample of 684 male truck drivers, which was collected in three highways in Sao Paulo between years 2012 and 2013. Demographic and occupational information was collected, as well as data on drug use and mental health (sleep quality, emotional stress, and psychiatric disorders). A logistic regression model was developed to identify factors associated with amphetamine use. Odds ratio (OR; 95%CI) was defined as the measure for association. The significance level was established as p < 0.05.RESULTS The studied sample was found to have an average age of 36.7 (SD = 7.8) years, as well as low education (8.6 [SD = 2.3] years); 29.0% of drivers reported having used amphetamines within the twelve months prior to their interviews. After demographic and occupational variables had been controlled for, the factors which indicated amphetamine use among truck drivers were the following: being younger than 38 years (OR = 3.69), having spent less than nine years at school (OR = 1.76), being autonomous (OR = 1.65), working night shifts or irregular schedules (OR = 2.05), working over 12 hours daily (OR = 2.14), and drinking alcohol (OR = 1.74).CONCLUSIONS Occupational aspects are closely related to amphetamine use among truck drivers, which reinforces the importance of closely following the application of law (Resting Act ("Lei do Descanso"); Law 12,619/2012) which regulates the workload and hours of those professionals. Our results show the need for increased strictness on the trade and prescription of amphetamines in Brazil.

Occupational conditions and the risk of the use of amphetamines by truck drivers

PubMed Central

de Oliveira, Lúcio Garcia; de Souza, Letícia Maria de Araújo; Barroso, Lúcia Pereira; Gouvêa, Marcela Júlio César; de Almeida, Carlos Vinícius Dias; Muñoz, Daniel Romero; Leyton, Vilma

2015-01-01

OBJECTIVE To test whether the occupational conditions of professional truck drivers are associated with amphetamine use after demographic characteristics and ones regarding mental health and drug use are controlled for. METHODS Cross-sectional study, with a non-probabilistic sample of 684 male truck drivers, which was collected in three highways in Sao Paulo between years 2012 and 2013. Demographic and occupational information was collected, as well as data on drug use and mental health (sleep quality, emotional stress, and psychiatric disorders). A logistic regression model was developed to identify factors associated with amphetamine use. Odds ratio (OR; 95%CI) was defined as the measure for association. The significance level was established as p < 0.05. RESULTS The studied sample was found to have an average age of 36.7 (SD = 7.8) years, as well as low education (8.6 [SD = 2.3] years); 29.0% of drivers reported having used amphetamines within the twelve months prior to their interviews. After demographic and occupational variables had been controlled for, the factors which indicated amphetamine use among truck drivers were the following: being younger than 38 years (OR = 3.69), having spent less than nine years at school (OR = 1.76), being autonomous (OR = 1.65), working night shifts or irregular schedules (OR = 2.05), working over 12 hours daily (OR = 2.14), and drinking alcohol (OR = 1.74). CONCLUSIONS Occupational aspects are closely related to amphetamine use among truck drivers, which reinforces the importance of closely following the application of law (Resting Act (“Lei do Descanso”); Law 12,619/2012) which regulates the workload and hours of those professionals. Our results show the need for increased strictness on the trade and prescription of amphetamines in Brazil. PMID:26398875

Dysregulation of apoptosis and autophagy gene expression in PBMCs of efficiently treated HIV-infected patients.

PubMed

Serrano, Amandine; El Haddad, Saïd; Moal, Frédéric; Prazuck, Thierry; Legac, Eric; Robin, Chloé; Brule, Fabienne; Charpentier, Stéphane; Normand, Thierry; Legrand, Alain; Hocqueloux, Laurent; Mollet, Lucile

2018-05-03

We measure the transcript levels of the pro-apoptotic GALIG, anti-apoptotic MCL1 genes and those of the autophagy genes BECN1, MAP1LC3B, ATG9a, P62/SQSTM1, GABARAP, GABARAPL1 and GABARAPL2 to define if mRNA alteration can characterize HIV infected patients effectively treated with combined antiretroviral therapy (cART). Monocentric pilot study conducted on PBMC of 40 uninfected donors and 27 HIV positive patients effectively treated by cART for at least 8.4 years. Transcripts of the various genes were quantified by RT-qPCR and RT- droplet digital PCR, and compared using the standard statistical Mann-Whitney U test and machine learning algorithms. A concomitant overexpression of GALIG and MCL1 is detected in PBMC of effectively cART-treated patients. Overexpression of MAP1LC3B and GABARAPL1 is also measured while BECN1 is under-expressed. Finally, accurate classification (94.5%) of our PBMC samples as HIV negative donors or HIV positive cART-treated is obtained in 3 separate machine-learning algorithms with GABARAPL1 and ATG9a as input variables. cART-treated HIV patients display altered transcript levels for 3 genes of basal autophagy. Some of these alterations may appear contradictory: BECN1 and ATG9a, both key actors in the formation of mammalian autophagosome, exhibit decreased amount of transcripts while mRNA from the ATG8 family increase. Given the known role of impaired basal autophagy in immune senescence and chronic inflammation, the functional significance of our findings should be explored in larger studies.

Methamphetamine, d-amphetamine and p-chloroamphetamine induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats

PubMed Central

Furlong, Teri M.; Leavitt, Lee S.; Keefe, Kristen A.; Son, Jong-Hyun

2016-01-01

Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e. a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e. a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning one week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e. impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ. PMID:26846719

A good walk spoiled: on the disappearance of golf as an active sport in America.

PubMed

Puterbaugh, James S

2011-07-01

During the past 60 years, there has been a major transition in the way golf is played in America. Its potential as exercise largely has been negated by the increase in motorized golf cart usage to approximately two of every three rounds played in this country. Accidents in golf carts have increased rapidly, which, by making the sport more dangerous, will likely bring future regulations. Consequently, playing golf has gradually become more of a public health threat than a benefit. The motorized cart also has resulted in an almost doubling of the size of golf courses, which now occupy a large amount of the built environment designated for activity. These changes are a major loss to society, portend future problems, and call for the sport to reevaluate its current model.

Targeted Immune Interventions for an HIV-1 Cure.

PubMed

Perreau, Matthieu; Banga, Riddhima; Pantaleo, Giuseppe

2017-10-01

Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure. Single intervention strategies have shown promise, albeit with limited efficacy. Consequently, a combination of interventions aiming to stimulate the immune response and prevent new rounds of viral infection and spreading may render the HIV functional cure a feasible goal. Copyright © 2017 Elsevier Ltd. All rights reserved.

Amphetamine sensitization in mice is sufficient to produce both manic- and depressive-related behaviors as well as changes in the functional connectivity of corticolimbic structures.

PubMed

Pathak, G; Ibrahim, B A; McCarthy, S A; Baker, K; Kelly, M P

2015-08-01

It has been suggested that amphetamine abuse and withdrawal mimics the diverse nature of bipolar disorder symptomatology in humans. Here, we determined if a single paradigm of amphetamine sensitization would be sufficient to produce both manic- and depressive-related behaviors in mice. CD-1 mice were subcutaneously dosed for 5 days with 1.8 mg/kg d-amphetamine or vehicle. On days 6-31 of withdrawal, amphetamine-sensitized (AS) mice were compared to vehicle-treated (VT) mice on a range of behavioral and biochemical endpoints. AS mice demonstrated reliable mania- and depression-related behaviors from day 7 to day 28 of withdrawal. Relative to VT mice, AS mice exhibited long-lasting mania-like hyperactivity following either an acute 30-min restraint stress or a low-dose 1 mg/kg d-amphetamine challenge, which was attenuated by the mood-stabilizers lithium and quetiapine. In absence of any challenge, AS mice showed anhedonia-like decreases in sucrose preference and depression-like impairments in the off-line consolidation of motor memory, as reflected by the lack of spontaneous improvement across days of training on the rotarod. AS mice also demonstrated a functional impairment in nest building, an ethologically-relevant activity of daily living. Western blot analyses revealed a significant increase in methylation of histone 3 at lysine 9 (H3K9), but not lysine 4 (H3K4), in hippocampus of AS mice relative to VT mice. In situ hybridization for the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) further revealed heightened activation of corticolimbic structures, decreased functional connectivity between frontal cortex and striatum, and increased functional connectivity between the amygdala and hippocampus of AS mice. The effects of amphetamine sensitization were blunted in C57BL/6J mice relative to CD-1 mice. These results show that a single amphetamine sensitization protocol is sufficient to produce behavioral, functional, and biochemical phenotypes in mice that are relevant to bipolar disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Endoplasmic reticulum stress responses differ in meninges and associated vasculature, striatum, and parietal cortex after a neurotoxic amphetamine exposure.

PubMed

Thomas, Monzy; George, Nysia I; Saini, Upasana T; Patterson, Tucker A; Hanig, Joseph P; Bowyer, John F

2010-08-01

Amphetamine (AMPH) is used to treat attention deficit and hyperactivity disorders, but it can produce neurotoxicity and adverse vascular effects at high doses. The endoplasmic reticulum (ER) stress response (ERSR) entails the unfolded protein response, which helps to avoid or minimize ER dysfunction. ERSR is often associated with toxicities resulting from the accumulation of unfolded or misfolded proteins and has been associated with methamphetamine toxicity in the striatum. The present study evaluates the effect of AMPH on several ERSR elements in meninges and associated vasculature (MAV), parietal cortex, and striatum. Adult, male Sprague-Dawley rats were exposed to saline, environmentally induced hyperthermia (EIH) or four consecutive doses of AMPH that produce hyperthermia. Expression changes (mRNA and protein levels) of key ERSR-related genes in MAV, striatum, and parietal cortex at 3 h or 1 day postdosing were monitored. AMPH increased the expression of some ERSR-related genes in all tissues. Atf4 (activating transcription factor 4, an indicator of Perk pathway activation), Hspa5/Grp78 (Glucose regulated protein 78, master regulator of ERSR), Pdia4 (protein disulfide isomerase, protein-folding enzyme), and Nfkb1 (nuclear factor of kappa b, ERSR sensor) mRNA increased significantly in MAV and parietal cortex 3 h after AMPH. In striatum, Atf4 and Hspa5/Grp78 mRNA significantly increased 3 h after AMPH, but Pdia4 and Nfkb11 did not. Thus, AMPH caused a robust activation of the Perk pathway in all tissues, but significant Ire1 pathway activation occurred only after AMPH treatment in the parietal cortex and striatum. Ddit3/Chop, a downstream effector of the ERSR pathway related to the neurotoxicity, was only increased in striatum and parietal cortex. Conversely, Pdia4, an enzyme protective in the ERSR, was only increased in MAV. The overall ERSR manifestation varied significantly between MAV, striatum, and parietal cortex after a neurotoxic exposure to AMPH.

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2012 CFR

2012-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2010 CFR

2010-07-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2014 CFR

2014-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2013 CFR

2013-07-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2011 CFR

2011-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats.

PubMed

Miszkiel, Joanna; Przegaliński, Edmund

2013-01-01

Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist. Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

PubMed Central

Del Prete, Gregory Q.; Shoemaker, Rebecca; Oswald, Kelli; Lara, Abigail; Trubey, Charles M.; Fast, Randy; Schneider, Douglas K.; Kiser, Rebecca; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Freemire, Brandi; Keele, Brandon F.; Estes, Jacob D.; Quiñones, Octavio A.; Smedley, Jeremy; Macallister, Rhonda; Sanchez, Rosa I.; Wai, John S.; Tan, Christopher M.; Alvord, W. Gregory; Hazuda, Daria J.; Piatak, Michael

2014-01-01

Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4+ T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches. PMID:25182644

Substance use - amphetamines

MedlinePlus

Substance abuse - amphetamines; Drug abuse - amphetamines; Drug use - amphetamines ... Amphetamine: goey, louee, speed, uppers, whiz Dextroamphetamine (ADHD medicine used illegally): dexies, kiddie-speed, pep pills, uppers; ...

Case report: Improvement in dissociative symptoms with mixed amphetamine salts.

PubMed

Scarella, Timothy M; Franzen, Jamie R

2017-01-01

Symptoms of dissociation, including dissociative amnesia, depersonalization, and derealization, commonly develop in individuals subject to chronic and repeated trauma during development. This includes the trauma of environmental inability to facilitate development of adequate cognitive strategies for coping with strong negative emotions. Dissociation likely involves dysregulated balance of prefrontal inhibition of limbic structures and inadequate regulation of attentional bias by both prefrontal and limbic systems. There is currently no established psychopharmacologic treatment for dissociative symptoms. Here the case of a woman with severe dissociative symptoms that were markedly improved with the administration of mixed amphetamine salts is discussed. Potential neurobiologic mechanisms for dissociative symptom improvement with psychostimulants are discussed.

Small interfering RNA mediated knockdown of irisin suppresses food intake and modulates appetite regulatory peptides in zebrafish.

PubMed

Sundarrajan, Lakshminarasimhan; Unniappan, Suraj

2017-10-01

Irisin is a myokine encoded in fibronectin type III domain containing 5 (FNDC5). FNDC5 forms an integral part of the muscle post-exercise, and causes an increase in energy expenditure in mammals. Irisin is abundantly expressed in cardiac and skeletal muscles and is secreted upon activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). Irisin regulates feeding behaviour and cardiovascular function in mammals. More recently, irisin has gained importance as a potential biomarker for myocardial infarction due to its abundance in cardiac muscle. The goal of this research was to determine whether irisin influences feeding, and regulates appetite regulatory peptides in zebrafish. Intraperitoneal injection of irisin [0.1, 1, 10 and 100ng/g body weight (BW)] did not affect feeding, but its knockdown using siRNA (10ng/g BW) caused a significant reduction in food intake. Knockdown of irisin reduced ghrelin and orexin-A mRNA expression, and increased cocaine and amphetamine regulated transcript mRNA expression in zebrafish brain and gut. siRNA mediated knockdown of irisin also downregulated brain derived neurotrophic factor mRNA in zebrafish. The role of endogenous irisin on food intake is likely mediated by its actions on other metabolic peptides. Collectively, these results indicate that unaltered endogenous irisin is required to maintain food intake in zebrafish. Copyright © 2017 Elsevier Inc. All rights reserved.

The role of HIV integration in viral persistence: no more whistling past the proviral graveyard

PubMed Central

Maldarelli, Frank

2016-01-01

A substantial research effort has been directed to identifying strategies to eradicate or control HIV infection without a requirement for combination antiretroviral therapy (cART). A number of obstacles prevent HIV eradication, including low-level viral persistence during cART, long-term persistence of HIV-infected cells, and latent infection of resting CD4+ T cells. Mechanisms of persistence remain uncertain, but integration of the provirus into the host genome represents a central event in replication and pathogenesis of all retroviruses, including HIV. Analysis of HIV proviruses in CD4+ lymphocytes from individuals after prolonged cART revealed that a substantial proportion of the infected cells that persist have undergone clonal expansion and frequently have proviruses integrated in genes associated with regulation of cell growth. These data suggest that integration may influence persistence and clonal expansion of HIV-infected cells after cART is introduced, and these processes may represent key mechanisms for HIV persistence. Determining the diversity of host genes with integrants in HIV-infected cells that persist for prolonged periods may yield useful information regarding pathways by which infected cells persist for prolonged periods. Moreover, many integrants are defective, and new studies are required to characterize the role of clonal expansion in the persistence of replication-competent HIV. PMID:26829624

Kisspeptin and Metabolism: The Brain and Beyond.

PubMed

Dudek, Monika; Ziarniak, Kamil; Sliwowska, Joanna H

2018-01-01

Apart from the well-established role of kisspeptin (Kp) in the regulation of reproductive functions, recent data described its action in the control of metabolism. Of particular interest for the review is the population of Kp neurons localized in the arcuate nucleus (ARC) of the hypothalamus, the site of the brain where reproductive and metabolic cross talk occurs. However, within the hypothalamus Kp does not work alone, but rather interacts with other neuropeptides, e.g., neurokinin B, dynorphin A, proopiomelanocortin, the cocaine- and amphetamine-regulated transcript, agouti-related peptide, and neuropeptide Y. Beyond the brain, Kp is expressed in peripheral tissues involved in metabolic functions. In this review, we will mainly focus on the local action of this peptide in peripheral organs such as the pancreas, liver, and the adipose tissue. We will concentrate on dysregulation of the Kp system in cases of metabolic imbalance, e.g., obesity and diabetes. Importantly, these patients besides metabolic health problems often suffer from disruptions of the reproductive system, manifested by abnormalities in menstrual cycles, premature child birth, miscarriages in women, decreased testosterone levels and spermatogenesis in men, hypogonadism, and infertility. We will review the evidence from animal models and clinical data indicating that Kp could serve as a promising agent with clinical applications in regulation of reproductive problems in individuals with obesity and diabetes. Finally, emerging data indicate a role of Kp in regulation of insulin secretion, potentially leading to development of further therapeutic uses of this peptide to treat metabolic problems in patients with these lifestyle diseases.

Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients.

PubMed

Chen, Jinyun; Pande, Mala; Huang, Yu-Jing; Wei, Chongjuan; Amos, Christopher I; Talseth-Palmer, Bente A; Meldrum, Cliff J; Chen, Wei V; Gorlov, Ivan P; Lynch, Patrick M; Scott, Rodney J; Frazier, Marsha L

2013-02-01

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10(-4)). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.

Cell cycle–related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients

PubMed Central

Chen, Jinyun; Pande, Mala

2013-01-01

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle–related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle–related genes and 31 DNA repair–related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan–Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5×10–4). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16–6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome. PMID:23125224

Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats

PubMed Central

Varela, Fausto A.; Der-Ghazarian, Taleen; Lee, Ryan J.; Charntikov, Sergios; Crawford, Cynthia A.; McDougall, Sanders A.

2017-01-01

Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10–20. After one, four, or eight days (i.e., on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least eight days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side-effects, including extrapyramidal symptoms. PMID:24045880

49 CFR 173.197 - Regulated medical waste.

Code of Federal Regulations, 2013 CFR

2013-10-01

... transported in a Cart or BOP. (v) Division 6.1 toxic waste or Class 7 radioactive waste, with the exception of... construction and a rigid, weatherproof top to prevent the intrusion of water (e.g., rain or snow). (iii) Each...

49 CFR 173.197 - Regulated medical waste.

Code of Federal Regulations, 2012 CFR

2012-10-01

... transported in a Cart or BOP. (v) Division 6.1 toxic waste or Class 7 radioactive waste, with the exception of... construction and a rigid, weatherproof top to prevent the intrusion of water (e.g., rain or snow). (iii) Each...

49 CFR 173.197 - Regulated medical waste.

Code of Federal Regulations, 2014 CFR

2014-10-01

... transported in a Cart or BOP. (v) Division 6.1 toxic waste or Class 7 radioactive waste, with the exception of... construction and a rigid, weatherproof top to prevent the intrusion of water (e.g., rain or snow). (iii) Each...

A New Take on Exploding Carts

ERIC Educational Resources Information Center

Broder, Darren; Burleigh, James; Christian, Matthew; Mowry, Shawn; Hassel, George E.

2017-01-01

The Exploding Carts is a popular introductory physics activity in which a one-dimensional explosion is simulated utilizing two dynamics carts that are pushed apart by a spring-loaded plunger released from one of the carts. Traditional treatments of the Exploding Carts usually involve multiple trials where the mass of one or both of the carts is…

Fruit Carts: A Domain and Corpus for Research in Dialogue Systems and Psycholinguistics.

PubMed

Aist, Gregory; Campana, Ellen; Allen, James; Swift, Mary; Tanenhaus, Michael K

2012-09-01

We describe a novel domain, Fruit Carts, aimed at eliciting human language production for the twin purposes of (a) dialogue system research and development and (b) psycholinguistic research. Fruit Carts contains five tasks: choosing a cart, placing it on a map, painting the cart, rotating the cart, and filling the cart with fruit. Fruit Carts has been used for research in psycholinguistics and in dialogue systems. Based on these experiences, we discuss how well the Fruit Carts domain meets four desired features: unscripted, context-constrained, controllable difficulty, and separability into semi-independent subdialogues. We describe the domain in sufficient detail to allow others to replicate it; researchers interested in using the corpora themselves are encouraged to contact the authors directly.

Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy.

PubMed

Burgess, Christian R; Tse, Gavin; Gillis, Lauren; Peever, John H

2010-10-01

To determine if the dopaminergic system modulates cataplexy, sleep attacks and sleep-wake behavior in narcoleptic mice. Hypocretin/orexin knockout (i.e., narcoleptic) and wild-type mice were administered amphetamine and specific dopamine receptor modulators to determine their effects on sleep, cataplexy and sleep attacks. Hypocretin knockout (n = 17) and wild-type mice (n = 21). Cataplexy, sleep attacks and sleep-wake behavior were identified using electroencephalogram, electromyogram and videography. These behaviors were monitored for 4 hours after an i.p. injection of saline, amphetamine and specific dopamine receptor modulators (D1- and D2-like receptor modulators). Amphetamine (2 mg/kg), which increases brain dopamine levels, decreased sleep attacks and cataplexy by 61% and 67%, suggesting that dopamine transmission modulates such behaviors. Dopamine receptor modulation also had powerful effects on sleep attacks and cataplexy. Activation (SKF 38393; 20 mg/kg) and blockade (SCH 23390; 1 mg/kg) of D1-like receptors decreased and increased sleep attacks by 77% and 88%, without affecting cataplexy. Pharmacological activation of D2-like receptors (quinpirole; 0.5 mg/kg) increased cataplectic attacks by 172% and blockade of these receptors (eticlopride; 1 mg/kg) potently suppressed them by 97%. Manipulation of D2-like receptors did not affect sleep attacks. We show that the dopaminergic system plays a role in regulating both cataplexy and sleep attacks in narcoleptic mice. We found that cataplexy is modulated by a D2-like receptor mechanism, whereas dopamine modulates sleep attacks by a D1-like receptor mechanism. These results support a role for the dopamine system in regulating sleep attacks and cataplexy in a murine model of narcolepsy.

Sensorimotor Gating in Neurotensin-1 Receptor Null Mice

PubMed Central

Feifel, D.; Pang, Z.; Shilling, P.D.; Melendez, G.; Schreiber, R.; Button, D.

2009-01-01

BACKGROUND Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist, PD149163, known to increase PPI in rats. METHODS Baseline PPI and acoustic startle response were measured in WT and NT1 knockout KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days. RESULTS Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice. CONCLUSIONS The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists. PMID:19596359

Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances.

PubMed

Sikiric, Predrag; Jelovac, Nikola; Jelovac-Gjeldum, Andjelka; Dodig, Goran; Staresinic, Mario; Anic, Tomislav; Zoricic, Ivan; Rak, Davor; Perovic, Darko; Aralica, Gorana; Buljat, Gojko; Prkacin, Ingrid; Lovric-Bencic, Martina; Separovic, Jadranka; Seiwerth, Sven; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Ziger, Tihomil; Boban-Blagaic, Alenka; Bedekovic, Vlado; Tonkic, Ante; Babic, Slaven

2002-05-01

To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.

Effect of changing from first- to second-line antiretroviral therapy on renal function: a retrospective study based on data from a single health facility in Namibia.

PubMed

Kalemeera, Francis; Mbango, Christofina; Mubita, Mwangana; Naikaku, Esther; Gaida, Razia; Godman, Brian

2016-08-01

Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. As a result, the aim of this study is to assess effects of second-line cART on renal function. Retrospective longitudinal study in patients receiving cART. 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART. Time spent on cART had a weak relationship with CrCl. Patients on first-line cART for several years without renal impairment may experience new onset impairment during second line cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline.

Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys.

PubMed

Banks, Matthew L; Smith, Douglas A; Kisor, David F; Poklis, Justin L

2016-02-01

Methamphetamine is a globally abused drug that is metabolized to amphetamine, which also produces abuse-related behavioral effects. However, the contributing role of methamphetamine metabolism to amphetamine in methamphetamine's abuse-related subjective effects is unknown. This preclinical study was designed to determine 1) the relationship between plasma methamphetamine levels and methamphetamine discriminative stimulus effects and 2) the contribution of the methamphetamine metabolite amphetamine in the discriminative stimulus effects of methamphetamine in rhesus monkeys. Adult male rhesus monkeys (n=3) were trained to discriminate 0.18mg/kg intramuscular (+)-methamphetamine from saline in a two-key food-reinforced discrimination procedure. Time course of saline, (+)-methamphetamine (0.032-0.32mg/kg), and (+)-amphetamine (0.032-0.32mg/kg) discriminative stimulus effects were determined. Parallel pharmacokinetic studies were conducted in the same monkeys to determine plasma methamphetamine and amphetamine levels after methamphetamine administration and amphetamine levels after amphetamine administration for correlation with behavior in the discrimination procedure. Both methamphetamine and amphetamine produced full, ≥90%, methamphetamine-like discriminative stimulus effects. Amphetamine displayed a slightly, but significantly, longer duration of action than methamphetamine in the discrimination procedure. Both methamphetamine and amphetamine behavioral effects were related to methamphetamine and amphetamine plasma levels by a clockwise hysteresis loop indicating acute tolerance had developed to the discriminative stimulus effects. Furthermore, amphetamine levels after methamphetamine administration were absent when methamphetamine stimulus effects were greatest and peaked when methamphetamine discriminative stimulus effects returned to saline-like levels. Overall, these results demonstrate the methamphetamine metabolite amphetamine does not contribute to methamphetamine's abuse-related subjective effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans.

PubMed

Stoops, William W; Vansickel, Andrea R; Lile, Joshua A; Rush, Craig R

2007-05-01

Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

Design and Evaluation of a Stand-Up Motorized Prone Cart

PubMed Central

Harrow, Jeffrey J; Malassigné, Pascal; Nelson, Audrey L; Jensen, Robert P; Amato, Margaret; Palacios, Polly L

2007-01-01

Background/Objective: Prone carts are used for mobility by individuals with spinal cord injury in whom seated mobility (wheelchair) is contraindicated due to ischial or sacral pressure ulcers. Currently available prone carts are uncomfortable, subjecting the user to neck and shoulder strain, and make social interaction and performing activities of daily living difficult. A better design of prone carts is needed. In addition, standing devices have shown some medical benefits. The objective was to design and evaluate an improved prone cart that facilitates standing. Design: Engineering development project with user feedback through questionnaire. Users selected by convenience sampling. Methods: A marketing survey was performed of nurse managers of spinal cord injury units. Then 2 prototype carts were designed and built. These carts are able to tilt up to 45° and have a joystick-controlled motor for propulsion and other design features, including a workspace storage shelf and rearview mirrors. The carts were evaluated by both patients and caregivers at 2 Veteran's Administration hospitals. Outcome Measures: Questionnaire of subjects, both patients and caregivers, who used the cart. Findings: Both patients and caregivers liked the carts and the ability to assume a nonhorizontal body angle. The major complaint about the cart was that it seemed too long when it came to making turns. Conclusion: This prone cart design is an improvement over the standard, flat variety. However, further design changes will be necessary. This study provided valuable information that will be useful in the next-generation prone cart design project. PMID:17385270

Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding.

PubMed

Stairs, Dustin J; Klein, Emily D; Bardo, Michael T

2006-11-01

The current experiments aimed to determine whether differential rearing alters extinction and/or reinstatement of amphetamine self-administration or sucrose-maintained responding. Male Sprague-Dawley rats were raised in either an enriched condition or an isolated condition. Rats were then trained to lever press on a continuous reinforcement schedule across either 15 daily amphetamine self-administration sessions or 15 sucrose-reinforced sessions, followed by 10 sessions of extinction. After the extinction sessions, priming doses of amphetamine (0, 0.25 or 1.0 mg/kg) were administered 15 min before the session, or sucrose (one or 10 pellets) was delivered non-contingently at the beginning of the session. Enriched condition rats showed greater extinction for amphetamine and sucrose-maintained responding than isolated condition rats. When primed with amphetamine, isolated condition rats reinstated responding following 0.25 mg/kg of amphetamine, whereas enriched condition rats only reinstated responding after 1.0 mg/kg of amphetamine. Isolated condition rats failed to reinstate responding following sucrose delivery, while enriched condition rats reinstated responding following the delivery of 10 sucrose pellets. These results indicate that environmental enrichment enhanced the extinction of both amphetamine and sucrose-maintained responding. Environmental enrichment also raised the reinstatement threshold specific to the amphetamine prime, suggesting a reduction in the incentive motivational effect of amphetamine.

Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence.

PubMed

Beloate, Lauren N; Omrani, Azar; Adan, Roger A; Webb, Ian C; Coolen, Lique M

2016-09-21

Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience. Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward. Copyright © 2016 the authors 0270-6474/16/369949-13$15.00/0.

Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo

PubMed Central

Xu, Xiao-Jun; Song, De-Gang; Poussin, Mathilde; Ye, Qunrui; Sharma, Prannda; Rodríguez-García, Alba; Tang, Yong-Min; Powell, Daniel J.

2016-01-01

Exogenous cytokines are widely applied to enhance the anti-tumor ability of immune cells. However, systematic comparative studies of their effects on chimeric antigen receptor (CAR)-engineered T (CART) cells are lacking. In this study, CART cells targeting folate receptor-alpha were generated and expanded ex vivo in the presence of different cytokines (IL-2, IL-7, IL-15, IL-18, and IL-21), and their expansion, phenotype and cytotoxic capacity were evaluated, in vitro and in vivo. Moreover, the effect of the administration of these cytokines along with CART cells in vivo was also studied. IL-2, IL-7, and IL-15 favored the ex vivo expansion of CART cells compared to other cytokines or no cytokine treatment. IL-7 induced the highest proportion of memory stem cell-like CART cells in the final product, and IL-21 supported the expansion of CART cells with a younger phenotype, while IL-2 induced more differentiated CART cells. IL-2 and IL-15-exposed CART cells secreted more proinflammatory cytokines and presented stronger tumor-lysis ability in vitro. However, when tested in vivo, CART cells exposed to IL-2 ex vivo showed the least anti-tumor effect. In contrast, the administration of IL-15 and IL-21 in combination with CART cells in vivo increased their tumor killing capacity. According to our results, IL-7 and IL-15 show promise to promote ex vivo expansion of CART cells, while IL-15 and IL-21 seem better suited for in vivo administration after CART cell infusion. Collectively, these results may have a profound impact on the efficacy of CART cells in both hematologic and solid cancers. PMID:27409425

Stuttering—The Effect of Treatment with D-Amphetamine and a Tranquilizing Agent, Trifluoperazine; A Preliminary Report on an Uncontrolled Study

PubMed Central

Fish, Charles H.; Bowling, Evelyn

1965-01-01

In an institution for the mentally retarded, an uncontrolled study was made on the effects of d-amphetamine, d-amphetamine followed by trifluoperazine, and of combined d-amphetamine and trifluoperazine on stuttering. Of 28 patients to whom d-amphetamine was given, 14 showed improvement after one month's treatment. Eight more showed improvement when trifluoperazine was given for one month to those who did not improve on d-amphetamine. In many cases, improvement was sustained at least six months after treatment was discontinued. Treatment with d-amphetamine was apparently more effective in patients with functional than with organic retardation. PMID:5836893

[Persistent amphetamine consumption by truck drivers in São Paulo State, Brazil, despite the ban on production, prescription, and use].

PubMed

Oliveira, Lúcio Garcia de; Endo, Ligia Goes; Sinagawa, Daniele Mayumi; Yonamine, Maurício; Munoz, Daniel Romero; Leyton, Vilma

2013-09-01

Amphetamine use by truck drivers for occupational purposes is widely known. The production and consumption of amphetamines was banned by the Brazilian National Health Surveillance Agency (ANVISA) in October 2011. This study analyzes persistent amphetamine use by truck drivers since the ban was implemented. A convenience sample of 427 truck drivers was taken along highways in São Paulo State in 2012. Participants were asked to answer a structured questionnaire and provide a urine sample to screen for recent amphetamine consumption through toxicological analysis. Among the interviewed drivers, 7% had used some illicit drug recently and 2.7% had used amphetamines. Amphetamines are still consumed by truck drivers despite the risks and the recent ban. The authorities should thus monitor the possession and use of amphetamines by drivers in order to effectively enforce the ban.

Differences in Expansion Potential of Naive Chimeric Antigen Receptor T Cells from Healthy Donors and Untreated Chronic Lymphocytic Leukemia Patients.

PubMed

Hoffmann, Jean-Marc; Schubert, Maria-Luisa; Wang, Lei; Hückelhoven, Angela; Sellner, Leopold; Stock, Sophia; Schmitt, Anita; Kleist, Christian; Gern, Ulrike; Loskog, Angelica; Wuchter, Patrick; Hofmann, Susanne; Ho, Anthony D; Müller-Tidow, Carsten; Dreger, Peter; Schmitt, Michael

2017-01-01

Therapy with chimeric antigen receptor T (CART) cells for hematological malignancies has shown promising results. Effectiveness of CART cells may depend on the ratio of naive (T N ) vs. effector (T E ) T cells, T N cells being responsible for an enduring antitumor activity through maturation. Therefore, we investigated factors influencing the T N /T E ratio of CART cells. CART cells were generated upon transduction of peripheral blood mononuclear cells with a CD19.CAR-CD28-CD137zeta third generation retroviral vector under two different stimulating culture conditions: anti-CD3/anti-CD28 antibodies adding either interleukin (IL)-7/IL-15 or IL-2. CART cells were maintained in culture for 20 days. We evaluated 24 healthy donors (HDs) and 11 patients with chronic lymphocytic leukemia (CLL) for the composition of cell subsets and produced CART cells. Phenotype and functionality were tested using flow cytometry and chromium release assays. IL-7/IL-15 preferentially induced differentiation into T N , stem cell memory (T SCM : naive CD27+ CD95+), CD4+ and CXCR3+ CART cells, while IL-2 increased effector memory (T EM ), CD56+ and CD4+ T regulatory (T Reg ) CART cells. The net amplification of different CART subpopulations derived from HDs and untreated CLL patients was compared. Particularly the expansion of CD4+ CART N cells differed significantly between the two groups. For HDs, this subtype expanded >60-fold, whereas CD4+ CART N cells of untreated CLL patients expanded less than 10-fold. Expression of exhaustion marker programmed cell death 1 on CART N cells on day 10 of culture was significantly higher in patient samples compared to HD samples. As the percentage of malignant B cells was expectedly higher within patient samples, an excessive amount of B cells during culture could account for the reduced expansion potential of CART N cells in untreated CLL patients. Final T N /T E ratio stayed <0.3 despite stimulation condition for patients, whereas this ratio was >2 in samples from HDs stimulated with IL-7/IL-15, thus demonstrating efficient CART N expansion. Untreated CLL patients might constitute a challenge for long-lasting CART effects in vivo since only a low number of T N among the CART product could be generated. Depletion of malignant B cells before starting CART production might be considered to increase the T N /T E ratio within the CART product.

77 FR 10509 - Agency Information Collection Activities; Proposed Collection; Comment Request; Drug Testing for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-22

... Activities; Proposed Collection; Comment Request; Drug Testing for Contract Employees (Renewal) AGENCY... electronic docket, go to www.regulations.gov . Title: Drug Testing for Contract Employees. ICR numbers: EPA..., amphetamines, phencyclidine (PCP), and any other controlled substances. The testing for drugs must be completed...

Polymorphism within thyroid hormone responsive (THRSP) associated with weaning-to-oestrus interval in swine

USDA-ARS?s Scientific Manuscript database

The objective of this study was to assess polymorphisms within lipogenic-related candidate genes for association with the reproductive traits; age at puberty (AP), ovulation rate (OR), and weaning-to-estrus interval (WEI). Variations within the anorectic gene Cocaine- and Amphetamine-Regulated Trans...

System frequency support of permanent magnet synchronous generator-based wind power plant

NASA Astrophysics Data System (ADS)

Wu, Ziping

With ever-increasing penetration of wind power into modern electric grids all over the world, a trending replacement of conventional synchronous generators by large wind power plants will likely result in the poor overall frequency regulation performance. On the other hand, permanent magnet synchronous generator wind Turbine System (PMSG-WTG) with full power back to back converters tends to become one of the most promising wind turbine technologies thanks to various advantages. It possesses a significant amount of kinetic energy stored in the rotating mass of turbine blades, which can be utilized to enhance the total inertia of power system. Additionally, the deloaded operation and decoupled control of active and reactive power make it possible for PMSG-WTG to provide a fast frequency regulation through full-power converter. First of all, a comprehensive and in-depth survey is conducted to analyze the motivations for incorporating the inertial response and frequency regulation of VSWT into the system frequency regulation. Besides, control classifications, fundamental control concepts and advanced control schemes implemented for auxiliary frequency support of individual WT or wind power plant are elaborated along with a comparison of the potential frequency regulation capabilities of four major types of WTs. Secondly, a Controls Advanced Research Turbine2-Permanent Magnet Synchronous Generator wind turbine (CART2-PMSG) integrated model representing the typical configuration and operation characteristics of PMSG-WT is established in Matlab/Simulink,. Meanwhile, two different rotor-side converter control schemes, including rotor speed-based control and active power-based control, are integrated into this CART2-PMSG integrated model to perform Maximum Power Point Tracking (MPPT) operation over a wide range of wind speeds, respectively. Thirdly, a novel comprehensive frequency regulation (CFR) control scheme is developed and implemented into the CART2-PMSG model based on rotor speed control. The proposed control scheme is achieved through the coordinated control between rotor speed and modified pitch angle in accordance with different specified wind speed modes. Fourth, an improved inertial control method based on the maximum power point tracking operation curve is introduced to boost the overall frequency support capability of PMSG-WTGs based on rotor speed control. Fifth, a novel control method based on the torque limit (TLC) is proposed for the purpose of maximizing the wind turbine (WT)'s inertial response. To avoid the SFD caused by the deloaded operation of WT, a small-scale battery energy storage system (BESS) model is established and implemented to eliminate this impact and meanwhile assist the restoration of wind turbine to MPPT mode by means of coordinated control strategy between BESS and PMSG-WTG. Last but not the least, all three types of control strategies are implemented in the CART2-PMSG integrated model based on rotor speed control or active power control respectively to evaluate their impacts on the wind turbine's structural loads during the frequency regulation process. Simulation results demonstrate that all the proposed methods can enhance the overall frequency regulation performance while imposing very slight negative impact on the major mechanical components of the wind turbine.

Characteristics of primary amphetamine users in Sweden: a criminal justice population examined with the Addiction Severity Index.

PubMed

Hakansson, A; Schlyter, F; Berglund, M

2009-01-01

Characteristics of primary amphetamine, heroin and cocaine users were compared in a criminal justice population. 7,085 clients with suspected or reported substance use were studied using the Addiction Severity Index. Variables separating amphetamine, heroin and cocaine users were analyzed in stepwise logistic regression. There were considerably more primary amphetamine users (n = 1,396) than heroin (n = 392) and cocaine (n = 119) users. Amphetamine users were older, a more rural population, and less likely to be non-Nordic immigrants. Compared with heroin, amphetamine use was associated with older age, Nordic origin, nonurban residence, memory/concentration problems, parental alcohol problems, and less history of other opioid use, overdose and detoxification. Compared with cocaine, amphetamine use was associated with older age, Nordic origin, nonurban residence, injecting, tobacco and institution treatment. Overlap of drug use between groups was relatively uncommon. This pattern of amphetamine use, common among Swedish criminals, has relatively distinct boundaries from heroin and cocaine use, commonly involves injecting, and differs from other countries. Psychiatric problems and alcohol heredity were common, and evidence-based treatment for amphetamine users is needed. The connection between amphetamine use and criminal behavior is insufficiently understood and should be further addressed. Copyright 2008 S. Karger AG, Basel.

Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable?

PubMed Central

2012-01-01

Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease. The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis. PMID:23216941

Estimation of neuronal numbers in rat hippocampus following neonatal amphetamine exposure: a stereology study.

PubMed

Smith, Andrew M; Pappalardo, Dana; Chen, Wei-Jung A

2008-01-01

In this study, the effects of amphetamine exposure during a portion of the brain growth spurt on the total number of hippocampal pyramidal cells (CA1/CA3 subregions) and the granule cells (dentate gyrus) were examined in both neonatal and adult rats. Intragastric intubation was used to administer 5, 15 or 25 mg/kg/day of amphetamine to Sprague-Dawley rat pups from PDs 4-9. Unbiased stereology was used to estimate the total number of cells present within each hippocampal subregion at both PD 9 and PD 68. The results indicated that neonatal amphetamine exposure did not alter the cell number, the reference volume or the density in any of the hippocampal subregions assessed, regardless of age. However, amphetamine significantly altered the rate of neuronal incorporation in both the hippocampal CA3 subregion and the dentate gyrus, and this effect appeared to be dose-related with the most robust effect observed in the highest amphetamine dose. While these findings did not demonstrate significant injurious effects of neonatal amphetamine treatment on the number of hippocampal neurons, these data suggest that amphetamine may interfere with proper hippocampal development. Future studies employing more sensitive measurements or exposing amphetamine during an alternate period of development may provide more information regarding amphetamine-mediated developmental neurotoxicity.

Demographic and financial characteristics of school districts with low and high à la Carte sales in rural Kansas Public Schools.

PubMed

Nollen, Nicole L; Kimminau, Kim S; Nazir, Niaman

2011-06-01

Reducing à la carte items in schools-foods and beverages sold outside the reimbursable meals program-can have important implications for childhood obesity. However, schools are reluctant to reduce à la carte offerings because of the impact these changes could have on revenue. Some foodservice programs operate with limited à la carte sales, but little is known about these programs. This secondary data analysis compared rural and urban/suburban school districts with low and high à la carte sales. Foodservice financial records (2007-2008) were obtained from the Kansas State Department of Education for all public K-12 school districts (n=302). χ² and t tests were used to examine the independent association of variables to à la carte sales. A multivariate model was then constructed of the factors most strongly associated with low à la carte sales. In rural districts with low à la carte sales, lunch prices and participation were higher, lunch costs and à la carte quality were lower, and fewer free/reduced price lunches were served compared to rural districts with high à la carte sales. Lunch price (odds ratio=1.2; 95% confidence interval, 1.1 to 1.4) and free/reduced price lunch participation (odds ratio=3.0; 95% confidence interval, 1.0 to 9.8) remained in the multivariate model predicting low à la carte sales. No differences were found between urban/suburban districts with low and high à la carte sales. Findings highlight important factors to maintaining low à la carte sales. Schools should consider raising lunch prices and increasing meal participation rates as two potential strategies for reducing the sale of à la carte items without compromising foodservice revenue. Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved.

[The medical treatment of attention deficit hyperactivity disorder (ADHD) with amphetamines in children and adolescents].

PubMed

Frölich, Jan; Banaschewski, Tobias; Spanagel, Rainer; Döpfner, Manfred; Lehmkuhl, Gerd

2012-09-01

Psychostimulants (methylphenidate and amphetamines) are the drugs of first choice in the pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). We summarize the pharmacological characteristics of amphetamines and compare them with methylphenidate, special emphasis being given to a comparison of effects and side effects of the two substances. Finally, we analyze the abuse and addiction risks. Publications were chosen based on a Medline analysis for controlled studies and meta-analyses published between 1980 and 2011; keywords were amphetamine, amphetamine salts, lisdexamphetamine, controlled studies, and metaanalyses. Amphetamines generally exhibit some pharmacologic similarities with methylphenidate. However, besides inhibiting dopamine reuptake amphetamines also cause the release of monoamines. Moreover, plasma half-life is significantly prolonged. The clinical efficacy and tolerability of amphetamines is comparable to methylphenidate. Amphetamines can therefore be used if the individual response to methylphenidate or tolerability is insufficient before switching to a nonstimulant substance, thus improving the total response rate to psychostimulant treatment. Because of the high abuse potential of amphetamines, especially in adults, the prodrug lisdexamphetamine (Vyvanse) could become an effective treatment alternative. Available study data suggest a combination of high clinical effect size with a beneficial pharmacokinetic profile and a reduced abuse risk. In addition to methylphenidate, amphetamines serve as important complements in the psychostimulant treatment of ADHD. Future studies should focus on a differential comparison of the two substances with regard to their effects on different core symptom constellations and the presence of various comorbidities.

Amphetamine derivative related deaths.

PubMed

Lora-Tamayo, C; Tena, T; Rodríguez, A

1997-02-28

Amphetamine its methylendioxy (methylendioxyamphetamine methylenedioxymethylamphetamine, methylenedioxyethylamphetamine) and methoxy derivatives (p-methoxyamphetamine and p-methoxymethylamphetamine) are widely abused in Spanish society. We present here the results of a systematic study of all cases of deaths brought to the attention of the Madrid department of the Instituto Nacional de Toxicologia from 1993 to 1995 in which some of these drugs have been found in the cadaveric blood. The cases were divided into three categories: amphetamine and derivatives, amphetamines and alcohol, amphetamines and other drugs. Data on age, sex, clinical symptoms, morphological findings, circumstances of death, when known, and concentration of amphetamine derivatives, alcohol and other drugs in blood are given for each group. The information provided here may prove to be useful for the forensic interpretation of deaths which are directly or indirectly related to abuse of amphetamine derivatives.

Predicting drug court outcome among amphetamine-using participants.

PubMed

Wu, Lora J; Altshuler, Sandra J; Short, Robert A; Roll, John M

2012-06-01

Amphetamine use and abuse carry with it substantial social costs. Although there is a perception that amphetamine users are more difficult to treat than other substance users, drug courts have been used to effectively address drug-related crimes and hold the potential to lessen the impact of amphetamine abuse through efficacious treatment and rehabilitation. The objective of this study was to identify predictors of drug court outcome among amphetamine-using participants. A drug court database was obtained (N = 540) and amphetamine-using participants (n= 341) identified. Multivariate binary regression models run for the amphetamine-using participants identified being employed and being a parent as predictive of successful completion of the program, whereas being sanctioned to jail during the program was inversely related to program completion. Copyright © 2012 Elsevier Inc. All rights reserved.

The effects of d-govadine on conditioned place preference with d-amphetamine or food reward.

PubMed

Nesbit, Maya O; Dias, Carine; Phillips, Anthony G

2017-03-15

Tetrahydroprotoberberines (THPB) have a high affinity for dopamine (DA) D1 and D2 receptors and may provide a novel treatment for drug addiction. We assessed the effects of the THPB d-govadine on the acquisition, expression, extinction and reinstatement of d-amphetamine-(1.5mg/kg, i.p.) induced conditioned place preference (CPP). Furthermore, the effects of d-govadine on conditioned association between contextual stimuli and a natural reward were examined using food-induced CPP. In separate experiments, rats received d-govadine (0, 0.5 or 1.0mg/kg, i.p.) before a) each d-amphetamine injection during conditioning, b) expression of amphetamine-induced CPP, c) each extinction session, d) amphetamine-induced reinstatement of CPP, or e) placement into a compartment containing food during conditioning. Although d-govadine had no effect on acquisition of amphetamine CPP, treatment with d-govadine during acquisition dose-dependently extinguished a preference for the amphetamine-associated context more quickly than vehicle treatment. Moreover, d-govadine treatment facilitated the extinction of amphetamine CPP when given repeatedly throughout the extinction phase. Although the expression of amphetamine CPP was not affected by d-govadine administered prior to the expression test, amphetamine-induced reinstatement of CPP following an extinction period was blocked by d-govadine (1.0mg/kg). The intermediate dose of d-govadine blocked the acquisition of food CPP, whereas the high dose facilitated extinction of this preference as compared to vehicle-treated animals. Therefore, d-govadine attenuates the maintenance of conditioned associations between contextual stimuli and amphetamine or food reward, as well as amphetamine-induced reinstatement of drug seeking behaviour. As such, d-govadine may be a candidate for further development as a pharmacological treatment of psychostimulant drug dependence. Copyright © 2017 Elsevier B.V. All rights reserved.

Interactions between radiation and amphetamine in taste-aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-01-01

Three experiments were run to assess the role of the area postrema in taste-aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning to intact ratsmore » and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less-severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste-aversion learning may involve area post-remamediated mechanisms, particularly at the lower doses, but an intact area postrema is not a necessary condition of the acquisition of an amphetamine-induced taste aversion.« less

Interactions between radiation and amphetamine in taste aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-08-01

Three experiments were run to assess the role of the area postrema in taste aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning in intactmore » rats and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste aversion learning may involve area postrema-mediated mechanisms, particularly at the lower doses, but that an intact area postrema is not a necessary condition for the acquisition of an amphetamine-induced taste aversion.« less

Destruction of amphetamine in aqueous solution using gamma irradiation

NASA Astrophysics Data System (ADS)

Alkhuraiji, Turki S.; Ajlouni, Abdul-Wali

2017-10-01

Amphetamine-type stimulants are among the most prevalent and widespread commonly abused drugs. Amphetamine and its derivatives were detected in aquatic environment. This study aimed to demonstrate experimentally the ability of γ-irradiation combined with persulfate anions (S2O82-) to degrade and mineralize the amphetamine in aqueous solution. An initial amphetamine concentration of 125 μM in distilled water was completely degraded by a γ-ray dose of 2.8 kGy. Generation of the sulfate radical (SO4•-) from the fast reaction of added S2O82- with hydrated electrons (eaq-; keaq-/S2O82- = 1.1×1010 M-1 s-1) improved the efficiency of amphetamine degradation and mineralization. A γ-ray dose of 0.667 and 0.350 kGy in the absence and presence of S2O82- anions degraded 90% of the amphetamine, respectively. For γ-ray/free O2 and γ-ray/S2O82- systems, 11.5 and 7 kGy was required for 50% amphetamine mineralization, respectively. Addition of HCO3- anions lowered the amphetamine degradation yield, whereas N2 gas, SO42-, and Cl- anions had a negligible effect.

A rapid novel derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography electron ionization and chemical ionization mass spectrometric analysis.

PubMed

Dasgupta, A; Spies, J

1998-05-01

Amphetamine and methamphetamine are commonly abused central nervous system stimulants. We describe a rapid new derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography-mass spectrometric analysis. Amphetamine and methamphetamine, along with N-propyl amphetamine (internal standard), were extracted from urine using 1-chlorobutane. The derivatization with 2,2,2-trichloroethyl chloroformate can be achieved at room temperature in 10 minutes. The electron ionization mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed two weak molecular ions at m/z 309 and 311, but showed diagnostic strong peaks at m/z 218, 220, and 222. In contrast, chemical ionization of the mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed strong (M + 1) ions at m/z 310 and 312 and other strong diagnostic peaks at m/z 274 and 276. The major advantages of this derivative are the presence of a diagnostic cluster of peaks due to the isotopic effect of three chlorine atoms (isotopes 35 and 37) in the derivatized molecule and the relative ease of its preparation. We also observed strong molecular ions for derivatized methamphetamine in the chemical ionization mass spectrum, but the molecular ions were very weak in the electron ionization mass spectrum. We used the scan mode of mass spectrometry in all analyses. When using a urine standard containing 1,000 ng/mL of amphetamine (a 7.4-micromol/L concentration) and methamphetamine (a 6.7-micromol/L concentration), the within-run precisions were 4.8% for amphetamine and 3.6% for methamphetamine. The corresponding between-run precisions were 5.3% for amphetamine and 6.7% for methamphetamine. The assay was linear for amphetamine and methamphetamine concentrations of 250 to 5,000 ng/mL (amphetamine, 1.9-37.0 micromol/L; methamphetamine, 1.7-33.6 micromol/L). The detection limit was 100 ng/mL (amphetamine, 0.74 micromol/L; methamphetamine, 0.67 micromol/L) using the scan mode of electron ionization mass spectrometry. We observed good a correlation between the concentrations of amphetamine and methamphetamine in five urine specimens positive for amphetamines using the more conventional pentafluoropropionyl derivative and our new derivative using 2,2,2-trichloroethyl chloroformate.

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

Daytime Ayahuasca administration modulates REM and slow-wave sleep in healthy volunteers.

PubMed

Barbanoj, Manel J; Riba, Jordi; Clos, S; Giménez, S; Grasa, E; Romero, S

2008-02-01

Ayahuasca is a traditional South American psychoactive beverage and the central sacrament of Brazilian-based religious groups, with followers in Europe and the United States. The tea contains the psychedelic indole N,N-dimethyltryptamine (DMT) and beta-carboline alkaloids with monoamine oxidase-inhibiting properties that render DMT orally active. DMT interacts with serotonergic neurotransmission acting as a partial agonist at 5-HT(1A) and 5-HT(2A/2C) receptor sites. Given the role played by serotonin in the regulation of the sleep/wake cycle, we investigated the effects of daytime ayahuasca consumption in sleep parameters. Subjective sleep quality, polysomnography (PSG), and spectral analysis were assessed in a group of 22 healthy male volunteers after the administration of a placebo, an ayahuasca dose equivalent to 1 mg DMT kg(-1) body weight, and 20 mg d-amphetamine, a proaminergic drug, as a positive control. Results show that ayahuasca did not induce any subjectively perceived deterioration of sleep quality or PSG-measured disruptions of sleep initiation or maintenance, in contrast with d-amphetamine, which delayed sleep initiation, disrupted sleep maintenance, induced a predominance of 'light' vs 'deep' sleep and significantly impaired subjective sleep quality. PSG analysis also showed that similarly to d-amphetamine, ayahuasca inhibits rapid eye movement (REM) sleep, decreasing its duration, both in absolute values and as a percentage of total sleep time, and shows a trend increase in its onset latency. Spectral analysis showed that d-amphetamine and ayahuasca increased power in the high frequency range, mainly during stage 2. Remarkably, whereas slow-wave sleep (SWS) power in the first night cycle, an indicator of sleep pressure, was decreased by d-amphetamine, ayahuasca enhanced power in this frequency band. Results show that daytime serotonergic psychedelic drug administration leads to measurable changes in PSG and sleep power spectrum and suggest an interaction between these drugs and brain circuits modulating REM and SWS.

Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study

PubMed Central

Jayaram-Lindström, N; Guterstam, J; Häggkvist, J; Ericson, M; Malmlöf, T; Schilström, B; Halldin, C; Cervenka, S; Saijo, T; Nordström, A-L; Franck, J

2017-01-01

The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [11C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence. PMID:28440810

The effects of amphetamine exposure on outcome-selective Pavlovian-instrumental transfer in rats

PubMed Central

Shiflett, Michael W.

2012-01-01

Rationale Repeated exposure to psychostimulants alters behavioral responses to reward-related cues; however, the motivational underpinnings of this effect have not been fully characterized. Objectives The following study was designed to examine how amphetamine sensitization affects performance in rats on a series of Pavlovian and operant tasks that distinguish between general-incentive and outcome-selective forms of conditioned responses. Methods Adult male rats underwent Pavlovian and instrumental training for food pellet rewards. Following training, rats were sensitized to d-amphetamine (2 mg/kg for 7 days). Rats were subsequently tested on an outcome-selective Pavlovian-instrumental transfer (PIT) task, an outcome-reinstatement task, and an outcome devaluation task. Additionally, in a separate experiment PIT was assessed in amphetamine-sensitized and control rats using a Pavlovian backward-conditioned stimulus. Results Repeated amphetamine exposure sensitized locomotor activity to acute amphetamine challenge. Amphetamine altered responses to CS presentations by increasing conditioned approach. During tests of PIT amphetamine-treated rats showed no outcome-selectivity in their responding, responding to a CS whether or not it shared a common outcome with the instrumental response. No effect of amphetamine sensitization was observed on tests of outcome-selective reinstatement by outcome delivery, or action selection based on outcome value. Amphetamine-sensitized rats showed impaired outcome-selective PIT to a backward CS but were unaltered in conditioned approach. Conclusions Amphetamine sensitization prevents outcome-selective responding during PIT, which is dissociable from amphetamine’s effects on conditioned approach. These data suggest fundamental alterations in how stimuli motivate action in addiction. PMID:22562522

Making `Internal Thermal Energy' Visible

NASA Astrophysics Data System (ADS)

Zou, Xueli

2004-09-01

In a 1992 paper published in this journal, Uri Ganiel described a pair of model carts used to demonstrate elastic and inelastic collisions. The wooden carts had low-friction wheels and a steel-strip bumper on one end. On one of the carts, a number of brass washers were rigidly mounted in vertical stacks to a wooden framework. The other cart was similar except that the washers were tied to rubber bands that were stretched horizontally and diagonally across the framework. When the first cart was rolled into a wall it bounced off with only a small reduction in speed ("elastic" collision). The second cart, on the other hand, was found to come nearly to a complete stop upon colliding with the wall ("inelastic" collision). Following the instructions given in Ganiel's paper, I built a pair of carts and demonstrated them to introductory-level physics students at a large public university. It was interesting to find that many students were distracted by the different-looking structures of the two model carts.2 They thought the different distributions of washers between the carts resulted in the rubber-band cart bouncing back a significantly shorter distance than the rigid-rod one after they both collided with a wall at the same initial speed. Apparently, the students had difficulties in understanding the collisions and used surface features to reason about them. To avoid this superficial distraction and to help students visualize easily "where the kinetic energy goes in an inelastic collision," I modified the rigid-rod cart to have washers fixed on hollow aluminum rods mounted at four different levels horizontally and diagonally (see Fig. 1). The new pair of the model carts look very similar to each other: They have the same bumpers, same wheels, same distributions of washers, and same masses.

Outcomes of Patients Lost to Follow-up in African Antiretroviral Therapy Programs: Individual Patient Data Meta-analysis.

PubMed

Chammartin, Frédérique; Zürcher, Kathrin; Keiser, Olivia; Weigel, Ralf; Chu, Kathryn; Kiragga, Agnes N; Ardura-Garcia, Cristina; Anderegg, Nanina; Laurent, Christian; Cornell, Morna; Tweya, Hannock; Haas, Andreas D; Rice, Brian D; Geng, Elvin H; Fox, Matthew P; Hargreaves, James R; Egger, Matthias

2018-06-08

Low retention on combination antiretroviral therapy (cART) has emerged as a threat to the Joint United Nations Programme on human immunodeficiency virus (HIV)/AIDS (UNAIDS) 90-90-90 targets. We examined outcomes of patients who started cART but were subsequently lost to follow-up (LTFU) in African treatment programs. This was a systematic review and individual patient data meta-analysis of studies that traced patients who were LTFU. Outcomes were analyzed using cumulative incidence functions and proportional hazards models for the competing risks of (i) death, (ii) alive but stopped cART, (iii) silent transfer to other clinics, and (iv) retention on cART. Nine studies contributed data on 7377 patients who started cART and were subsequently LTFU in sub-Saharan Africa. The median CD4 count at the start of cART was 129 cells/μL. At 4 years after the last clinic visit, 21.8% (95% confidence interval [CI], 20.8%-22.7%) were known to have died, 22.6% (95% CI, 21.6%-23.6%) were alive but had stopped cART, 14.8% (95% CI, 14.0%-15.6%) had transferred to another clinic, 9.2% (95% CI, 8.5%-9.8%) were retained on cART, and 31.6% (95% CI, 30.6%-32.7%) could not been found. Mortality was associated with male sex, more advanced disease, and shorter cART duration; stopping cART with less advanced disease andlonger cART duration; and silent transfer with female sex and less advanced disease. Mortality in patients LTFU must be considered for unbiased assessments of program outcomes and UNAIDS targets in sub-Saharan Africa. Immediate start of cART and early tracing of patients LTFU should be priorities.

Mercury Shopping Cart Interface

NASA Technical Reports Server (NTRS)

Pfister, Robin; McMahon, Joe

2006-01-01

Mercury Shopping Cart Interface (MSCI) is a reusable component of the Power User Interface 5.0 (PUI) program described in another article. MSCI is a means of encapsulating the logic and information needed to describe an orderable item consistent with Mercury Shopping Cart service protocol. Designed to be used with Web-browser software, MSCI generates Hypertext Markup Language (HTML) pages on which ordering information can be entered. MSCI comprises two types of Practical Extraction and Report Language (PERL) modules: template modules and shopping-cart logic modules. Template modules generate HTML pages for entering the required ordering details and enable submission of the order via a Hypertext Transfer Protocol (HTTP) post. Shopping cart modules encapsulate the logic and data needed to describe an individual orderable item to the Mercury Shopping Cart service. These modules evaluate information entered by the user to determine whether it is sufficient for the Shopping Cart service to process the order. Once an order has been passed from MSCI to a deployed Mercury Shopping Cart server, there is no further interaction with the user.

Control of an Omni-directional Power-assisted Cart

NASA Astrophysics Data System (ADS)

Maeda, Hiroshi; Fujiwara, Shigeki; Kitano, Hitoshi; Yamashita, Hideki; Fukunaga, Hideo

This paper describes an easy-to-operate, omni-directional cart. This cart includes power assist technology that acts for both the longitudinal and rotational motions of the cart. Two objectives are set for this development. The first objective is to overcome the difficulty of shifting the cart laterally. Therefore, the equation for calculating the cart turning speed is modified so that the moment, which is driven by the operating force in the right/left direction, is offset. As a result, it becomes possible to stabilize the balance between the operating force in the right/left direction and the operating moment, and improve the operating performance. The second objective is to overcome the other difficulty whereby, during the one-hand pull-operation, the cart tended to run off course to the right/left. To solve this problem, we add a positional control in the right/left direction. As a result, we reduce the lateral deviation of the cart, and improve the operating performance.

Building community resilience to disasters through a community-based intervention: CART applications.

PubMed

Pfefferbaum, Rose L; Pfefferbaum, Betty; Van Horn, Richard L; Neas, Barbara R; Houston, J Brian

2013-01-01

The Communities Advancing Resilience Toolkit (CART)* is a community-driven, publicly available, theory-based, and evidence-informed community intervention designed to build community resilience to disasters and other adversities. Based on principles of participatory action research, CART applications contribute to community resilience by encouraging and supporting community participation and cooperation, communication, self-awareness, and critical reflection. The primary value of CART lies in its ability to stimulate analysis, collaboration, skill building, resource sharing, and purposeful action. In addition to generating community assessment data, CART can be used as a vehicle for delivering other interventions and creating sustainable capacity within communities. Two models for CART implementation are described.

Designation of Alpha-Phenylacetoacetonitrile (APAAN), a Precursor Chemical Used in the Illicit Manufacture of Phenylacetone, Methamphetamine, and Amphetamine, as a List I Chemical. Final rule.

PubMed

2017-07-14

The Drug Enforcement Administration (DEA) is finalizing the designation of the chemical alpha-phenylacetoacetonitrile (APAAN) and its salts, optical isomers, and salts of optical isomers, as a list I chemical under the Controlled Substances Act (CSA). The DEA proposed control of APAAN, due to its use in clandestine laboratories to illicitly manufacture the schedule II controlled substances phenylacetone (also known as phenyl-2-propanone or P2P), methamphetamine, and amphetamine. This rulemaking finalizes, without change, the control of APAAN as a list I chemical. This action does not establish a threshold for domestic and international transactions of APAAN. As such, all transactions involving APAAN, regardless of size, shall be regulated. In addition, chemical mixtures containing APAAN are not exempt from regulatory requirements at any concentration. Therefore, all transactions of chemical mixtures containing any quantity of APAAN shall be regulated pursuant to the CSA. However, manufacturers may submit an application for exemption for those mixtures that do not qualify for automatic exemption.

Low Prolactin and High 20-α-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor-Based Combination Antiretroviral Therapy.

PubMed

Papp, Eszter; Balogun, Kayode; Banko, Nicole; Mohammadi, Hakimeh; Loutfy, Mona; Yudin, Mark H; Shah, Rajiv; MacGillivray, Jay; Murphy, Kellie E; Walmsley, Sharon L; Silverman, Michael; Serghides, Lena

2016-05-15

It has been reported that pregnant women receiving protease inhibitor (PI)-based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)-infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00-4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66-1.26 AU;P= .002). Prolactin, a key regulator of 20α-HSD, was lower (P= .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART-induced decreases in progesterone levels. Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Low Prolactin and High 20-α-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor–Based Combination Antiretroviral Therapy

PubMed Central

Papp, Eszter; Balogun, Kayode; Banko, Nicole; Mohammadi, Hakimeh; Loutfy, Mona; Yudin, Mark H.; Shah, Rajiv; MacGillivray, Jay; Murphy, Kellie E.; Walmsley, Sharon L.; Silverman, Michael; Serghides, Lena

2016-01-01

Background. It has been reported that pregnant women receiving protease inhibitor (PI)–based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. Methods. We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)–infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. Results. HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P = .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00–4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66–1.26 AU; P = .002). Prolactin, a key regulator of 20α-HSD, was lower (P = .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART–induced decreases in progesterone levels. Conclusions. Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women. PMID:26740274

Predicting outcome on admission and post-admission for acetaminophen-induced acute liver failure using classification and regression tree models.

PubMed

Speiser, Jaime Lynn; Lee, William M; Karvellas, Constantine J

2015-01-01

Assessing prognosis for acetaminophen-induced acute liver failure (APAP-ALF) patients often presents significant challenges. King's College (KCC) has been validated on hospital admission, but little has been published on later phases of illness. We aimed to improve determinations of prognosis both at the time of and following admission for APAP-ALF using Classification and Regression Tree (CART) models. CART models were applied to US ALFSG registry data to predict 21-day death or liver transplant early (on admission) and post-admission (days 3-7) for 803 APAP-ALF patients enrolled 01/1998-09/2013. Accuracy in prediction of outcome (AC), sensitivity (SN), specificity (SP), and area under receiver-operating curve (AUROC) were compared between 3 models: KCC (INR, creatinine, coma grade, pH), CART analysis using only KCC variables (KCC-CART) and a CART model using new variables (NEW-CART). Traditional KCC yielded 69% AC, 90% SP, 27% SN, and 0.58 AUROC on admission, with similar performance post-admission. KCC-CART at admission offered predictive 66% AC, 65% SP, 67% SN, and 0.74 AUROC. Post-admission, KCC-CART had predictive 82% AC, 86% SP, 46% SN and 0.81 AUROC. NEW-CART models using MELD (Model for end stage liver disease), lactate and mechanical ventilation on admission yielded predictive 72% AC, 71% SP, 77% SN and AUROC 0.79. For later stages, NEW-CART (MELD, lactate, coma grade) offered predictive AC 86%, SP 91%, SN 46%, AUROC 0.73. CARTs offer simple prognostic models for APAP-ALF patients, which have higher AUROC and SN than KCC, with similar AC and negligibly worse SP. Admission and post-admission predictions were developed. • Prognostication in acetaminophen-induced acute liver failure (APAP-ALF) is challenging beyond admission • Little has been published regarding the use of King's College Criteria (KCC) beyond admission and KCC has shown limited sensitivity in subsequent studies • Classification and Regression Tree (CART) methodology allows the development of predictive models using binary splits and offers an intuitive method for predicting outcome, using processes familiar to clinicians • Data from the ALFSG registry suggested that CART prognosis models for the APAP population offer improved sensitivity and model performance over traditional regression-based KCC, while maintaining similar accuracy and negligibly worse specificity • KCC-CART models offered modest improvement over traditional KCC, with NEW-CART models performing better than KCC-CART particularly at late time points.

The modulation effects of d-amphetamine and procaine on the spontaneously generated action potentials in the central neuron of snail, Achatina fulica Ferussac.

PubMed

Lin, Chia-Hsien; Tsai, Ming-Cheng

2005-05-01

The modulation effects of d-amphetamine and procaine on the spontaneously generated action potentials were studied on the RP1 central neuron of giant African snails (Achatina fulica Ferussac). Extra-cellular application of d-amphetamine or procaine reversibly elicited bursts of potential (BoP). Prazosin, propranolol, atropine or d-tubocurarine did not alter the BoP elicited by either d-amphetamine or procaine. KT-5720 or H89 (protein kinase A inhibitors) blocked d-amphetamine-elicited BoP, whereas they did not block the procaine-elicited BoP. U73122, neomycin (phospholipase C inhibitors) blocked the procaine-elicited BoP, whereas they did not block the d-amphetamine-elicited BoP in the same neuron. These results suggest that BoP elicited by d-amphetamine or procaine were associated with protein kinase A and phospholipase C activity in the neuron.

CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

PubMed

Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

2017-10-01

Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

Narcolepsy Treated with Racemic Amphetamine during Pregnancy and Breastfeeding.

PubMed

Öhman, Inger; Wikner, Birgitta Norstedt; Beck, Olof; Sarman, Ihsan

2015-08-01

This case report describes a woman with narcolepsy treated with racemic amphetamine (rac-amphetamine) during pregnancy and breastfeeding with follow-up on the infant's development up to 10 months of age. The pregnancy outcome and the pharmacokinetics of rac-amphetamine were studied during breastfeeding. The pregnancy and the delivery were uneventful. Concentrations of rac-amphetamine were determined in the plasma of the mother and infant, and in the breast milk with a liquid chromatography-mass spectrometry method. Samples were obtained at 2, 5, and 9 weeks postpartum. The transfer of rac-amphetamine to the breast milk was extensive (mean milk/maternal plasma concentration ratio approximately 3). The breastfed infant had a low plasma concentration of rac-amphetamine (about 9% of the maternal plasma level) and the calculated relative infant dose was low (2%). No adverse effects were observed in the breastfed infant. The infant's somatic and psychomotor development up to 10 months of age was normal. Further studies of amphetamine prescribed for medical reasons during pregnancy and lactation are needed. © The Author(s) 2015.

Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.

PubMed

Thomas, David M; Dowgiert, Jennifer; Geddes, Timothy J; Francescutti-Verbeem, Dina; Liu, Xiuli; Kuhn, Donald M

2004-09-09

Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

Altered regulation of Nur77 nuclear receptor gene expression in the mesocorticolimbic regions of rat brain by amphetamine sensitization.

PubMed

Bhardwaj, Sanjeev K; Dodat, Fatéma; Lévesque, Daniel; Srivastava, Lalit K

2018-05-08

The mechanisms underlying psychostimulant drug-induced sensitization include long-term cellular and molecular adaptations in dopaminergic circuits. Nur77, a member of the Nur family of transcription factors, is expressed in brain regions receiving dopamine inputs and plays a role in activity-induced synaptic modification. Here we evaluated changes in Nur77 mRNA levels in the medial prefrontal cortex (mPFC), dorsal striatum (Str) and nucleus accumbens (NAc) of rats receiving a repeated, sensitizing regimen of amphetamine (AMPH). Results were compared to two groups of controls - animals receiving repeated injections of saline (Rp-SAL) or with no treatment (CON). Two weeks after the last injection, the effect of an acute challenge dose of AMPH on Nur77 expression was evaluated using in-situ hybridization. Repeated AMPH treatment (Rp-AMPH) increased the levels of Nur77 mRNA in the mPFC, NAc core and shell regions. However, the effects of an acute injection of AMPH in each of the three groups of animals was distinct. Whereas an acute AMPH led to a significant increase of Nur77 in all brain regions of the CON animals, it had no significant effect in Rp-SAL animals. Interestingly, in acute AMPH-injected Rp-AMPH animals, Nur77 mRNA levels in the mPFC, Str and NAc regions were significantly lower compared to CON and Rp-SAL animals treated with acute AMPH. There was a positive correlation between AMPH -induced locomotor activity and Nur77 mRNA expression in CON animals; however, this relationship was absent in Rp-SAL and Rp-AMPH animals. The data suggest that Nur77 is a part of neuroadaptive changes caused by either mild stress of repeated injections as well as AMPH-sensitization and may play a role in abnormal behaviors induced by the drug. Copyright © 2018. Published by Elsevier B.V.

Enhanced stereotyped response to amphetamine after pretreatment with small doses of molindone.

PubMed

Conway, P; Uretsky, N J

1983-05-01

Pretreatment of rats with small doses of the antipsychotic drug, molindone, enhanced the stereotyped behavioral response to amphetamine. In order to determine whether molindone enhanced amphetamine-induced stereotypy by the same mechanism as chronic administration of amphetamine or drugs that inhibit central noradrenergic transmission, the effect of these drugs on the stereotyped behavior produced by beta-phenethylamine (PEA) was compared. Following the administration of phenoxybenzamine, reserpine and diethyldithiocarbamate, the stereotyped response produced by beta-phenethylamine was intensified. In contrast, neither molindone nor chronic pretreatment with amphetamine altered beta-phenethylamine-induced stereotypy. As shown previously with chronic amphetamine pretreatment, molindone also failed to enhance the stereotyped response produced by apomorphine. However, in contrast to the effects of chronic administration of amphetamine, molindone both increased the striatal concentration of dihydroxyphenylacetic acid (DOPAC) and blocked the ability of small doses of apomorphine to decrease this dopamine (DA) metabolite. The doses of molindone that blocked the apomorphine-induced reduction in the concentration of DOPAC in the striatum correlated with the doses that enhanced amphetamine-induced stereotypy. Since the decrease in DOPAC in the striatum produced by apomorphine is thought to be mediated through the stimulation of striatal DA autoreceptors, these results suggest that molindone enhances amphetamine-induced stereotypy by selectively inhibiting DA autoreceptors.

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

PubMed

Gustavsen, Ingebjørg; Mørland, Jørg; Bramness, Jørgen G

2006-05-01

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

Functional neuroimaging of amphetamine-induced striatal neurotoxicity in the pleiotrophin knockout mouse model.

PubMed

Soto-Montenegro, María Luisa; Vicente-Rodríguez, Marta; Pérez-García, Carmen; Gramage, Esther; Desco, Manuel; Herradón, Gonzalo

2015-03-30

Amphetamine-induced neurotoxic effects have traditionally been studied using immunohistochemistry and other post-mortem techniques, which have proven invaluable for the definition of amphetamine-induced dopaminergic damage in the nigrostriatal pathway. However, these approaches are limited in that they require large numbers of animals and do not provide the temporal data that can be collected in longitudinal studies using functional neuroimaging techniques. Unfortunately, functional imaging studies in rodent models of drug-induced neurotoxicity are lacking. The aim of this study was to evaluate in vivo the changes in brain glucose metabolism caused by amphetamine in the pleiotrophin knockout mouse (PTN-/-), a genetic model with increased vulnerability to amphetamine-induced neurotoxic effects. We showed that administration of amphetamine causes a significantly greater loss of striatal tyrosine hydroxylase content in PTN-/- mice than in wild-type (WT) mice. In addition, [(18)F]-FDG-PET shows that amphetamine produces a significant decrease in glucose metabolism in the striatum and prefrontal cortex in the PTN-/- mice, compared to WT mice. These findings suggest that [(18)F]-FDG uptake measured by PET is useful for detecting amphetamine-induced changes in glucose metabolism in vivo in specific brain areas, including the striatum, a key feature of amphetamine-induced neurotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Amphetamine as a social drug: Effects of d-amphetamine on social processing and behavior

PubMed Central

Wardle, Margaret C.; Garner, Matthew J.; Munafò, Marcus R.; de Wit, Harriet

2012-01-01

Rationale Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others. Objectives We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness. Methods Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking. Results Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine. Conclusions The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine. PMID:22526538

Predictors of young adults' amphetamine use and disorders: a prospective study.

PubMed

Hayatbakhsh, Mohammad R; Najman, Jake M; Bor, William; Williams, Gail M

2009-05-01

Understanding the risk factors that predict amphetamine use and development of amphetamine abuse or dependence (disorder) may help guide preventive interventions. This study aimed to investigate the correlates and predictors of young adults' amphetamine use and use disorders. Prospective cohort, population-based study which started in Brisbane, South East Queensland (Australia) in 1981. The study participants were a cohort of 2042 young adults, followed up from birth to young adulthood. At the 21-year follow-up, amphetamine use was assessed via a self-report questionnaire, and amphetamine use disorder (AUD) was assessed using the Composite International Diagnostic Interview (CIDI-Auto). Potential predictors (15 risk factors) were assessed between baseline (antenatal visit) and the 21-year follow-up. These included participant's gender, mother's age and education, maternal marital status and quality of marital relationship, maternal tobacco and alcohol consumption, mother-child communication, child mental health and problem behaviours, child smoking and alcohol consumption and child school performance. Young adult amphetamine users were more likely to have concurrent symptoms of mental illness and problem behaviours and to use or abuse cigarettes, cannabis, or other illicit drugs. In multivariate analyses, young adults' amphetamine use and disorder were disproportionately more common among males and those who have prospectively reported aggression/delinquency or smoking at 14 years, or who have experienced childhood sexual abuse. Our findings suggest that problem behaviours, smoking and childhood sexual abuse are predictors of initiation to use of amphetamines and development of amphetamine abuse and dependence.

Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice123

PubMed Central

Storey, Granville P.; Heimbigner, Lauren; Walwyn, Wendy M.; Bamford, Nigel S.

2016-01-01

Abstract Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca2+ influx and desensitizes α4β2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge. PMID:26866057

Extended Detection of Amphetamine and Methamphetamine in Oral Fluid.

PubMed

Andås, Hilde T; Enger, Asle; Øiestad, Åse Marit L; Vindenes, Vigdis; Christophersen, Asbjørg S; Huestis, Marilyn A; Øiestad, Elisabeth L

2016-02-01

Amphetamine and methamphetamine are popular drugs of abuse worldwide and are important components of drug monitoring programs. Windows of detection for amphetamine and methamphetamine in oral fluid after high doses have not been investigated. Repeated high-dose ingestions are likely to cause positive samples for extended periods. Common routes of administration of amphetamine/methamphetamine in Norway are oral intake or injection. The aim of this study was to investigate windows of detection for amphetamine and methamphetamine in oral fluid from drug addicts under sustained abstinence during detoxification. Twenty-five patients admitted to a closed detoxification unit were included in this study. Oral fluid samples were collected daily in the morning and evening, and urine every morning for 10 days. A blood sample was drawn during the first 5 days after admission if the patient consented. Oral fluid results were compared with urine results to determine whether a new ingestion occurred. Oral fluid was collected with the Intercept oral fluid collection device. In-house cutoff concentrations for amphetamine and methamphetamine were 6.8 and 7.5 mcg/L, respectively, in oral fluid, and 135 and 149 mcg/L, respectively, in urine. Amphetamines were detected in 11 oral fluid, 5 urine, and 2 blood specimens from 25 patients. Patients self-reported amphetamines intake of up to 0.5-2 g daily. Windows of detection for amphetamine and methamphetamine in oral fluid were up to 8 days, longer than in urine at the applied cutoff values. These data confirm that oral fluid is a viable alternative to urine for monitoring amphetamine abuse, and that these substances might be detected in oral fluid for at least 1 week after ingestion of high doses. Such long detection times were, as far as we are aware, never reported previously for oral fluid amphetamines.

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

PubMed

Kraemer, Thomas; Roditis, Susanne K; Peters, Frank T; Maurer, Hans H

2003-03-01

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

Amphetamine enhances endurance by increasing heat dissipation.

PubMed

Morozova, Ekaterina; Yoo, Yeonjoo; Behrouzvaziri, Abolhassan; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav

2016-09-01

Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine-trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline). Experimental results showed that rats treated with amphetamine (2 mg/kg) were able to run significantly longer than control rats. Due to a progressively increasing workload, which was matched by oxygen consumption, the control group exhibited a steady increase in the body temperature. The administration of amphetamine slowed down the temperature rise (thus decreasing core body temperature) in the beginning of the run without affecting oxygen consumption. In contrast, a lower dose of amphetamine (1 mg/kg) had no effect on measured parameters. Using a mathematical model describing temperature dynamics in two compartments (the core and the muscles), we were able to infer what physiological parameters were affected by amphetamine. Modeling revealed that amphetamine administration increases heat dissipation in the core. Furthermore, the model predicted that the muscle temperature at the end of the run in the amphetamine-treated group was significantly higher than in the control group. Therefore, we conclude that amphetamine may mask or delay fatigue by slowing down exercise-induced core body temperature growth by increasing heat dissipation. However, this affects the integrity of thermoregulatory system and may result in potentially dangerous overheating of the muscles. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Amphetamine Self-Administration and Dopamine Function: Assessment of Gene x Environment Interactions in Lewis and Fischer 344 Rats

PubMed Central

Meyer, Andrew C.; Bardo, Michael T.

2015-01-01

Rationale Previous research suggests both genetic and environmental influences on substance abuse vulnerability. Objectives The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration, as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. Methods Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). Results “Addiction-prone” LEW had greater acquisition of amphetamine self-administration on a FR1 schedule compared to “addiction-resistant” F344 when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW. While no group differences were obtained in extracellular DA, gene x environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW showed an attenuation in the amphetamine-induced decrease in DOPAC compared to F344. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW. Conclusions The current results demonstrate gene x environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in NAc shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene x environment effects in amphetamine self-administration. PMID:25566972

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys.

PubMed

Banks, Matthew L; Snyder, Rodney W; Fennell, Timothy R; Negus, S Stevens

2017-05-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats.

PubMed

Meyer, Andrew C; Bardo, Michael T

2015-07-01

Previous research suggests both genetic and environmental influences on substance abuse vulnerability. The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). "Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats. The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that mechanisms independent of DA metabolism in NAc shell likely mediate the gene × environment effects in amphetamine self-administration.

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations.

PubMed

Marchese, Natalia Andrea; Artur de laVillarmois, Emilce; Basmadjian, Osvaldo Martin; Perez, Mariela Fernanda; Baiardi, Gustavo; Bregonzio, Claudia

2016-03-01

Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.

Treatment for amphetamine withdrawal.

PubMed

Srisurapanont, M; Jarusuraisin, N; Kittirattanapaiboon, P

2001-01-01

Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. The evidence about the treatment for amphetamine withdrawal is very limited. Amineptine has limited benefits on some amphetamine withdrawal symptoms. Due to a number of reports of amineptine abuse, it has been withdrawn from the market for a few years. At present, no available treatment has been demonstrated to be effective in the treatment of amphetamine withdrawal. The medications that should be considered for further treatment studies may be those with the propensities to increase dopamine, norepinephrine and/or serotonin activities of the brain. Naturalistic studies of amphetamine withdrawal symptoms and course are also crucial for the development of study designs appropriate for further treatment studies of amphetamine withdrawal.

78 FR 38102 - Passenger Vessels Accessibility Guidelines

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-25

... translation (CART) web streaming link will be posted on the Access Board's Passenger Vessels homepage at http... guidelines use mandatory language (i.e., shall) so DOT and DOJ can adopt the guidelines as accessibility... passenger vessels subject to U.S. Coast Guard regulations in 46 CFR Chapter I, Subchapters H and K.\\6...

Dampened Amphetamine-Stimulated Behavior and Altered Dopamine Transporter Function in the Absence of Brain GDNF.

PubMed

Kopra, Jaakko J; Panhelainen, Anne; Af Bjerkén, Sara; Porokuokka, Lauriina L; Varendi, Kärt; Olfat, Soophie; Montonen, Heidi; Piepponen, T Petteri; Saarma, Mart; Andressoo, Jaan-Olle

2017-02-08

Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditional Gdnf deletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum. SIGNIFICANCE STATEMENT Delivery of ectopic glial cell line-derived neurotrophic factor (GDNF) promotes the function, plasticity, and survival of midbrain dopaminergic neurons, the dysfunction of which contributes to various neurological and psychiatric diseases. However, how the deletion or reduction of GDNF in the CNS affects the function of dopaminergic neurons has remained unknown. Using conditional Gdnf knock-out mice, we found that endogenous GDNF affects striatal dopamine homeostasis and regulates amphetamine-induced behaviors by regulating the level and function of dopamine transporters. These data regarding the physiological role of GDNF are relevant in the context of neurological and neurodegenerative diseases that involve changes in dopamine transporter function. Copyright © 2017 the authors 0270-6474/17/371581-10$15.00/0.

Feedback from Arctic charr: Feed flavour stimulation and re-feeding after feed deprivation stimulate genes encoding both orexigenic and anorexigenic neuropeptides.

PubMed

Striberny, Anja; Jørgensen, Even H

2017-05-15

Despite vast research attention, the knowledge about central mechanisms of appetite regulation in teleost remains inconclusive. A common strategy in studies on appetite regulating mechanisms is to measure the response to feed restriction or - deprivation, but responses vary between fish species and between experiments, and are also likely dependent on the degree of energy perturbation. The anadromous Arctic charr is an interesting model for studying appetite regulation as its feeding cycle comprises months of winter anorexia, and hyperphagia during summer. Here we studied how the gene expression of putative hypothalamic appetite regulators were affected by two days, one week and one month feed deprivation during summer, and subsequent re-feeding and exposure to feed flavour. Short-term feed deprivation caused only a minor reduction in condition factor and had no effect on hypothalamic gene expression. Long-term feed-deprivation caused a marked reduction in weight and condition factor which contrasted the increase in weight and condition factor seen in ad libitum fed controls. A marked energy perturbation by feed deprivation was also indicated by a lower hypothalamic expression of the genes encoding insulin-like growth factor 1 (IGF1) and IGF1 binding protein 5 in the feed deprived charr compared to fed controls. Surprisingly, long-term feed deprivation and energy perturbation did not induce changes in hypothalamic appetite regulators. Unexpectedly, re-feeding and exposure to feed flavour caused an increase in the expression of the genes encoding the orexigenic agouti-related peptide and the anorexigenic melanocortin receptor 4 and cocaine- and amphetamine-regulated transcript. Our study gives strong evidence for a role of these in appetite regulation in Arctic charr, but their mechanisms of action remain unknown. We suggest that changes in gene expression are more likely to be registered during transition phases, e.g. from fasting to feeding and upon stimulatory inputs such as feed flavour. Copyright © 2017 Elsevier Inc. All rights reserved.

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2012 CFR

2012-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2010 CFR

2010-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2011 CFR

2011-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2013 CFR

2013-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

49 CFR 40.137 - On what basis does the MRO verify test results involving marijuana, cocaine, amphetamines, or PCP?

Code of Federal Regulations, 2014 CFR

2014-10-01

... involving marijuana, cocaine, amphetamines, or PCP? 40.137 Section 40.137 Transportation Office of the... results involving marijuana, cocaine, amphetamines, or PCP? (a) As the MRO, you must verify a confirmed positive test result for marijuana, cocaine, amphetamines, and/or PCP unless the employee presents a...

[Driving under the influence of amphetamine and metamphetamine].

PubMed

Lia, Kjersti; Spigset, Olav; Slørdal, Lars

2009-01-15

The CNS stimulatory agents amphetamine and methamphetamine are often detected in blood samples from apprehended subjects driving under the influence of drugs. Relevant literature was identified through searches in PubMed and Google Scholar. The current state of knowledge regarding effects of amphetamines on traffic behaviour is reviewed and discussed. Limited epidemiological data and a small number of experimental studies using low doses of amphetamines are available. Low amphetamine doses have been associated with enhanced performance in studies of sleep-deprived subjects. Theoretical considerations and empirical observations suggest that higher doses may impede performance, but not in accordance with usual concentration/effect relationships. There is a conspicuous lack of data on how to handle cases of driving under the influence of amphetamines.

Evaluation of Nigerian hospital meal carts

NASA Astrophysics Data System (ADS)

Ayodeji, Sesan P.; Adeyeri, Michael K.; Omoniyi, Olaoluwa

2015-09-01

Hospital meal carts are used to deliver meals, drugs and some other materials to patients in the hospital environment. These carts which are moved manually by operators, the health workers, mostly do not comply with ergonomics guidelines and physical requirements of the equipment users in terms of anthropometry data of the region thus increasing the risk of musculoskeletal disorder among the meal cart users. This study carried out ergonomic evaluation of the available meal carts in some western Nigeria hospitals. A well-structured questionnaire has two major segments: Operational survey and biomechanical survey, which were administered to the health workers using hospital meal carts in some hospitals in southwestern Nigeria, and physical assessment, which was undertaken to collect data for the ergonomic evaluation. The responses from the questionnaires show that some areas on the existing hospital meal carts are of concern to the users which need to be improved upon.

Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nonogaki, Katsunori; Nozue, Kana; Oka, Yoshitomo

2006-12-29

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration ofmore » sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.« less

Tributyltin disrupts feeding and energy metabolism in the goldfish (Carassius auratus).

PubMed

Zhang, Jiliang; Sun, Ping; Yang, Fan; Kong, Tao; Zhang, Ruichen

2016-06-01

Tributyltin (TBT) can induce obesogen response. However, little is known about the adverse effects of TBT on food intake and energy metabolism. The present study was designed to investigate the effects of TBT, at environmental concentrations of 2.44 and 24.4 ng/L (1 and 10 ng/L as Sn), on feeding and energy metabolism in goldfish (Carassius auratus). After exposure for 54 d, TBT increased the weight gain and food intake in fish. The patterns of brain neuropeptide genes expression were in line with potential orexigenic effects, with increased expression of neuropeptide Y and apelin, and decreased expression of pro-opiomelanocortin, ghrelin, cocaine and amphetamine-regulated transcript, and corticotropin-releasing factor. Interestingly, the energy metabolism indicators (oxygen consumption, ammonia exertion and swimming activity) and the serum thyroid hormones were all significantly increased at the 2.44 ng/L TBT group in fish. However, no changes of energy metabolism indicators or a decrease of thyroid hormones was found at the 24.4 ng/L TBT group, which indicated a complex disrupting effect on metabolism of TBT. In short, TBT can alter feeding and energy metabolism in fish, which might promote the obesogenic responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cable-Dispensing Cart

NASA Technical Reports Server (NTRS)

Bredberg, Alan S.

2003-01-01

A versatile cable-dispensing cart can support as many as a few dozen reels of cable, wire, and/or rope. The cart can be adjusted to accommodate reels of various diameters and widths, and can be expanded, contracted, or otherwise reconfigured by use of easily installable and removable parts that can be carried onboard. Among these parts are dispensing rods and a cable guide that enables dispensing of cables without affecting the direction of pull. Individual reels can be mounted on or removed from the cart without affecting the other reels: this feature facilitates the replacement or reuse of partially depleted reels, thereby helping to reduce waste. Multiple cables, wires, or ropes can be dispensed simultaneously. For maneuverability, the cart is mounted on three wheels. Once it has been positioned, the cart is supported by rubber mounts for stability and for prevention of sliding or rolling during dispensing operations. The stability and safety of the cart are enhanced by a low-center-of-gravity design. The cart can readily be disassembled into smaller units for storage or shipping, then reassembled in the desired configuration at a job site.

Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity.

PubMed

Iwasaki, Yusaku; Maejima, Yuko; Suyama, Shigetomo; Yoshida, Masashi; Arai, Takeshi; Katsurada, Kenichi; Kumari, Parmila; Nakabayashi, Hajime; Kakei, Masafumi; Yada, Toshihiko

2015-03-01

Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity. Copyright © 2015 the American Physiological Society.

Shoulder joint loading and posture during medicine cart pushing task.

PubMed

Xu, Xu; Lin, Jia-Hua; Boyer, Jon

2013-01-01

Excessive physical loads and awkward shoulder postures during pushing and pulling are risk factors for shoulder pain. Pushing a medicine cart is a major component of a work shift for nurses and medical assistants in hospitals and other health care facilities. A laboratory experiment was conducted to examine the effects of common factors (e.g., lane congestion, cart load stability, floor surface friction) on shoulder joint moment and shoulder elevation angle of participants during cart pushing. Participants pushed a medicine cart on straight tracks and turning around right-angle corners. Peak shoulder joint moments reached 25.1 Nm, 20.3 Nm, and 26.8 Nm for initial, transition, and turning phases of the pushing tasks, indicating that shoulder joint loading while pushing a medical cart is comparable to levels previously reported from heavy manual activities encountered in industry (e.g., garbage collection). Also, except for user experience, all other main study factors, including congestion level, cart load stability, location of transition strip, shoulder tendency, surface friction, and handedness, significantly influenced shoulder joint moment and shoulder elevation angle. The findings provide a better understanding of shoulder exposures associated with medicine cart operations and may be helpful in designing and optimizing the physical environment where medicine carts are used.

Survival of HIV-1 vertically infected children

PubMed Central

Davies, Mary-Ann; Gibb, Diana; Turkova, Anna

2017-01-01

Purpose of review It is 20 years since the start of the combination antiretroviral therapy (cART) era and >10 years since cART scale-up began in resource-limited settings. We examined survival of vertically HIV-infected infants and children in the cART era. Recent findings Good survival has been achieved on cART in all settings with up to ten-fold mortality reductions compared to before cART availability. Although mortality risk remains high in the first few months after cART initiation in young children with severe disease, it drops rapidly thereafter even for those who started with advanced disease, and longer term mortality risk is low. However, suboptimal retention on cART in routine programs threatens good survival outcomes and even on treatment children continue to experience high comorbidity risk; infections remain the major cause of death. Interventions to address infection risk include co-trimoxazole prophylaxis, isoniazid preventive therapy, routine childhood and influenza immunization and improving maternal survival. Summary Pediatric survival has improved substantially with cART and HIV-infected children are aging into adulthood. It is important to ensure access to diagnosis and early cART, good program retention and optimal co-morbidity prophylaxis and treatment to achieve the best possible long-term survival and health outcomes for vertically infected children. PMID:27716730

Combination antiretroviral therapy and cancer risk.

PubMed

Borges, Álvaro H

2017-01-01

To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk of Kaposi sarcoma and NHL also during early HIV infection before overt immunosuppression occurs. Long-term effects of cART exposure on cancer risk are not well defined; according to basic and epidemiological research, there might be specific associations of each cART class with distinct patterns of cancer risk. The relationship between cART exposure and cancer risk is complex and nuanced. It is an intriguing fact that, whether initiated during severe immunosuppression or not, cART reduces risk of Kaposi sarcoma and NHL. Further research should identify mediators of the benefit of immediate cART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.

Myeloid Conditioning with c-kit-Targeted CAR-T Cells Enables Donor Stem Cell Engraftment.

PubMed

Arai, Yasuyuki; Choi, Uimook; Corsino, Cristina I; Koontz, Sherry M; Tajima, Masaki; Sweeney, Colin L; Black, Mary A; Feldman, Steven A; Dinauer, Mary C; Malech, Harry L

2018-05-02

We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c-kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (<1%-13.1%). This resulted in significant depletion of the BM c-kit + population (9.0%-0.1%). Because congenic Thy1.1 CAR-T cells were used in the Thy1.2-recipient mice, anti-Thy1.1 antibody could be used to deplete CAR-T cells in vivo before donor BM transplant. This achieved 20%-40% multilineage engraftment. We applied this conditioning to achieve an average of 28% correction of chronic granulomatous disease mice by wild-type BM transplant. Our findings provide a proof of concept that c-kit CAR-T cells can achieve effective BM conditioning without chemo-/radiotherapy. Our work also demonstrates that co-expression of a trafficking receptor can enhance targeting of CAR-T cells to a designated tissue. Published by Elsevier Inc.

Evaluation of the Placement of Mobile Fruit and Vegetable Vendors to Alleviate Food Deserts in New York City

PubMed Central

Cromley, Ellen K.; Fox, Ashley M.; Horowitz, Carol R.

2014-01-01

Introduction In 2008, the New York City (NYC) health department licensed special mobile produce vendors (Green Carts) to increase access to fruits and vegetables in neighborhoods with the lowest reported fruit and vegetable consumption and the highest obesity rates. Because economic incentives may push vendors to locate in more trafficked, less produce-deprived areas, we examined characteristics of areas with and without Green Carts to explore whether Carts are positioned to reach the intended populations. Methods Using ArcGIS software, we mapped known NYC Green Cart locations noted through 2013 and generated a list of potential (candidate) sites where Carts could have located. We compared the food environment (via categorizing “healthy” or “unhealthy” food stores using federal classification codes corroborated by online storefront images) and other factors that might explain Cart location (eg, demographic, business, neighborhood characteristics) near actual and candidate sites descriptively and inferentially. Results Seven percent of Green Carts (n = 265) were in food deserts (no healthy stores within one-quarter mile) compared with 36% of candidate sites (n = 644, P < .001). Most Carts (78%) were near 2 or more healthy stores. Green Carts had nearly 60 times the odds of locating near subway stops (P < .001), were closer to large employers (odds ratio [OR], 6.4; P < .001), other food stores (OR, 14.1; P < .001), and in more populous tracts (OR, 2.9, P <.01) compared with candidate sites. Conclusion Green Carts were rarely in food deserts and usually had multiple healthy stores nearby, suggesting that Carts may not be serving the neediest neighborhoods. Exploration of Carts’ benefits in non–food desert areas is needed, but incentivizing vendors to locate in still-deprived places may increase program impact. PMID:25211506

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age.

PubMed

Snijdewind, Ingrid J M; Smit, Colette; Godfried, Mieke H; Bakker, Rachel; Nellen, Jeannine F J B; Jaddoe, Vincent W V; van Leeuwen, Elisabeth; Reiss, Peter; Steegers, Eric A P; van der Ende, Marchina E

2018-01-01

The benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands. We included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery. A total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03-1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94-1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94-1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception. In our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age.

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age

PubMed Central

Smit, Colette; Godfried, Mieke H.; Bakker, Rachel; Nellen, Jeannine F. J. B.; Jaddoe, Vincent W. V.; van Leeuwen, Elisabeth; Reiss, Peter; Steegers, Eric A. P.; van der Ende, Marchina E.

2018-01-01

Background The benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands. Materials and methods We included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery. Results A total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03−1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94−1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94−1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception. Conclusion In our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age. PMID:29351561

Amphetamine abuse in Sweden: subject demographics, changes in blood concentrations over time, and the types of coingested substances.

PubMed

Jones, Alan Wayne; Holmgren, Anita

2013-04-01

Amphetamine is a major drug of abuse in Sweden and in the other Nordic countries. The demographics of amphetamine abusers in Sweden and the concentrations of this stimulant in blood are reported for 10 years of forensic blood samples (2001-2010). Using a forensic toxicology database (TOXBASE), we studied 1183 amphetamine-related deaths, 20,452 users of illicit drugs, and 47,366 people arrested for driving under the influence of drugs (DUID). Most amphetamine abusers were male (82%-87%), and their average age was 33 to 39 years with males being 2 to 3 years older than females (P < 0.001). Mean (median) concentrations of amphetamine in blood were 1.25 (0.40) mg/L in autopsy cases, 0.61 (0.40) mg/L in users of illicit drugs, and 0.76 (0.58) mg/L in DUID suspects. Median concentration in DUID suspects was significantly higher than in the other forensic materials (P < 0.001). Women also had higher median concentrations of amphetamine in blood than male abusers of this central stimulant (P < 0.001). The major coingested drugs were benzodiazepines (41%), cannabis (26%), opiates (21%), and alcohol (18%) in autopsy cases. Polydrug use was less common in DUID suspects and users of illicit drugs, although benzodiazepines (13%), tetrahydrocannabinol (12%), and opiates (5%) were often identified along with amphetamine. Because median concentration of amphetamine was higher in living subjects (DUID suspects) compared with amphetamine-related deaths, this points toward toxicity of coingested drugs or adverse drug-drug interaction as being responsible for death.

Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers.

PubMed

Chait, L D; Johanson, C E

1988-01-01

The discriminative stimulus (DS) and subjective effects of caffeine (100 and 300 mg, PO) and benzphetamine (12.5 and 50 mg, PO) were studied in 18 normal human volunteers trained to discriminate between d-amphetamine (10 mg) and placebo. d-Amphetamine increased ratings of drug liking and activity level and produced a profile of subjective effects characteristic of amphetamine and related psychomotor stimulants. The DS effects of d-amphetamine generalized only partially to caffeine and benzphetamine; mean percent d-amphetamine-appropriate responding was 42 and 58 after 100 and 300 mg caffeine, respectively, and 17 and 56 after 12.5 and 50 mg benzphetamine, respectively. Neither dose of caffeine affected ratings of drug liking or activity level, but 300 mg caffeine did produce a profile of subjective effects that partially overlapped with that produced by d-amphetamine. Benzphetamine 50 mg, but not 12.5 mg, increased ratings of drug liking and activity level and produced a profile of subjective effects qualitatively similar to, but weaker than, that produced by d-amphetamine. For both caffeine and benzphetamine, a close relationship was observed between their subjective effects and their ability to substitute for the DS effects of d-amphetamine. These results correspond well with findings obtained from similar studies conducted with laboratory animals, providing further support for the reliability and validity of human drug discrimination paradigms.

Carotenoid Biosynthesis in Fusarium

PubMed Central

Avalos, Javier; Pardo-Medina, Javier; Parra-Rivero, Obdulia; Ruger-Herreros, Macarena; Rodríguez-Ortiz, Roberto; Hornero-Méndez, Dámaso; Limón, María Carmen

2017-01-01

Many fungi of the genus Fusarium stand out for the complexity of their secondary metabolism. Individual species may differ in their metabolic capacities, but they usually share the ability to synthesize carotenoids, a family of hydrophobic terpenoid pigments widely distributed in nature. Early studies on carotenoid biosynthesis in Fusarium aquaeductuum have been recently extended in Fusarium fujikuroi and Fusarium oxysporum, well-known biotechnological and phytopathogenic models, respectively. The major Fusarium carotenoid is neurosporaxanthin, a carboxylic xanthophyll synthesized from geranylgeranyl pyrophosphate through the activity of four enzymes, encoded by the genes carRA, carB, carT and carD. These fungi produce also minor amounts of β-carotene, which may be cleaved by the CarX oxygenase to produce retinal, the rhodopsin’s chromophore. The genes needed to produce retinal are organized in a gene cluster with a rhodopsin gene, while other carotenoid genes are not linked. In the investigated Fusarium species, the synthesis of carotenoids is induced by light through the transcriptional induction of the structural genes. In some species, deep-pigmented mutants with up-regulated expression of these genes are affected in the regulatory gene carS. The molecular mechanisms underlying the control by light and by the CarS protein are currently under investigation. PMID:29371556

Class identity assignment for amphetamines using neural networks and GC-FTIR data

NASA Astrophysics Data System (ADS)

Gosav, S.; Praisler, M.; Van Bocxlaer, J.; De Leenheer, A. P.; Massart, D. L.

2006-08-01

An exploratory analysis was performed in order to evaluate the feasibility of building of neural network (NN) systems automating the identification of amphetamines necessary in the investigation of drugs of abuse for epidemiological, clinical and forensic purposes. A first neural network system was built to distinguish between amphetamines and nonamphetamines. A second, more refined system, aimed to the recognition of amphetamines according to their toxicological activity (stimulant amphetamines, hallucinogenic amphetamines, nonamphetamines). Both systems proved that discrimination between amphetamines and nonamphetamines, as well as between stimulants, hallucinogens and nonamphetamines is possible (83.44% and 85.71% correct classification rate, respectively). The spectroscopic interpretation of the 40 most important input variables (GC-FTIR absorption intensities) shows that the modeling power of an input variable seems to be correlated with the stability and not with the intensity of the spectral interaction. Thus, discarding variables only because they correspond to spectral windows with weak absorptions does not seem be not advisable.

Fenetylline: new results on pharmacology, metabolism and kinetics.

PubMed

Nickel, B; Niebch, G; Peter, G; von Schlichtegroll, A; Tibes, U

1986-06-01

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.

Service Cart For Engines

NASA Technical Reports Server (NTRS)

Ng, Gim Shek

1995-01-01

Cart supports rear-mounted air-cooled engine from Volkswagen or Porsche automobile. One person removes, repairs, tests, and reinstalls engine of car, van, or home-built airplane. Consists of framework of wood, steel, and aluminum components supported by four wheels. Engine lifted from vehicle by hydraulic jack and gently lowered onto waiting cart. Jack removed from under engine. Rear of vehicle raised just enough that engine can be rolled out from under it. Cart easily supports 200-lb engine. Also used to hold transmission. With removable sheet-metal top, cart used as portable seat.

Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review

PubMed Central

Berman, Steven M.; Kuczenski, Ronald; McCracken, James T.; London, Edythe D.

2009-01-01

Rationale Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority 1. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Findings Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several-fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection are also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults. PMID:18698321

Association study of GABA system genes polymorphisms with amphetamine-induced psychotic disorder in a Han Chinese population.

PubMed

Zhang, Kai; Zhao, Yan; Wang, Qingzhong; Jiang, Haifeng; Du, Jiang; Yu, Shunying; Zhao, Min

2016-05-27

GABA system genes have been implicated in neurotrophy and neurogenesis, which play pivotal roles in an individual's variation in vulnerability to amphetamine addiction or amphetamine-induced psychosis (AIP). We hypothesized that common genetic variants in the GABA system genes may be associated with amphetamine-induced psychotic disorder. In our study, thirty-six single nucleotide polymorphisms (SNPs) within the GABA system genes were genotyped in 400 amphetamine-induced psychotic disorder patients and 400 amphetamine use disorders patients (AUP) (not including those categorized as psychosis) in the Han Chinese population. In this study, 51.88% of the Han Chinese amphetamine-type substance use disorder patients met the criteria of amphetamine-induced psychotic disorder, and 79.5% amphetamine-induced psychotic disorder patients had auditory hallucinations, while 46.5% had delusions of reference. The allele frequency of rs1129647 showed nominal association with AIP in the Han Chinese population (P=0.03). Compared with AUP group patients, T allele frequency of AIP group patients was significantly increased. The adjustment for age and gender factors in the AIP and AUP patients was executed using unconditional logistic regression under five inheritance models. The genotype frequency of rs1129647 showed nominal association with AIP in the log-additive model (P=0.04). The genotype frequency of rs2290733 showed nominal association with AIP in the recessive model (P=0.04). Compared with female AIP patients, male patients were more likely to have the CC genotype of rs17545383 (P=0.04). Moreover, we determined that more male patients carried the T allele of rs2290733 in the AIP group (P=0.004). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P>0.05). No association between the SNPs of the GABA system genes and amphetamine-induced psychotic disorder risk was identified. No haplotype of the GABA system genes affected amphetamine-induced psychotic disorder risk. This report describes the first association study between the GABA system genes and amphetamine-induced psychotic disorder in the Han Chinese population. Our data may provide a reference for future research. Copyright © 2016. Published by Elsevier Ireland Ltd.

Upregulation of gene expression in reward-modulatory striatal opioid systems by sleep loss.

PubMed

Baldo, Brian A; Hanlon, Erin C; Obermeyer, William; Bremer, Quentin; Paletz, Elliott; Benca, Ruth M

2013-12-01

Epidemiological studies have shown a link between sleep loss and the obesity 'epidemic,' and several observations indicate that sleep curtailment engenders positive energy balance via increased palatable-food 'snacking.' These effects suggest alterations in reward-modulatory brain systems. We explored the effects of 10 days of sleep deprivation in rats on the expression of striatal opioid peptide (OP) genes that subserve food motivation and hedonic reward, and compared effects with those seen in hypothalamic energy balance-regulatory systems. Sleep-deprived (Sleep-Dep) rats were compared with yoked forced-locomotion apparatus controls (App-Controls), food-restricted rats (Food-Restrict), and unmanipulated controls (Home-Cage). Detection of mRNA levels with in situ hybridization revealed a subregion-specific upregulation of striatal preproenkephalin and prodynorhin gene expression in the Sleep-Dep group relative to all other groups. Neuropeptide Y (NPY) gene expression in the hippocampal dentate gyrus and throughout neocortex was also robustly upregulated selectively in the Sleep-Dep group. In contrast, parallel gene expression changes were observed in the Sleep-Dep and Food-Restrict groups in hypothalamic energy-sensing systems (arcuate nucleus NPY was upregulated, and cocaine- and amphetamine-regulated transcript was downregulated), in alignment with leptin suppression in both groups. Together, these results reveal a novel set of sleep deprivation-induced transcriptional changes in reward-modulatory peptide systems, which are dissociable from the energy-balance perturbations of sleep loss or the potentially stressful effects of the forced-locomotion procedure. The recruitment of telencephalic food-reward systems may provide a feeding drive highly resistant to feedback control, which could engender obesity through the enhancement of palatable feeding.

Association between travel length and drug use among Brazilian truck drivers.

PubMed

Sinagawa, Daniele Mayumi; De Carvalho, Heráclito Barbosa; Andreuccetti, Gabriel; Do Prado, Natanael Vitoriano; De Oliveira, Keziah Cristina Barbosa Gruber; Yonamine, Mauricio; Muñoz, Daniel Romero; Gjerde, Hallvard; Leyton, Vilma

2015-01-01

To investigate whether the use of the stimulants amphetamines and cocaine by truck drivers in Brazil was related to travel length. Truck drivers were randomly stopped by the Federal Highway Police on interstate roads in Sao Paulo State during morning hours from 2008 to 2011 and invited to participate in the project "Comandos de Saúde nas Rodovias" (Health Commands on the Roads). Participants were asked about the use of drugs, travel distance, and age, and gender was recorded. Samples of urine were collected and analyzed for amphetamine, benzoylecgonine (a metabolite of cocaine), and carboxytetrahydrocannabinol (THC-COOH; a metabolite of cannabis) by immunological screening and quantification by gas chromatography-mass spectroscopy. Current use of amphetamine, cocaine, and cannabis was reported by 5.7%, 0.7%, and 0.3% of the truck drivers, respectively. Amphetamine, benzoylecgonine, and THC-COOH were found in urine samples from 5.4%, 2.6,% and in 1.0% of the drivers, respectively. There was a significant association between the positive cases for amphetamine and reported travel length; 9.9% of urine samples from drivers who reported travel length of more than 270 km were positive for amphetamine, and 10.9% of those drivers reported current use of amphetamines. In most cases, appetite suppressants containing amphetamines had been used, but the purpose was most often to stay awake and alert while driving. Truck drivers with travel length of more than 270 km had significantly higher odds ratio (OR) for having a urine sample that was positive for amphetamine when adjusted for age as confounding factor (OR = 9.41, 95% confidence interval [CI], 3.97-22.26). No significant association was found between the use of cocaine or cannabis and travel length. Truck drivers who reported driving more than 270 km had significantly higher frequencies of urine samples positive for amphetamine and reported significantly more frequent current use of amphetamines than those who reported shorter driving distances.

Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys

PubMed Central

Banks, Matthew L.; Snyder, Rodney W.; Fennell, Timothy R.; Negus, S. Stevens

2017-01-01

Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an “agonist” medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10–18 mg/kg, intramuscular (IM)) and d-amphetamine (0.032–0.32 mg/kg, IM) in monkeys (n=3–4) trained to discriminate IM cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥ 90% cocaine-appropriate responding,in all monkeys without altering response rates. The time course of d-amphetamine’s cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100 min) and d-amphetamine (peak at 24 h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. PMID:28373066

The Impact of Verbal Prompts on Child Safety-Belt Use in Shopping Carts

ERIC Educational Resources Information Center

Barker, Mae R.; Bailey, Jon S.; Lee, Natalie

2004-01-01

Each year thousands of children are injured by falling from shopping carts. Buckling children into the seats of shopping carts could prevent many of these injuries. A combined reversal and multiple baseline across settings design was used to evaluate the impact of verbal prompts on shopping cart safety-belt use in two stores. Safety-belt use…

Art on a Cart: A National Mixed Methods Investigation of Elementary Art Teacher Experiences and Perceptions

ERIC Educational Resources Information Center

Lung, Heidi K.

2013-01-01

This study investigated the practice of elementary art teachers who utilize carts for the delivery of art lessons; to understand how the art on a cart practice influences art educators' approaches to curriculum development and instruction; and to identify challenges, benefits, and best practices. The practice of art on a cart is defined as the…

Association between prescription cost sharing and adherence to initial combination antiretroviral therapy in commercially insured antiretroviral-naïve patients with HIV.

PubMed

Johnston, Stephen S; Juday, Timothy; Seekins, Daniel; Espindle, Derek; Chu, Bong-Chul

2012-03-01

In treatment of human immunodeficiency virus (HIV), high levels of adherence to combination antiretroviral therapy (cART) are required to prevent failure of virologic suppression, development of drug resistance, and permanent loss of therapeutic options. No published research has assessed the association between cART prescription cost sharing and adherence to cART. To analyze the association between cART prescription cost sharing and adherence to initial cART in commercially insured antiretroviral (ARV)-naïve patients with HIV. This retrospective observational cohort study used 2002-2008 data from a large U.S. claims database of more than 56 million commercially insured individuals. Study subjects were patients aged 18 years or older who initiated cART during the period January 1, 2003, to December 31, 2007, had no ARV claims during the 6-month period prior to the initiation date, and had at least 1 ICD-9-CM diagnosis code for HIV infection (042, 795.71, V08) from 12 months before to 12 months after cART initiation. A minimum 12-month period of continuous enrollment after cART initiation was used to construct a patient-quarter repeated measures panel dataset in which each quarter of data that a patient contributed represented an observation. The evaluation period extended from cART initiation until the occurrence of 1 of the following events: addition of an ARV that was not part of the initial cART regimen, 30-day gap in possession of an ARV within the initiated cART regimen, hospitalization of 30 or more days, loss to follow-up due to study end (December 31, 2008), or disenrollment. The study's outcome was quarterly adherence to cART, defined as the number of days within the quarter that a patient possessed all components of the initial cART regimen. Each patient's cART cost-sharing amount was calculated per 30-day supply of the entire cART regimen. Adherence was dichotomized for analysis at the clinically meaningful thresholds of 95% and 78%. The dichotomized adherence outcomes were separately modeled using population-averaged generalized estimating equations (GEEs) with time-varying and time-constant covariates and an exchangeable working correlation structure. Independent variables included cost-sharing amount; sequential quarter number after cART initiation; interaction between cost-sharing amount and sequential quarter number (to capture any changes in the association of cost sharing with adherence that may occur over time after initiation of cART); and patient demographic, clinical, and insurance characteristics. For each sequential quarter after cART initiation, the GEE models were used to generate average predicted probabilities of adherence reaching each threshold (95% and 78%) at cost-sharing levels of $25, $75, and $144, which represented the 25th, 75th, and 90th percentiles of the cost-sharing distribution, respectively. The study sample included 19,199 patient-quarters and 3,731 patients: mean age 41.1 years; 83.2% male; mean (SD) duration of post-index period 5.1 (4.2) quarters; mean (SD) daily cART pill count 3.2 (2.2); mean (median) cost sharing per 30-day supply of the entire cART regimen $67 ($40). In the unadjusted analyses of patient-quarters, mean adherence ranged from 97.2% for cost-sharing levels within the 0-20th percentiles (from $0 to $20 per 30-day cART supply) to 94.0% for cost-sharing levels exceeding the 80th percentile (from $84 to $3,832 per 30-day cART supply). In the adjusted analyses for the second quarter (25th percentile of follow-up duration, n = 3,117 cases still under observation) at the cost-sharing levels of $25, $75, and $144, the predicted probabilities of at least 95% adherence were 0.782, 0.770, and 0.752, respectively, and the predicted probabilities of at least 78% adherence were 0.936, 0.931, and 0.924, respectively. The differences in the predicted probabilities of adherence grew over time. By the seventh quarter (the 75th percentile of follow-up duration, n = 1,096 cases still under observation), the predicted probabilities were 0.773, 0.746, and 0.707 for 95% adherence and 0.933, 0.922, and 0.904 for 78% adherence at cost-sharing levels of $25, $75, and $144, respectively. Increasing cART prescription cost sharing was associated with modestly decreased probability of maintaining clinically meaningful levels of cART adherence.

49 CFR 173.197 - Regulated medical waste.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., one-piece body with a nominal volume not exceeding 1,655 L (437 gallons). (ii) Each Cart must be...., rain or snow). (iii) Each opening in a BOP must be fitted with a closure to prevent the intrusion of... to absorb and retain all liquid during transportation. (i) The film bag may not exceed a volume of...

Who are the new amphetamine users? A 10-year prospective study of young Australians.

PubMed

Degenhardt, Louisa; Coffey, Carolyn; Carlin, John B; Moran, Paul; Patton, George C

2007-08-01

Despite good evidence of increased availability and use of amphetamines world-wide, relatively little is known about the epidemiology of young adult amphetamine use; relationships with social functioning, other drug use and mental health at this age; nor of the adolescent predictors of such use. We examined these issues using a representative cohort of young people followed-up in Victoria, Australia. A stratified, random sample of 1943 adolescents was recruited from secondary schools across Victoria at age 14-15 years. This cohort was interviewed on eight occasions until the age of 24-25 years (78% follow-up at that age). Cross-sectional and predictive associations were assessed using logistic regression. At age 24 years, 12% of the sample had used amphetamines in the past year, with 1-2% using at least weekly. Young adult amphetamine use was predicted strongly by adolescent drug use and was associated robustly with other drug use and dependence in young adulthood. Associations were stronger for more frequent users. Among young adults who had not been using amphetamines at age 20 years, the strongest predictor of use at age 24 years was the use of other drugs, particularly cannabis, at 20 years. Psychological distress did not predict independently an increased likelihood of amphetamine use in this cohort. Young people in Australia using amphetamine at age 24 years are highly likely to be significant polydrug users. The risks for both initiation of young adult amphetamine use, and maintenance of such use, pertain to the heavy use of other drugs. Interventions for heavy amphetamine users at this age are likely to require attention to multiple drug problems.

Enhancement of a visual reinforcer by D-amphetamine and nicotine in adult rats: relation to habituation and food restriction.

PubMed

Wright, Jennifer M; Ren, Suelynn; Constantin, Annie; Clarke, Paul B S

2018-03-01

Nicotine and D-amphetamine can strengthen reinforcing effects of unconditioned visual stimuli. We investigated whether these reinforcement-enhancing effects reflect a slowing of stimulus habituation and depend on food restriction. Adult male rats pressed an active lever to illuminate a cue light during daily 60-min sessions. Depending on the experiment, rats were challenged with fixed or varying doses of D-amphetamine (0.25-2 mg/kg IP) and nicotine (0.025-0.2 mg/kg SC) or with the tobacco constituent norharman (0.03-10 μg/kg IV). Experiment 1 tested for possible reinforcement-enhancing effects of D-amphetamine and norharman. Experiment 2 investigated whether nicotine and amphetamine inhibited the spontaneous within-session decline in lever pressing. Experiment 3 assessed the effects of food restriction. Amphetamine (0.25-1 mg/kg) and nicotine (0.1 mg/kg) increased active lever pressing specifically (two- to threefold increase). The highest doses of nicotine and amphetamine also affected inactive lever responding (increase and decrease, respectively). With the visual reinforcer omitted, responding was largely extinguished. Neither drug appeared to slow habituation, as assessed by the within-session decline in lever pressing, and reinforcement-enhancing effects still occurred if the drugs were given after this decline had occurred. Food restriction enhanced the reinforcement-enhancing effect of amphetamine but not that of nicotine. Responding remained goal-directed after several weeks of testing. Low doses of D-amphetamine and nicotine produced reinforcement enhancement even in free-feeding subjects, independent of the spontaneous within-session decline in responding. Reinforcement enhancement by amphetamine, but not nicotine, was enhanced by concurrent subchronic food restriction.

Circulating adrenal hormones are not necessary for the development of sensitization to the psychomotor activating effects of amphetamine.

PubMed

Badiani, A; Morano, M I; Akil, H; Robinson, T E

1995-02-27

We reported previously that when amphetamine is given in NOVEL test cages both its acute psychomotor activating effects (rotational behaviour and locomotor activity) and the degree of sensitization are greater than when amphetamine is given in HOME cages that are physically identical to the NOVEL test cages. Since exposure to the NOVEL environment increases plasma corticosterone levels (Experiment 1) it is possible that the enhancement in the effects of amphetamine in the NOVEL condition is mediated by corticosterone. If this hypothesis is correct adrenalectomy (ADX) should abolish the difference between the HOME and NOVEL groups. This was tested in three independent experiments, in which the response (rotational behavior in Experiments 2 and 3; locomotor activity and rearing behavior in Experiment 4) to repeated injections of amphetamine was assessed in rats that underwent adrenalectomy (ADX) or a sham operation (SHAM). ADX animals received either no corticosterone replacement or one of two corticosterone replacement treatments. Adrenalectomy, with or without corticosterone replacement treatment, had no significant effect on the development of amphetamine sensitization, either in the HOME or the NOVEL environment. By contrast, the effects of adrenalectomy on the acute response to amphetamine varied depending on the behavioral measure and possibly on the dose of amphetamine (2.0 mg/kg, 3.0 mg/kg and 1.5 mg/kg IP, in Experiments 2, 3 and 4, respectively). We conclude that: (i) a stress-induced secretion of adrenal hormones is not responsible for the enhancement in sensitization to amphetamine seen in animals tested in a NOVEL environment; (ii) circulating adrenal hormones are not necessary for development of sensitization to the psychomotor activating effects of amphetamine.

Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

PubMed

Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

2017-12-01

Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys.

PubMed

Smith, Douglas A; Blough, Bruce E; Banks, Matthew L

2017-01-01

Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models. The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016). The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.

PubMed

Plessinger, M A

1998-03-01

Based on findings in humans and the confirmation of prenatal exposures in animals, amphetamines and methamphetamines increase the risk of an adverse outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal growth reduction deficits that have been seen in infants exposed to amphetamines during pregnancy have all been reproduced in animal studies involving prenatal exposures to amphetamines. The differential effects of amphetamines between genetic strains of mice and between species demonstrate that pharmacokinetics and the genetic disposition of the mother and developing embryo can have an enormous influence on enhancing or reducing these potential risks. The effects of prenatal exposure to amphetamines in producing altered behavior in humans appear less compelling when one considers other confounding variables of human environment, genetics, and polydrug abuse. In view of the animal data concerning altered behavior and learning tasks in comparison with learning deficits observed in humans, the influence of the confounding variables in humans may serve to increase the sensitivity of the developing embryo/fetus to prenatal exposure to amphetamines. These factors and others may predispose the developing conceptus to the damaging effects of amphetamines by actually lowering the threshold of susceptibility at the sites where damage occurs. Knowledge of the effects of prenatal exposure of the fetus and the mother to designer amphetamines is lacking. Based on the few studies in which designer drugs have been examined in animal models, more questions are raised than answered. Possible reasons why no malformations or significant fetal effects were found in the study by St. Omer include the genetic strain of rat used, the conservative exposure profile, or the fact that the placenta metabolized MDMA before reaching the embryo. These questions underscore the need for further investigations concerning the prenatal exposure effects of designer compounds and the effects of amphetamine and methamphetamine in general.

Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats.

PubMed

Ruksee, Nootchanart; Tongjaroenbuangam, Walaiporn; Casalotti, Stefano O; Govitrapong, Piyarat

2008-10-06

Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants. This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations. This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and pseudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants.

Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats

PubMed Central

Ruksee, Nootchanart; Tongjaroenbuangam, Walaiporn; Casalotti, Stefano O; Govitrapong, Piyarat

2008-01-01

Background Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants. Results This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations. Conclusion This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and psudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants. PMID:18834549

The association between spending on methamphetamine/amphetamine and cannabis for personal use and earnings from acquisitive crime among police detainees in New Zealand.

PubMed

Wilkins, Chris; Sweetsur, Paul

2011-04-01

Few studies have examined the statistical association between methamphetamine/amphetamine use and acquisitive crime. Both methamphetamine/amphetamine and cannabis use have been implicated by New Zealand Police as factors in acquisitive offending among active criminal populations. The aim of our study was to examine the statistical association between spending on methamphetamine/amphetamine and cannabis and earnings from acquisitive crime among police detainees in New Zealand. Four police stations in different regions. A sample of 2125 police detainees were interviewed about their drug use and acquisitive crime. Statistical models were developed to predict involvement in acquisitive crime using spending on methamphetamine/amphetamine and cannabis for personal use, and to examine associations between the level of spending on methamphetamine/amphetamine and cannabis for personal use and level of dollar earnings from acquisitive crime. Self-reported spending on drug use and self-reported earnings from acquisitive crime in the past 30 days. Spending on cannabis and methamphetamine/amphetamine could predict involvement in acquisitive crime. Level of spending on methamphetamine/amphetamine and cannabis was associated positively with the level of earnings from property crime. Level of spending on methamphetamine/amphetamine was also associated positively with level of earnings from drug dealing. There was a largely negative association between level of spending on cannabis and level of earnings from drug dealing. High spending on methamphetamine/amphetamine is associated statistically with higher earnings from acquisitive crime among police detainees. Further research into this association, and in particular the causal nature of the association, is required to obtain clear policy recommendations. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

PubMed Central

Smith, Douglas A.; Blough, Bruce. E.; Banks, Matthew L.

2016-01-01

Rationale Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SAR) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in nonhuman primate models. Objectives The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, (±)-methamphetamine, and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Methods Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Results Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full, ≥90% cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than methamphetamine or previously published methcathinone (Smith et al. 2016). Conclusion The presence of an N-methyl group blunted both the potency and efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs. PMID:27709249

Chimeric Antigen Receptor-Modified T Cells for Solid Tumors: Challenges and Prospects

PubMed Central

Guo, Yelei; Wang, Yao; Han, Weidong

2016-01-01

Recent studies have highlighted the successes of chimeric antigen receptor-modified T- (CART-) cell-based therapy for B-cell malignancies, and early phase clinical trials have been launched in recent years. The few published clinical studies of CART cells in solid tumors have addressed safety and feasibility, but the clinical outcome data are limited. Although antitumor effects were confirmed in vitro and in animal models, CART-cell-based therapy still faces several challenges when directed towards solid tumors, and it has been difficult to achieve the desired outcomes in clinical practice. Many studies have struggled to improve the clinical responses to and benefits of CART-cell treatment of solid tumors. In this review, the status quo of CART cells and their clinical applications for solid tumors will be summarized first. Importantly, we will suggest improvements that could increase the therapeutic effectiveness of CART cells for solid tumors and their future clinical applications. These interventions will make treatment with CART cells an effective and routine therapy for solid tumors. PMID:26998495

Chimeric antigen receptor T cells: a novel therapy for solid tumors.

PubMed

Yu, Shengnan; Li, Anping; Liu, Qian; Li, Tengfei; Yuan, Xun; Han, Xinwei; Wu, Kongming

2017-03-29

The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

Characteristics of treatment provided for amphetamine use in New South Wales, Australia.

PubMed

McKetin, Rebecca; Kelly, Erin; Indig, Devon

2005-09-01

The purpose of this study was to examine the types of treatment services provided for amphetamine use, the characteristics of amphetamine treatment clients and the geographic areas most affected by amphetamine treatment provision within New South Wales (NSW), Australia. Data on completed amphetamine treatment episodes were extracted from the NSW Minimum Data Set for Alcohol and Other Drug Treatment Services for the year 2002/03 (n = 4,337). The geographic area of treatment presentations was based on the location of the treatment service, and was categorized as metropolitan, regional or rural. Treatment disproportionately affected regional and rural NSW, and treatment clients often presented with concurrent cannabis and/or alcohol problems. Clients were overwhelmingly injecting drug users with poor socio-demographic characteristics. Counselling was the most common treatment service provided, followed by detoxification and residential rehabilitation. Detoxification was usually provided in an in-patient setting, particularly within metropolitan NSW. Compliance with residential rehabilitation was notably poor. In conclusion, the development of appropriate interventions for amphetamine use needs to consider that the majority of treatment recipients will be based in a regional or rural setting, and treating amphetamine users will often involve treatment of concurrent cannabis and alcohol problems. The nature and appropriateness of treatment services provided for amphetamine use needs to be reviewed in detail, and further research is needed into the nature of problematic amphetamine use and factors affecting treatment demand in regional and rural NSW.

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant.

PubMed

Xu, Tai-Xiang; Ma, Qi; Spealman, Roger D; Yao, Wei-Dong

2010-12-01

Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of β-adrenergic receptors, or by inhibition of cAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post-synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via cAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Spending at mobile fruit and vegetable carts and using SNAP benefits to pay, Bronx, New York, 2013 and 2014.

PubMed

Breck, Andrew; Kiszko, Kamila M; Abrams, Courtney; Elbel, Brian

2015-06-04

This study examines purchases at fruit and vegetable carts and evaluates the potential benefits of expanding the availability of electronic benefit transfer machines at Green Carts. Customers at 4 Green Carts in the Bronx, New York, were surveyed in 3 waves from June 2013 through July 2014. Customers who used Supplemental Nutrition Assistance Program benefits spent on average $3.86 more than customers who paid with cash. This finding suggests that there may be benefits to increasing the availability of electronic benefit transfer machines at Green Carts.

S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis

PubMed Central

Rodriguez-Menchaca, Aldo A; Solis Jr, Ernesto; Cameron, Krasnodara; De Felice, Louis J

2012-01-01

BACKGROUND AND PURPOSE Wherever they are located, dopamine transporters (DATs) clear dopamine (DA) from the extracellular milieu to help regulate dopaminergic signalling. Exposure to amphetamine (AMPH) increases extracellular DA in the synaptic cleft, which has been ascribed to DAT reverse transport. Increased extracellular DA prolongs postsynaptic activity and reinforces abuse and hedonic behaviour. EXPERIMENTAL APPROACH Xenopus laevis oocytes expressing human (h) DAT were voltage-clamped and exposed to DA, R(-)AMPH, or S(+)AMPH. KEY RESULTS At -60mV, near neuronal resting potentials, S(+)AMPH induced a depolarizing current through hDAT, which after removing the drug, persisted for more than 30 min. This persistent leak in the absence of S(+)AMPH was in contrast to the currents induced by R(-)AMPH and DA, which returned to baseline immediately after their removal. Our data suggest that S(+)AMPH and Na+ carry the initial S(+)AMPH-induced current, whereas Na+ and Cl- carry the persistent leak current. We propose that the persistent current results from the internal action of S(+)AMPH on hDAT because the temporal effect was consistent with S(+)AMPH influx, and intracellular S(+)AMPH activated the effect. The persistent current was dependent on Na+ and was blocked by cocaine. Intracellular injection of S(+)AMPH also activated a DA-induced persistent leak current. CONCLUSIONS AND IMPLICATIONS We report a hitherto unknown action of S(+)AMPH on hDAT that potentially affects AMPH-induced DA release. We propose that internal S(+)AMPH acts as a molecular stent that holds the transporter open even after external S(+)AMPH is removed. Amphetamine-induced persistent leak currents are likely to influence dopaminergic signalling, DA release mechanisms, and amphetamine abuse. PMID:22014068

Similar discriminative-stimulus effects of D-amphetamine in women and men.

PubMed

Vansickel, Andrea R; Lile, Joshua A; Stoops, William W; Rush, Craig R

2007-01-01

The results of controlled non-human animal and human laboratory studies are mixed regarding whether women and men respond differently to stimulant drugs. In order to assess potential gender differences in the effects of D-amphetamine, we conducted a retrospective analysis of six studies conducted in our laboratory that used identical procedures and measures. Thirteen women and fourteen men learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (i.e., >or=80% correct responding on 4 consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg) alone and in combination with other drugs, were assessed. Only data from sessions in which D-amphetamine was administered alone were included in this analysis. D-amphetamine functioned as a discriminative stimulus and dose-dependently increased drug-appropriate responding. Women and men did not differ in their ability to discriminate D-amphetamine. Women and men differed on participant-ratings of high (womenmen) and sluggish (women

Demonstration of the Berkeley UXO Discrimination at Live Sites

DTIC Science & Technology

2010-02-01

BUD then occupied each of the 11 points and acquired a stationary measurement. The cart was equipped with a two-component tiltmeter and three...component magnetometer. Both devices were calibrated before the survey. The tiltmeters readings were used to compute the cart pitch (positive pitch...cart front down = negative tiltmeter change), and roll (positive=cart rightside down - positive tiltmeter change). The magnetometer values were used to

An Extension of CART's Pruning Algorithm. Program Statistics Research Technical Report No. 91-11.

ERIC Educational Resources Information Center

Kim, Sung-Ho

Among the computer-based methods used for the construction of trees such as AID, THAID, CART, and FACT, the only one that uses an algorithm that first grows a tree and then prunes the tree is CART. The pruning component of CART is analogous in spirit to the backward elimination approach in regression analysis. This idea provides a tool in…

OPRM1 gene variants modulate amphetamine-induced euphoria in humans

PubMed Central

Dlugos, Andrea M.; Hamidovic, Ajna; Hodgkinson, Colin; Pei-Hong, Shen; Goldman, David; Palmer, Abraham A.; de Wit, Harriet

2012-01-01

The μ-opioid receptor is involved in the rewarding effects of not only opioids like morphine but also psychostimulants like amphetamine. This study aimed to investigate associations between subjective response to amphetamine and genetic polymorphisms and haplotypes in the μ-opioid receptor including the exonic variant rs1799971 (Asp40Asn). 162 Caucasian volunteers participated in three sessions receiving either placebo or d-amphetamine (10 and 20 mg). Associations between levels of self-reported Euphoria, Energy and Stimulation (ARCI-49) after d-amphetamine ingestion and polymorphisms in OPRM1 were investigated. The intronic SNPs rs510769 and rs2281617 were associated with significantly higher ratings of Euphoria, Energy and Stimulation after 10 mg amphetamine. Feelings of Euphoria, Energy and Stimulation were also found to be associated with a 2-SNP haplotype formed with rs1799971 and rs510769 and a 3-SNP haplotype formed with rs1918760, rs2281617 and rs1998220. These results support the hypothesis that genetic variability in the μ-opioid receptor gene influences the subjective effects of amphetamine and may suggest new strategies for prevention and treatment of psychostimulant abuse. PMID:21029375

Effect of amphetamine on human macronutrient intake.

PubMed

Foltin, R W; Kelly, T H; Fischman, M W

1995-11-01

Six male subjects participated in a 15-day residential study examining the effects of amphetamine on macronutrient intake. During the first 11 days, carbohydrate intake was manipulated by providing lunch meals high (155 g) or low (25 g) in carbohydrate. Subjects received oral d-amphetamine (5, 10 mg/70 kg, BID) or placebo. Total daily caloric intake was similar under both lunch conditions (approximately 3400/Kcal), but carbohydrate contributed more energy under the high-carbohydrate condition. Both doses of amphetamine decreased total caloric intake to approximately 2600 Kcal, by decreasing the number of eating bouts, without affecting macronutrient selection. During the last four days subjects received a higher daily dose of amphetamine (30 mg/70 kg in four doses) or placebo, and were allowed to self-select lunch. Although 30 mg amphetamine decreased intake of all macronutrients, the relative contribution of carbohydrate to total caloric intake was increased from 54% to 62%, while the contribution of fat was decreased from 32% to 26% and the contribution of protein was decreased from 14% to 12%. Thus, at a high dose, amphetamine altered the relative contribution of specific macronutrients to total caloric intake.

Italian translation and cross-cultural comparison with the Childhood Attachment and Relational Trauma Screen (CARTS).

PubMed

Simonelli, A; Sacchi, C; Cantoni, L; Brown, M; Frewen, P

2017-01-01

Background : The Childhood Attachment and Relational Trauma Screen (CARTS) is a computer-administered survey designed to assess retrospectively the socio-ecological context in which instances of child abuse may have occurred. To date, studies supporting the validity of the CARTS have only been undertaken in English-speaking North American populations. Validation projects in other countries and cross-cultural comparisons are therefore warranted. Objective : Develop and preliminarily evaluate the psychometric properties of an Italian version of the CARTS on college students and compare such observations to data acquired from Canadian students. Method : Seventy-nine undergraduate students from the University of Padua (Italy) completed an Italian translation of the CARTS as well as measures of childhood experiences, mental health and attachment, responses to which were compared to those obtained in 288 Canadian students who completed the CARTS in English. Results : Internal consistency and convergent validity with the Childhood Trauma Questionnaire and Parental Bonding Instrument were found to be acceptable for the Italian translation. Within the Italian sample, correlation analyses suggested that CARTS Mother ratings referring to attachment and abuse were associated with romantic attachment, whereas CARTS Father ratings were significantly correlated to PTSD symptoms and other symptoms of psychopathology-distress. Significant differences between Italian and Canadian students across the relationship types for the CARTS abuse and attachment scales were found, indicating that Italian students rated their mothers and fathers as simultaneously less abusive, but also less as a source of secure attachment. Conclusions : The results of this preliminary study seem to suggest convergent validity of the Italian CARTS and the association between childhood attachment-related experiences and romantic attachment. Cultural variations were identified between Canadian and Italian students in both attachment and abuse scales. Future studies to investigate cross-cultural variations in the relational context of childhood abuse and in order to boost Italian CARTS psychometric features are warranted.

Italian translation and cross-cultural comparison with the Childhood Attachment and Relational Trauma Screen (CARTS)

PubMed Central

Simonelli, A.; Sacchi, C.; Cantoni, L.; Brown, M.; Frewen, P.

2017-01-01

ABSTRACT Background: The Childhood Attachment and Relational Trauma Screen (CARTS) is a computer-administered survey designed to assess retrospectively the socio-ecological context in which instances of child abuse may have occurred. To date, studies supporting the validity of the CARTS have only been undertaken in English-speaking North American populations. Validation projects in other countries and cross-cultural comparisons are therefore warranted. Objective: Develop and preliminarily evaluate the psychometric properties of an Italian version of the CARTS on college students and compare such observations to data acquired from Canadian students. Method: Seventy-nine undergraduate students from the University of Padua (Italy) completed an Italian translation of the CARTS as well as measures of childhood experiences, mental health and attachment, responses to which were compared to those obtained in 288 Canadian students who completed the CARTS in English. Results: Internal consistency and convergent validity with the Childhood Trauma Questionnaire and Parental Bonding Instrument were found to be acceptable for the Italian translation. Within the Italian sample, correlation analyses suggested that CARTS Mother ratings referring to attachment and abuse were associated with romantic attachment, whereas CARTS Father ratings were significantly correlated to PTSD symptoms and other symptoms of psychopathology-distress. Significant differences between Italian and Canadian students across the relationship types for the CARTS abuse and attachment scales were found, indicating that Italian students rated their mothers and fathers as simultaneously less abusive, but also less as a source of secure attachment. Conclusions: The results of this preliminary study seem to suggest convergent validity of the Italian CARTS and the association between childhood attachment-related experiences and romantic attachment. Cultural variations were identified between Canadian and Italian students in both attachment and abuse scales. Future studies to investigate cross-cultural variations in the relational context of childhood abuse and in order to boost Italian CARTS psychometric features are warranted. PMID:29163857

CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study.

PubMed

Wei, Guoqing; Hu, Yongxian; Pu, Chengfei; Yu, Jian; Luo, Yi; Shi, Jimin; Cui, Qu; Wu, Wenjun; Wang, Jinping; Xiao, Lei; Wu, Zhao; Huang, He

2018-05-01

Chimeric antigen receptor modified T cells against CD19 (CART19s) have potent anti-leukemia activities in patients with refractory/relapsed acute lymphoblastic leukemia (R/R ALL). This study was designed to investigate the correlation between safety/efficacy and therapeutic modalities including chemotherapy and CART19 therapy. Total 23 and 69 patients were enrolled in the CART19 group and in the chemotherapy group, respectively. The safety and efficacy profiles of 66 and 22 patients in the 2 groups were evaluated. The complete remission (CR) rate was higher in the CART19 group than that in the chemotherapy group (90.9 vs 37.9%, P = 0.000). For patients relapsed after allo-HSCT and chemotherapy, CR rates were 100% (8/8) vs 48.0% (12/25) (P = 0.009) and 85.7% (12/14) vs 31.7% (13/41) (P = 0.000), respectively. Moreover, a higher percentage in the CART19 group had results below the threshold for minimal residual disease (100 vs 7.58%, P = 0.000). In survival analysis, the overall survival rate at 12 months was higher in the CART19 group than that in the chemotherapy group (60.9 vs 10.1%, P = 0.000). For post-transplant patients achieving CR, 25.0% (2/8) and 75.0% (9/12) complicated with GVHD (P = 0.04) in the CART19 group and chemotherapy group, respectively. For all CR patients, the median duration of absolute neutrophil count less than 500/μL and platelet count less than 20,000/μL were longer in the CART19 group than in the chemotherapy group (p = 0.0047 and 0.0003, respectively). Our data demonstrated that patients with CART19s therapy acquired higher rates of remission and longer survival, confirming the encouraging application of CART19 therapy in R/R ALL.

Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager.

PubMed

Wing, Anna; Fajardo, Carlos Alberto; Posey, Avery D; Shaw, Carolyn; Da, Tong; Young, Regina M; Alemany, Ramon; June, Carl H; Guedan, Sonia

2018-05-01

T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR . ©2018 American Association for Cancer Research.

Actual use of and satisfaction associated with rollators and "shopping carts" among frail elderly Japanese people using day-service facilities.

PubMed

Kitajima, Eiji; Moriuchi, Takefumi; Iso, Naoki; Sagari, Akira; Kikuchi, Yasuyuki; Higashi, Toshio

2017-07-01

Purpose This study aimed at clarifying the actual use of and satisfaction with rollators and "shopping carts" (wheeled walkers with storage) among frail elderly people, who were certified by a long-term care insurance system as users of facilities that provide day-service nursing care and rehabilitation. Methods We identified 1247 frail elderly people who used day-service facilities, and evaluated their actual use of, and satisfaction with, rollators and shopping carts. Results Forty-four (3.5%) individuals used rollators, and 53 (4.3%) used shopping carts. The shopping cart group contained more individuals who were certified as care level 1 (26.4%), than the rollator group (20.5%), and 52.8% of the shopping cart group was certified as care levels 1-3. The scores for "repairs and services" and "follow-up" from the Quebec User Evaluation of Satisfaction with assistive Technology second version (QUEST 2.0) survey were significantly higher in the rollator group than in the shopping cart group. Conclusions The QUEST 2.0 scores revealed that shopping cart users exhibit insufficient "repairs and services" and "follow-up" scores. As frail elderly people with poor care status accounted for >50% of the shopping cart group, these individuals urgently need walking aids that are tailored to their care status. Implications for Rehabilitation We conclude that walking aid fitting must be tailored to each persons care status, and suggest that a system should be established to allow occupational or physical therapists to provide this fitting Moreover, our analysis of the QUEST2.0 service scores revealed that repairs, services, and follow-up are insufficient to meet the needs of shopping cart users.

Metabolic Precursors to Amphetamine and Methamphetamine.

PubMed

Cody, J D

1993-12-01

Analysis and interpretation of amphetamine results is a challenging process made difficult by a number of factors. One of the complications comes from determination of the origin of amphetamine or methamphetamine in a sample. Given the relatively rare occasions that either of these two drugs are prescribed, legal prescription of one of these drugs is seldom a reason for positive findings. A number of other precursor compounds are metabolized by the body to amphetamine or methamphetamine, many of which could be used for legitimate reasons. Fourteen different metabolic precursors of amphetamine or methamphetamine are included in this review. They are amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Medical use, metabolism, analysis, and interpretation are described to afford sufficient information to evaluate the possible involvement of these drugs in positive amphetamine or methamphetamine results. Copyright © 1993 Central Police University.

Nesfatin-1-Like Peptide Encoded in Nucleobindin-1 in Goldfish is a Novel Anorexigen Modulated by Sex Steroids, Macronutrients and Daily Rhythm

PubMed Central

Sundarrajan, Lakshminarasimhan; Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Ramesh, Naresh; Canosa, Luis Fabián; Unniappan, Suraj

2016-01-01

Nesfatin-1 is an 82 amino acid anorexigen encoded in a secreted precursor nucleobindin-2 (NUCB2). NUCB2 was named so due to its high sequence similarity with nucleobindin-1 (NUCB1). It was recently reported that NUCB1 encodes an insulinotropic nesfatin-1-like peptide (NLP) in mice. Here, we aimed to characterize NLP in fish. RT- qPCR showed NUCB1 expression in both central and peripheral tissues. Western blot analysis and/or fluorescence immunohistochemistry determined NUCB1/NLP in the brain, pituitary, testis, ovary and gut of goldfish. NUCB1 mRNA expression in goldfish pituitary and gut displayed a daily rhythmic pattern of expression. Pituitary NUCB1 mRNA expression was downregulated by estradiol, while testosterone upregulated its expression in female goldfish brain. High carbohydrate and fat suppressed NUCB1 mRNA expression in the brain and gut. Intraperitoneal injection of synthetic rat NLP and goldfish NLP at 10 and 100 ng/g body weight doses caused potent inhibition of food intake in goldfish. NLP injection also downregulated the expression of mRNAs encoding orexigens, preproghrelin and orexin-A, and upregulated anorexigen cocaine and amphetamine regulated transcript mRNA in goldfish brain. Collectively, these results provide the first set of results supporting the anorectic action of NLP, and the regulation of tissue specific expression of goldfish NUCB1. PMID:27329836

Predicting hydration free energies of amphetamine-type stimulants with a customized molecular model

NASA Astrophysics Data System (ADS)

Li, Jipeng; Fu, Jia; Huang, Xing; Lu, Diannan; Wu, Jianzhong

2016-09-01

Amphetamine-type stimulants (ATS) are a group of incitation and psychedelic drugs affecting the central nervous system. Physicochemical data for these compounds are essential for understanding the stimulating mechanism, for assessing their environmental impacts, and for developing new drug detection methods. However, experimental data are scarce due to tight regulation of such illicit drugs, yet conventional methods to estimate their properties are often unreliable. Here we introduce a tailor-made multiscale procedure for predicting the hydration free energies and the solvation structures of ATS molecules by a combination of first principles calculations and the classical density functional theory. We demonstrate that the multiscale procedure performs well for a training set with similar molecular characteristics and yields good agreement with a testing set not used in the training. The theoretical predictions serve as a benchmark for the missing experimental data and, importantly, provide microscopic insights into manipulating the hydrophobicity of ATS compounds by chemical modifications.

Novelty response and 50 kHz ultrasonic vocalizations: Differential prediction of locomotor and affective response to amphetamine in Sprague-Dawley rats.

PubMed

Garcia, Erik J; Cain, Mary E

2016-02-01

Novelty and sensation seeking (NSS) predisposes humans and rats to experiment with psychostimulants. In animal models, different tests of NSS predict different phases of drug dependence. Ultrasonic vocalizations (USVs) are evoked by psychomotor stimulants and measure the affective/motivation response to stimuli, yet the role NSS has on USVs in response to amphetamine is not determined. The aim of the present study was to determine if individual differences in NSS and USVs can predict locomotor and USV response to amphetamine (0.0, 0.3, and 1.0 mg/kg) after acute and chronic exposure. Thirty male rats were tested for their response to novelty (IEN), choice to engage in novelty (NPP), and heterospecific play (H-USV). Rats were administered non-contingent amphetamine or saline for seven exposures, and USVs and locomotor activity were measured. After a 14-day rest, rats were administered a challenge dose of amphetamine. Regression analyses indicated that amphetamine dose-dependently increased locomotor activity and the NPP test negatively predicted treatment-induced locomotor activity. The H-USV test predicted treatment-induced frequency-modulated (FM) USVs, but the strength of prediction depended on IEN response. Results provide evidence that locomotor activity and FM USVs induced by amphetamine represent different behavioral responses. The prediction of amphetamine-induced FM USVs by the H-USV screen was changed by the novelty response, indicating that the affective value of amphetamine-measured by FM USVs-depends on novelty response. This provides evidence that higher novelty responders may develop a tolerance faster and may escalate intake faster.

Chronic amphetamine enhances visual input to and suppresses visual output from the superior colliculus in withdrawal.

PubMed

Turner, Amy C; Kraev, Igor; Stewart, Michael G; Stramek, Agata; Overton, Paul G; Dommett, Eleanor J

2018-06-04

Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10 mg/kg) or a vehicle for one month after which local field potential and multiunit recordings were made from the superficial layers of the SC in response to whole-field light flashes in withdrawal. Rapid Golgi staining was also used to assess dendritic spines, and synaptophysin staining was used to assess synaptic integrity. Chronic amphetamine increased local field potential responses at higher doses, and increased synaptophysin expression, suggesting enhanced visual input involving presynaptic remodelling. No comparable increases in multiunit activity were found suggesting amphetamine suppresses collicular output activity, counterbalancing the increased input. We also report, for the first time, five different dendritic spine types in the superficial layers and show these to be unaffected by amphetamine, indicating that suppression does not involve gross postsynaptic structural alterations. In conclusion, we suggest that amphetamine produces changes at the collicular level that potentially stabilise the structure and may prevent the worsening of symptoms in disorders like ADHD. Copyright © 2018. Published by Elsevier Ltd.

Amphetamine increases activity but not exploration in humans and mice

PubMed Central

Minassian, Arpi; Young, Jared W.; Cope, Zackary A.; Henry, Brook L.; Geyer, Mark A.; Perry, William

2015-01-01

Rationale Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as Bipolar Disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. Objectives The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. Methods Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n=25), 10 mg d-amphetamine (n=18), or 20 mg amphetamine (n=23). 80 mice were administered one of 4 doses of d-amphetamine or vehicle. Humans and mice were tested in the Behavioral Pattern Monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. Results In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. Conclusions Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases. PMID:26449721

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues.

PubMed

Robinson, Mike J F; Anselme, Patrick; Suchomel, Kristen; Berridge, Kent C

2015-08-01

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever-conditioned stimulus; CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in 3 successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the CS+ lever versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also reported that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction. (c) 2015 APA, all rights reserved).

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues

PubMed Central

Robinson, Mike J.F.; Anselme, Patrick; Suchomel, Kristen; Berridge, Kent C.

2015-01-01

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine-sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in three successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the lever CS+ versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also report that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions together did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction. PMID:26076340

Fan Cart: The Next Generation

NASA Astrophysics Data System (ADS)

Lamore, Brian

2016-10-01

For years the fan cart has provided physics students with an excellent resource for exploring fundamental mechanics concepts such as acceleration, Newton's laws, impulse, momentum, work-energy, and energy conversions. The Physics Teacher has even seen some excellent do-it-yourself (DIY) fan carts and activities. If you are interested in developing the `E' portion of your and your students' STEM (science, technology, engineering, and math) skills, one way to accomplish this is to revisit the DIY fan cart. In this article I share a design of a new edition of the DIY fan cart and some ideas for incorporating the engineering design process into your high school curriculum.

Treatment for amphetamine withdrawal.

PubMed

Shoptaw, Steven J; Kao, Uyen; Heinzerling, Keith; Ling, Walter

2009-04-15

Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse to amphetamine use. In clinical practice, medications for cocaine withdrawal are commonly used to manage amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two illicit substances are different. To assess the effectiveness of pharmacological alone or in combination with psychosocial treatment for amphetamine withdrawals on discontinuation rates, global state, withdrawal symptoms, craving, and other outcomes. MEDLINE (1966 - 2008), CINAHL (1982 - 2008), PsycINFO (1806 - 2008), CENTRAL (Cochrane Library 2008 issue 2), references of obtained articles. All randomised controlled and clinical trials evaluating pharmacological and or psychosocial treatments (alone or combined) for people with amphetamine withdrawal symptoms. Two authors evaluated and extracted data independently. The data were extracted from intention-to-treat analyses. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess dichotomous outcomes. The Weighted Mean Difference (WMD) with 95% CI was used to assess continuous outcomes. Four randomised controlled trials (involving 125 participants) met the inclusion criteria for the review. Two studies found that amineptine significantly reduced discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or craving compared to placebo. The benefits of mirtazapine over placebo for reducing amphetamine withdrawal symptoms were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms. No medication is effective for treatment of amphetamine withdrawal. Amineptine showed reduction in discontinuation rates and improvement in clinical presentation compared to placebo, but had no effect on reducing withdrawal symptoms or craving. In spite of these limited benefits, amineptine is not available for use due to concerns over abuse liability when using the drug. The benefits of mirtazapine as a withdrawal agent are less clear based on findings from two randomised controlled trials: one report showed improvements in amphetamine withdrawal symptoms over placebo; a second report showed no differences in withdrawal symptoms compared to placebo. Further potential treatment studies should examine medications that increase central nervous system activity involving dopamine, norepinephrine and/or serotonin neurotransmitters, including mirtazapine.

Fault detection and diagnosis of induction motors using motor current signature analysis and a hybrid FMM-CART model.

PubMed

Seera, Manjeevan; Lim, Chee Peng; Ishak, Dahaman; Singh, Harapajan

2012-01-01

In this paper, a novel approach to detect and classify comprehensive fault conditions of induction motors using a hybrid fuzzy min-max (FMM) neural network and classification and regression tree (CART) is proposed. The hybrid model, known as FMM-CART, exploits the advantages of both FMM and CART for undertaking data classification and rule extraction problems. A series of real experiments is conducted, whereby the motor current signature analysis method is applied to form a database comprising stator current signatures under different motor conditions. The signal harmonics from the power spectral density are extracted as discriminative input features for fault detection and classification with FMM-CART. A comprehensive list of induction motor fault conditions, viz., broken rotor bars, unbalanced voltages, stator winding faults, and eccentricity problems, has been successfully classified using FMM-CART with good accuracy rates. The results are comparable, if not better, than those reported in the literature. Useful explanatory rules in the form of a decision tree are also elicited from FMM-CART to analyze and understand different fault conditions of induction motors.

The Role of Hypothalamic Insulin and Dopamine in the Anorectic Effect of Cocaine and d-amphetamine

DTIC Science & Technology

1992-08-21

15: Figure 16: Figure 17: Figure 18: LIST OF FIGURES Chemical structure of cocaine Chemical structure of amphetamine Cocaine groups! Average...prevent hypotension (Hoffman, 1987). The chemical structure of amphetamine is shown in figure 2. General Aspects: The term amphetamine applies to a group...cormnunication, 1991). 26 Germany in the 1930’s, with c hemical structures resembling those of epinephrine and NE. Their effects are similar to those of

Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3-4, methylenedioxymethamphetamine (MDMA) in female SD rats

PubMed Central

Yang, Pamela B.; Atkins, Kristal D.; Dafny, Nachum

2014-01-01

The psychostimulants amphetamine and methylphenidate (MPD / Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such 3,4 methylenedioxymethamphetamine (MDMA / ecstasy) are used / abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are 1. Acute amphetamine, MPD and MDMA all elicited increases in locomotor activity. 2. Chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization. 3. Chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others. 4. Cross sensitization between MPD and amphetamine was observed. 5. MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA act by different mechanisms compared to MPD and amphetamine. PMID:21549116

Enantioselective degradation of amphetamine-like environmental micropollutants (amphetamine, methamphetamine, MDMA and MDA) in urban water.

PubMed

Evans, Sian E; Bagnall, John; Kasprzyk-Hordern, Barbara

2016-08-01

This paper aims to understand enantioselective transformation of amphetamine, methamphetamine, MDMA (3,4-methylenedioxy-methamphetamine) and MDA (3,4-methylenedioxyamphetamine) during wastewater treatment and in receiving waters. In order to undertake a comprehensive evaluation of the processes occurring, stereoselective transformation of amphetamine-like compounds was studied, for the first time, in controlled laboratory experiments: receiving water and activated sludge simulating microcosm systems. The results demonstrated that stereoselective degradation, via microbial metabolic processes favouring S-(+)-enantiomer, occurred in all studied amphetamine-based compounds in activated sludge simulating microcosms. R-(-)-enantiomers were not degraded (or their degradation was limited) which proves their more recalcitrant nature. Out of all four amphetamine-like compounds studied, amphetamine was the most susceptible to biodegradation. It was followed by MDMA and methamphetamine. Photochemical processes facilitated degradation of MDMA and methamphetamine but they were not, as expected, stereoselective. Preferential biodegradation of S-(+)-methamphetamine led to the formation of S-(+)-amphetamine. Racemic MDMA was stereoselectively biodegraded by activated sludge which led to its enrichment with R-(-)-enantiomer and formation of S-(+)-MDA. Interestingly, there was only mild stereoselectivity observed during MDMA degradation in rivers. This might be due to different microbial communities utilised during activated sludge treatment and those present in the environment. Kinetic studies confirmed the recalcitrant nature of MDMA. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

NASA Astrophysics Data System (ADS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning.

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian-instrumental transfer task in rats.

PubMed

Shiflett, Michael W; Riccie, Meaghan; DiMatteo, RoseMarie

2013-11-01

Psychostimulant sensitization heightens behavioral and motivational responses to reward-associated stimuli; however, its effects on stimuli associated with reward absence are less understood. We examined whether amphetamine sensitization alters performance during Pavlovian-instrumental transfer (PIT) to conditioned excitors and inhibitors. We further sought to characterize the effects of amphetamine sensitization on learning versus performance by exposing rats to amphetamine prior to Pavlovian training or between training and test. Adult male Long-Evans rats were given conditioned inhibition (A+/AX-) and Pavlovian (B+) training, followed by variable-interval instrumental conditioning. Rats were sensitized to D-amphetamine (2 mg/kg daily injections for 7 days) or served as non-exposed controls. Rats were given a PIT test, in which they were presented with stimulus B alone or in compound with the conditioned inhibitor (BX). During the PIT test, control rats significantly reduced instrumental responding on BX trials (to approximately 50 % of responding to B). Amphetamine sensitization prior to Pavlovian conditioning increased lever pressing on BX trials and reduced lever pressing on B trials compared to controls. Amphetamine sensitization between training and test increased lever pressing on B and BX trials compared to controls. No effects of sensitization were observed on conditioned food cup approach. Amphetamine sensitization increases instrumental responding during PIT to a conditioned inhibitor by enhancing the excitation of conditioned stimuli and reducing the inhibition of conditioned inhibitors.

Emergency-Evacuation Cart

NASA Technical Reports Server (NTRS)

Fedor, Otto H.; Owens, Lester J.

1988-01-01

Proposed cart designed to remove injured worker from vicinity of hazardous chemical spill. Self-propelled cart enables rescuer to move victim of industrial accident quickly away from toxic, flammable, explosive, corrosive, carcinogenic, asphyxiating, or extremely cold liquids. Intended for use where too dangerous for ambulances and other vehicles to approach accident site. Constructed of high-strength tubing, rides on bicycle wheels with balloon tires. Rescuer steers cart with handle at rear. Estimated mass of fully equipped vehicle is 650 lb.

CRISIS UNDER THE RADAR: ILLICIT AMPHETAMINE USE IS REACHING EPIDEMIC PROPORTIONS AND CONTRIBUTING TO RESOURCE OVER-UTILIZATION AT A LEVEL 1 TRAUMA CENTER.

PubMed

Gemma, Vincent A; Chapple, Kristina A; Goslar, Pamela W; Israr, Sharjeel; Petersen, Scott R; Weinberg, Jordan A

2018-05-21

Trauma centers reported illicit amphetamine use in approximately 10% of trauma admissions in the previous decade. From experience at a trauma center located in a southwestern metropolis, our perception is that illicit amphetamine use is on the rise, and that these patients utilize in-hospital resources beyond what would be expected for their injuries. The purpose of this study was to document the incidence of illicit amphetamine use among our trauma patients and to evaluate its impact on resource utilization. We conducted a retrospective cohort study using 7 consecutive years of data (starting July 2010) from our institution's trauma registry. Toxicology screenings were used to categorize patients into one of three groups: illicit amphetamine, other drugs, or drug free. Adjusted linear and logistic regression models were used to predict hospital cost, length of stay, ICU admission and ventilation between drug groups. Models were conducted with combined injury severity (ISS) and then repeated for ISS <9, ISS 9-15 and ISS 16 and above. 8,589 patients were categorized into the following three toxicology groups: 1255 (14.6%) illicit amphetamine, 2214 (25.8%) other drugs, and 5120 (59.6%) drug free. Illicit amphetamine use increased threefold over the course of the study (from 7.85% to 25.0% of annual trauma admissions). Adjusted linear models demonstrated that illicit amphetamine among patients with ISS<9 was associated with 4.6% increase in hospital cost (P=.019) and 7.4% increase in LOS (P=.043). Logistic models revealed significantly increased odds of ventilation across all ISS groups and increased odds of ICU admission when all ISS groups were combined (P=.001) and within the ISS<9 group (P=.002). Hospital resource utilization of amphetamine patients with minor injuries is significant. Trauma centers with similar epidemic growth in proportion of amphetamine patients face a potentially significant resource strain relative to other centers. Prognostic and Epidemiological LEVEL OF EVIDENCE: III.

Involvement of Glutamate NMDA Receptors in the Acute, Long-Term, and Conditioned Effects of Amphetamine on Rat 50kHz Ultrasonic Vocalizations

PubMed Central

Costa, Giulia; Morelli, Micaela

2015-01-01

Background: Rats emit 50kHz ultrasonic vocalizations (USVs) in response to either natural or pharmacological pleasurable stimuli, and these USVs have emerged as a new behavioral measure for investigating the motivational properties of drugs. Earlier studies have indicated that activation of the dopaminergic system is critically involved in 50kHz USV emissions. However, evidence also exists that non-dopaminergic neurotransmitters participate in this behavioral response. Methods: To ascertain whether glutamate transmission plays a role in 50kHz USV emissions stimulated by amphetamine, rats received five amphetamine (1–2mg/kg, i.p.) administrations on alternate days in a test cage, either alone or combined with the glutamate N-methyl-D-aspartate receptor antagonist MK-801 (0.1–0.5mg/kg, i.p.). Seven days after treatment discontinuation, rats were re-exposed to the test cage to assess drug conditioning, and afterwards received a drug challenge. USVs and locomotor activity were evaluated, along with immunofluorescence for Zif-268 in various brain regions and spontaneous alternation in a Y maze. Results: Amphetamine-treated rats displayed higher 50kHz USV emissions and locomotor activity than vehicle-treated rats, and emitted conditioned vocalizations on test cage re-exposure. Rats co-administered amphetamine and MK-801 displayed lower and dose-dependent 50kHz USV emissions, but not lower locomotor activity, during repeated treatment and challenge, and scarce conditioned vocalization compared with amphetamine-treated rats. These effects were associated with lower levels of Zif-268 after amphetamine challenge and spontaneous alternation deficits. Conclusions: These results indicate that glutamate transmission participates in the acute, long-term, and conditioned effects of amphetamine on 50kHz USVs, possibly by influencing amphetamine-induced long-term neuronal changes and/or amphetamine-associated memories. PMID:25991653

Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Mei-Fang

The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O{sub 2} demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp,more » and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100 μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8 Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine > methamphetamine > hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem. - Highlights: • Ketamine/amphetamines inhibit nicotine-induced cerebral neurogenic vasdilation. • Ketamine/amphetamines block cerebral perivascular sympathetic nAChR-mediated current. • The inhibitory potency is ketamine > D-amphetamine > methamphetamine > OH-amphetamine.« less

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

PubMed

Hege, Kristen M; Bergsland, Emily K; Fisher, George A; Nemunaitis, John J; Warren, Robert S; McArthur, James G; Lin, Andy A; Schlom, Jeffrey; June, Carl H; Sherwin, Stephen A

2017-01-01

T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s. Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 10 10 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72. Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111 Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed. These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.

Sleep deprivation precipitates the development of amphetamine-induced conditioned place preference in rats.

PubMed

Berro, Laís F; Tufik, Sergio B; Frussa-Filho, Roberto; Andersen, Monica L; Tufik, Sergio

2018-04-03

Sleep deprivation (SD) and amphetamine use are commonly associated conditions. SD shares similar neurobiological effects with psychostimulants, playing an important role in drug addiction, especially through conditioning manipulations. The aim of the present study was to investigate the effects of SD on the development of amphetamine-induced conditioned place preference (CPP) in a protocol with a reduced number of conditioning sessions. Male adult Wistar rats were submitted to 4 conditioning sessions (2 sessions/day) in the CPP apparatus, half with saline (non-drug-paired compartment) and half with 2 mg/kg amphetamine (drug-paired compartment) after control (home-cage maintained) or SD (6 h gentle handling method) conditions. Control animals did not express a preference for the amphetamine-paired compartment, showing that 2 conditioning sessions with the drug were not sufficient to establish CPP. On the other hand, animals submitted to SD during the conditioning sessions expressed a preference for the amphetamine-paired compartment, which was maintained across the entire test session. SD precipitated the development of CPP to amphetamine, showing that lack of sleep can contribute to the establishment of a conditioning between the drug effect and environmental cues. Copyright © 2018 Elsevier B.V. All rights reserved.

Alx1, a member of the Cart1/Alx3/Alx4 subfamily of Paired-class homeodomain proteins, is an essential component of the gene network controlling skeletogenic fate specification in the sea urchin embryo.

PubMed

Ettensohn, Charles A; Illies, Michele R; Oliveri, Paola; De Jong, Deborah L

2003-07-01

In the sea urchin embryo, the large micromeres and their progeny function as a critical signaling center and execute a complex morphogenetic program. We have identified a new and essential component of the gene network that controls large micromere specification, the homeodomain protein Alx1. Alx1 is expressed exclusively by cells of the large micromere lineage beginning in the first interphase after the large micromeres are born. Morpholino studies demonstrate that Alx1 is essential at an early stage of specification and controls downstream genes required for epithelial-mesenchymal transition and biomineralization. Expression of Alx1 is cell autonomous and regulated maternally through beta-catenin and its downstream effector, Pmar1. Alx1 expression can be activated in other cell lineages at much later stages of development, however, through a regulative pathway of skeletogenesis that is responsive to cell signaling. The Alx1 protein is highly conserved among euechinoid sea urchins and is closely related to the Cart1/Alx3/Alx4 family of vertebrate homeodomain proteins. In vertebrates, these proteins regulate the formation of skeletal elements of the limbs, face and neck. Our findings suggest that the ancestral deuterostome had a population of biomineral-forming mesenchyme cells that expressed an Alx1-like protein.

Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response.

PubMed

Xue, Qiong; Bettini, Emily; Paczkowski, Patrick; Ng, Colin; Kaiser, Alaina; McConnell, Timothy; Kodrasi, Olja; Quigley, Máire F; Heath, James; Fan, Rong; Mackay, Sean; Dudley, Mark E; Kassim, Sadik H; Zhou, Jing

2017-11-21

It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti-CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16-plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. We demonstrate a new method for single-cell profiling of CD19 CAR-T pre-infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-γ, MIP-1α, TNF-α), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL-17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high dimensional data requires new visualization methods to further define precise polyfunctional response differences in these products. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy.

Amphetamine self-administration in light and moderate drinkers.

PubMed

Stanley, Matthew D; Poole, Mégan M; Stoops, William W; Rush, Craig R

2011-03-01

Light and moderate drinkers respond differently to the effects of abused drugs, including stimulants such as amphetamine. The purpose of this study was to determine whether light and moderate drinkers differ in their sensitivity to the reinforcing and subjective effects of d-amphetamine. We hypothesized that moderate drinkers (i.e., participants that reported consuming at least seven alcohol-containing beverages per week) would be more sensitive to the reinforcing and positive subject-rated effects of d-amphetamine than light drinkers. Data from four studies that employed similar d-amphetamine self-administration procedures and subject-rated drug-effect measures were included in the analysis. Light (n = 17) and moderate (n = 16) drinkers sampled placebo, low (8 to 10 mg), and high (16 to 20 mg) doses of oral d-amphetamine administered in eight capsules. Following sampling sessions, participants worked for a maximum of eight capsules, each containing 12.5% of the previously sampled dose, on a modified progressive-ratio schedule of reinforcement. Both active doses of d-amphetamine functioned as a reinforcer in the moderate drinkers, while only the high dose did so in the light drinkers. The moderate drinkers worked for significantly more capsules that contained the high dose of d-amphetamine than did the light drinkers. d-Amphetamine produced prototypical stimulant-like subjective effects (e.g., dose-dependent increases in ratings of Good Effects; Like Drug and Willing to Take Again). Moderate drinkers reported significantly greater subjective effects than the light drinkers. These results are consistent with those from previous laboratory experiments and suggest that moderate alcohol consumption may increase vulnerability to the abuse-related effects of stimulants. Copyright © 2010 by the Research Society on Alcoholism.

Breakingtheice: a protocol for a randomised controlled trial of an internet-based intervention addressing amphetamine-type stimulant use.

PubMed

Tait, Robert J; McKetin, Rebecca; Kay-Lambkin, Frances; Bennett, Kylie; Tam, Ada; Bennett, Anthony; Geddes, Jenny; Garrick, Adam; Christensen, Helen; Griffiths, Kathleen M

2012-06-25

The prevalence of amphetamine-type stimulant use is greater than that of opioids and cocaine combined. Currently, there are no approved pharmacotherapy treatments for amphetamine-type stimulant problems, but some face-to-face psychotherapies are of demonstrated effectiveness. However, most treatment services focus on alcohol or opioid disorders, have limited reach and may not appeal to users of amphetamine-type stimulants. Internet interventions have proven to be effective for some substance use problems but none has specifically targeted users of amphetamine-type stimulants. The study will use a randomized controlled trial design to evaluate the effect of an internet intervention for amphetamine-type stimulant problems compared with a waitlist control group. The primary outcome will be assessed as amphetamine-type stimulant use (baseline, 3 and 6 months). Other outcomes measures will include 'readiness to change', quality of life, psychological distress (K-10 score), days out of role, poly-drug use, help-seeking intention and help-seeking behavior. The intervention consists of three modules requiring an estimated total completion time of 90 minutes. The content of the modules was adapted from face-to-face clinical techniques based on cognitive behavior therapy and motivation enhancement. The target sample is 160 men and women aged 18 and over who have used amphetamine-type stimulants in the last 3 months. To our knowledge this will be the first randomized controlled trial of an internet intervention specifically developed for users of amphetamine-type stimulants. If successful, the intervention will offer greater reach than conventional therapies and may engage clients who do not generally seek treatment from existing service providers. Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) ACTRN12611000947909.

Breakingtheice: A protocol for a randomised controlled trial of an internet-based intervention addressing amphetamine-type stimulant use

PubMed Central

2012-01-01

Background The prevalence of amphetamine-type stimulant use is greater than that of opioids and cocaine combined. Currently, there are no approved pharmacotherapy treatments for amphetamine-type stimulant problems, but some face-to-face psychotherapies are of demonstrated effectiveness. However, most treatment services focus on alcohol or opioid disorders, have limited reach and may not appeal to users of amphetamine-type stimulants. Internet interventions have proven to be effective for some substance use problems but none has specifically targeted users of amphetamine-type stimulants. Design/method The study will use a randomized controlled trial design to evaluate the effect of an internet intervention for amphetamine-type stimulant problems compared with a waitlist control group. The primary outcome will be assessed as amphetamine-type stimulant use (baseline, 3 and 6 months). Other outcomes measures will include ‘readiness to change’, quality of life, psychological distress (K-10 score), days out of role, poly-drug use, help-seeking intention and help-seeking behavior. The intervention consists of three modules requiring an estimated total completion time of 90 minutes. The content of the modules was adapted from face-to-face clinical techniques based on cognitive behavior therapy and motivation enhancement. The target sample is 160 men and women aged 18 and over who have used amphetamine-type stimulants in the last 3 months. Discussion To our knowledge this will be the first randomized controlled trial of an internet intervention specifically developed for users of amphetamine-type stimulants. If successful, the intervention will offer greater reach than conventional therapies and may engage clients who do not generally seek treatment from existing service providers. Trial registration Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au/) ACTRN12611000947909 PMID:22731926

Cross-Reactivity of Chloroquine and Hydroxychloroquine With DRI Amphetamine Immunoassay.

PubMed

Gomila, Isabel; Quesada, Loreto; López-Corominas, Victoria; Fernández, Julia; Servera, Miguel Á; Sahuquillo, Laura; Dastis, Macarena; Torrents, Albert; Barceló, Bernardino

2017-04-01

Chloroquine and hydroxychloroquine are medical drugs used to treat the chemoprophylaxis of malaria and a second-line anti-inflammatory drug. We performed a study of cross-reactivity of chloroquine and hydroxychloroquine in the DRI Amphetamine Assay inspired by a case report of a self-ingestion of chloroquine after a family dispute, that involved the following: (1) an in vitro study with control samples of healthy subjects, (2) an in vivo study with samples of patients with rheumatoid arthritis, and (3) an evaluation of the cross-reactivity of chloroquine and hydroxychloroquine in 3 additional immunoassays. In the case report, the Amphetamine DRI assay resulted positive both at 1000 ng/mL cutoff (1507 and 1137 ng/mL) and at 500 ng/mL cutoff (1178 and 642 ng/mL). Chloroquine urine levels were 103,900 and 100,900 ng/mL at 5 and 9 hours after ingestion. The results with control samples showed a positive cross-reactivity of chloroquine in the DRI Amphetamine Assay (approximately 0.74% and 0.89% at cutoff of 1000 and 500 ng/mL, respectively). Hydroxychloroquine did not cross-react with the DRI Amphetamine Assay up to 1,000,000 ng/mL. In patients treated with chloroquine or hydroxychloroquine, DRI Amphetamine did not produce false-positive results. The comparative assay study showed a positive cross-reactivity of chloroquine in the Emit II Plus Amphetamines Assay with control samples. Chloroquine can cause false-positive results in the DRI Amphetamine Assay when it is present at high concentrations. Hydroxychloroquine did not produce false-positive results neither in the DRI Amphetamine Assay nor in the others immunoassays evaluated.

Case Reports of Aripiprazole Causing False-Positive Urine Amphetamine Drug Screens in Children.

PubMed

Kaplan, Justin; Shah, Pooja; Faley, Brian; Siegel, Mark E

2015-12-01

Urine drug screens (UDSs) are used to identify the presence of certain medications. One limitation of UDSs is the potential for false-positive results caused by cross-reactivity with other substances. Amphetamines have an extensive list of cross-reacting medications. The literature contains reports of false-positive amphetamine UDSs with multiple antidepressants and antipsychotics. We present 2 cases of presumed false-positive UDSs for amphetamines after ingestion of aripiprazole. Case 1 was a 16-month-old girl who accidently ingested 15 to 45 mg of aripiprazole. She was lethargic and ataxic at home with 1 episode of vomiting containing no identifiable tablets. She remained sluggish with periods of irritability and was admitted for observation. UDS on 2 consecutive days came back positive for amphetamines. Case 2 was of a 20-month-old girl who was brought into the hospital after accidental ingestion of an unknown quantity of her father's medications which included aripiprazole. UDS on the first day of admission came back positive only for amphetamines. Confirmatory testing with gas chromatography-mass spectrometry (GC-MS) on the blood and urine samples were also performed for both patients on presentation to detect amphetamines and were subsequently negative. Both patients returned to baseline and were discharged from the hospital. To our knowledge, these cases represent the first reports of false-positive amphetamine urine drug tests with aripiprazole. In both cases, aripiprazole was the drug with the highest likelihood of causing the positive amphetamine screen. The implications of these false-positives include the possibility of unnecessary treatment and monitoring of patients. Copyright © 2015 by the American Academy of Pediatrics.

Contextual conditioning enhances the psychostimulant and incentive properties of d-amphetamine in humans

PubMed Central

Childs, Emma; de Wit, Harriet

2014-01-01

Learned associations between drugs and the places they are used are critical to the development of drug addiction. Contextual conditioning has long been studied in animals as an indirect measure of drug reward, but little is known about the process in humans. Here, we investigated de novo contextual conditioning with d-amphetamine in healthy humans (n = 34). Volunteers underwent four conditioning sessions conducted in two testing rooms with double-blind, alternating d-amphetamine (20 mg) and placebo administration. Before conditioning procedures began, they rated the two rooms to examine pre-existing preferences. One group (Paired, n = 19) always received d-amphetamine in their least preferred room and placebo in the other during conditioning sessions. Another group (Unpaired, n = 15) received d-amphetamine and placebo in both rooms. Subjective drug effects were monitored at repeated times. At a separate re-exposure test, preference ratings for the drug-associated room were increased among the Paired group only, and more subjects in the Paired than the Unpaired group switched their preference to their initially least preferred room. Also, ratings of d-amphetamine drug liking independently predicted room liking at test among the Paired group only. Further, Paired group subjects reported greater stimulation and drug craving after d-amphetamine on the second administration, relative to the first. This study supports preliminary findings that humans, like animals, develop a preference for a place associated with d-amphetamine that is related to its subjective effects. These findings also suggest that experiencing d-amphetamine in a consistent environment produces context-dependent changes in its subjective effects, including an enhanced rewarding efficacy and abuse potential. PMID:22129527

MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia.

PubMed

Talpos, John; Aerts, Nancy; Waddell, Jason; Steckler, Thomas

2015-11-01

Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia. The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL. Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination. While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model. These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

The PASCO Wireless Smart Cart: A Game Changer in the Undergraduate Physics Laboratory

NASA Astrophysics Data System (ADS)

Shakur, Asif; Connor, Rainor

2018-03-01

With the introduction of the Wireless Smart Cart by PASCO scientific in April 2016, we expect a paradigm shift in undergraduate physics laboratory instruction. We have evaluated the feasibility of using the smart cart by carrying out experiments that are usually performed using traditional PASCO equipment. The simplicity, convenience, and cost-saving achieved by replacing a plethora of traditional laboratory sensors, wires, and equipment clutter with the smart cart are reported here.

Data mining of tree-based models to analyze freeway accident frequency.

PubMed

Chang, Li-Yen; Chen, Wen-Chieh

2005-01-01

Statistical models, such as Poisson or negative binomial regression models, have been employed to analyze vehicle accident frequency for many years. However, these models have their own model assumptions and pre-defined underlying relationship between dependent and independent variables. If these assumptions are violated, the model could lead to erroneous estimation of accident likelihood. Classification and Regression Tree (CART), one of the most widely applied data mining techniques, has been commonly employed in business administration, industry, and engineering. CART does not require any pre-defined underlying relationship between target (dependent) variable and predictors (independent variables) and has been shown to be a powerful tool, particularly for dealing with prediction and classification problems. This study collected the 2001-2002 accident data of National Freeway 1 in Taiwan. A CART model and a negative binomial regression model were developed to establish the empirical relationship between traffic accidents and highway geometric variables, traffic characteristics, and environmental factors. The CART findings indicated that the average daily traffic volume and precipitation variables were the key determinants for freeway accident frequencies. By comparing the prediction performance between the CART and the negative binomial regression models, this study demonstrates that CART is a good alternative method for analyzing freeway accident frequencies. By comparing the prediction performance between the CART and the negative binomial regression models, this study demonstrates that CART is a good alternative method for analyzing freeway accident frequencies.

Amphetamines and pH-shift agents for brain imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biersack, H.J.; Winkler, C.

1986-01-01

This book gives a review of the results of experimental and clinical research on both I-amphetamine derivatives and pH-shift agents. Virtually all relevant working groups from the USA and Europe have contributed to this volume. The pharmacology of amphetamine and the corresponding receptor theories are described in detail, whereas other chapters deal with the labeling as well as the metabolic process of this drug. In addition to this, new amphetamine derivatives are presented together with other essential products which play a significant role in scintigraphy of the brain function. Finally, there are two chapters on instrumentation problems followed by eightmore » contributions on the clinical results of amphetamine scintigraphy in cerebral vascular diseases, epilepsy, migraine and brain tumors.« less

Age at initiation of amphetamine use and age at onset of psychosis: the Australian Survey of High Impact Psychosis.

PubMed

Power, Brian D; Stefanis, Nikos C; Dragovic, Milan; Jablensky, Assen; Castle, David; Morgan, Vera

2014-01-01

Individuals with a psychotic disorder who had a premorbid history of amphetamine use (n=382) were analyzed in groups according to age of initiation to amphetamine (AIA) and mean number of years of duration of premorbid exposure to amphetamine (DPEA) was calculated. Univariate General Linear Models were used to test for group differences in age at onset of psychotic illness (AOI) and DPEA. Although a temporal direct relationship between AIA and AOI was detected (mean duration 5.3 years), our findings suggested this association was spurious and better explained by a later initiation to amphetamine than to cannabis (by 2-3 years). Copyright © 2013 Elsevier B.V. All rights reserved.

Surveillance of Diversion and Nonmedical Use of Extended-Release Prescription Amphetamine and Oral Methylphenidate in the United States

PubMed Central

Sembower, Mark A.; Ertischek, Michelle D.; Buchholtz, Chloe; Dasgupta, Nabarun; Schnoll, Sidney H.

2013-01-01

This article examines rates of nonmedical use and diversion of extended-release amphetamine and extended-release oral methylphenidate in the United States. Prescription dispensing data were sourced from retail pharmacies. Nonmedical use data were collected from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Drug Diversion Program and Poison Center Program. Drug diversion trends nearly overlapped for extended-release amphetamine and extended-release oral methylphenidate. Calls to poison centers were generally similar; however, calls regarding extended-release amphetamine trended slightly lower than those for extended-release oral methylphenidate. Data suggest similar diversion and poison center call rates for extended-release amphetamine and extended-release oral methylphenidate. PMID:23480245

Professor: A motorized field-based phenotyping cart

USDA-ARS?s Scientific Manuscript database

An easy-to-customize, low-cost, low disturbance, motorized proximal sensing cart for field-based high-throughput phenotyping is described. General dimensions, motor specifications, and a remote operation application are given. The cart, named Professor, supports mounting multiple proximal sensors an...

Access to nicotine in drinking water reduces weight gain without changing caloric intake on high fat diet in male C57BL/6J mice.

PubMed

Calarco, Cali A; Lee, Somin; Picciotto, Marina R

2017-09-01

Nicotine and tobacco use is associated with lower body weight, and many smokers report concerns about weight. In animal studies, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Previous studies have used standardized nicotine doses, however, in this study, male and female mice had free access to nicotine drinking water for 30 days while fed either a high fat diet (HFD) or chow, allowing animals to titrate their nicotine intake. In male mice, HFD increased body weight and caloric intake. Nicotine attenuated this effect and decreased weight gain per calorie consumed without affecting overall caloric intake or acute locomotion, suggesting metabolic changes. Nicotine did not decrease weight in chow-fed animals. In contrast, the same paradigm did not result in significant differences in weight gain in female animals, but did alter corticosterone levels and locomotion, indicating sex differences in the response to HFD and nicotine. We measured levels of mRNAs encoding nicotinic acetylcholine receptor subunits, uncoupling proteins (UCP) 1-3, and neuropeptides involved in energy balance in adipose tissues and the arcuate nucleus of the hypothalamus (ARC). HFD and nicotine regulated UCP levels in adipose tissues and ARC from female, but not male, mice. Regulation of agouti-related peptide, neuropeptide-Y, melanin-concentrating hormone, and cocaine- and amphetamine-regulated transcript in ARC varied with diet and nicotine in a sex-dependent manner. These data demonstrate that chronic consumption of nicotine moderates the effect of HFD in male mice by changing metabolism rather than food intake, and identify a differential effect on female mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanisms of antimotion sickness drugs

NASA Technical Reports Server (NTRS)

Wood, C. D.; Manno, J. E.; Wood, M. J.; Manno, B. R.; Redetzki, H. M.

1987-01-01

Eight subjects, male and female, were rotated using the step method to progressively increase the speed of rotation (+2 rpm) after every 40 head movements to a maximum of 35 rpm. The end point for motion sickness was the Graybiel Malaise III total of symptoms short of frank nausea. The drug treatments were placebo, scopolamine 0.6 mg and 1 mg, scopolamine 0.6 mg/d-amphetamine 10 mg, scopolamine 1 mg/d-amphetamine 10 mg, and amphetamine 10 mg. Scopolamine increased tolerated head movements over placebo level by + 81; scopolamine 1 mg + 183; d-amphetamine by + 118; scopolamine 0.6/d-amphetamine by + 165; and scopolamine 1 mg/d-amphetamine 10 mg by + 201. The drugs effective in preventing motion sickness are considered to be divided into those with central acetylcholine blocking activity and those which enhance norepinephrine activity. A combination of both of these actions produces the most effective antimotion sickness medications. It is concluded that the balance between the acetylcholine and norepinephrine activity in the CNS appears to be responsible for motion sickness.

Transcriptomic configuration of mouse brain induced by adolescent exposure to 3,4-methylenedioxymethamphetamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eun, Jung Woo; Kwack, Seung Jun; Noh, Ji Heon

The amphetamine derivative ({+-})-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a synthetic amphetamine analogue used recreationally to obtain an enhanced affiliative emotional response. MDMA is a potent monoaminergic neurotoxin with the potential to damage brain serotonin and/or dopamine neurons. As the majority of MDMA users are young adults, the risk that users may expose the fetus to MDMA is a concern. However, the majority of studies on MDMA have investigated the effects on adult animals. Here, we investigated whether long-term exposure to MDMA, especially in adolescence, could induce comprehensive transcriptional changes in mouse brain. Transcriptomic analysis of mouse brain regions demonstrated significantmore » gene expression changes in the cerebral cortex. Supervised analysis identified 1028 genes that were chronically dysregulated by long-term exposure to MDMA in adolescent mice. Functional categories most represented by this MDMA characteristic signature are intracellular molecular signaling pathways of neurotoxicity, such as, the MAPK signaling pathway, the Wnt signaling pathway, neuroactive ligand-receptor interaction, long-term potentiation, and the long-term depression signaling pathway. Although these resultant large-scale molecular changes remain to be studied associated with functional brain damage caused by MDMA, our observations delineate the possible neurotoxic effects of MDMA on brain function, and have therapeutic implications concerning neuro-pathological conditions associated with MDMA abuse.« less

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

PubMed Central

Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya; Tojais, Nancy F.; Hennigs, Jan K.; Li, Caiyun G.; Sweeney, Nathaly M.; Inglis, Audrey S.; Wang, Lingli; Li, Dan; Ye, Matthew; Feldman, Brian J.

2017-01-01

Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochrome c oxidase 4 isoform switch. Mitochondrial oxidative phosphorylation is inappropriately enhanced and, as a result of impaired electron transport and mitochondrial ROS increase, caspase-3 is activated and DNA damage is induced. In mice given binge doses of METH followed by hypoxia, HIF1α is suppressed and pulmonary artery DNA damage foci are associated with worse pulmonary vascular remodeling. Thus, chronic AMPH/METH can induce DNA damage associated with vascular disease by subverting the adaptive responses to oxidative stress. PMID:28138562

[Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

PubMed

Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

2010-09-01

To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

Improvement of attention with amphetamine in low- and high-performing rats.

PubMed

Turner, Karly M; Burne, Thomas H J

2016-09-01

Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25 mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. Acute low dose amphetamine (0.1 and 0.25 mg/kg) improved accuracy, while the highest dose (1.25 mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

NASA Technical Reports Server (NTRS)

Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

2003-01-01

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0 Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

Withdrawal from repeated treatment with amphetamine reduces novelty-seeking behavior and enhances environmental habituation in mice.

PubMed

Fukushiro, Daniela F; Mári-Kawamoto, Elisa; Aramini, Tatiana C F; Saito, Luis P; Costa, Jacqueline M; Josino, Fabiana S; Frussa-Filho, Roberto

2011-11-01

Anhedonia associated with a dysphoric state is an important feature of amphetamine withdrawal in humans. We aimed to investigate the effects of amphetamine withdrawal on two motivation-related behaviors in mice: novelty seeking and environmental habituation. Because anxiety can interfere with the behavioral outcome of other tasks, amphetamine-withdrawn mice were also evaluated in the elevated plus maze. Swiss male mice (three months old) were treated with 2.0mg/kg amphetamine for 13 days, every other day, in their home cages (a total of seven injections). Twenty-four hours after withdrawal from drug treatment, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment or in the elevated plus maze. Novelty-seeking behavior was assessed by comparing the time spent in the novel compartment vs. the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased during amphetamine withdrawal, and this result was not associated with changes in the anxiety-like behavior of mice. Additionally, amphetamine withdrawal enhanced environmental habituation. The concomitant decrease in novelty seeking and the increase in environmental habituation seem to be related to amphetamine withdrawal-induced anhedonia. Thus, the model proposed here could be used as a tool for the study of mechanisms and potential treatment of the anhedonic behavioral consequences of psychostimulant withdrawal. Copyright © 2011 Elsevier Inc. All rights reserved.

The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats.

PubMed

Koltunowska, D; Gibula-Bruzda, E; Kotlinska, J H

2013-08-01

Chronic amphetamine use results in anxiety-like states after drug cessation. The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptor ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats. In our study memantine (8 and 12 mg/kg), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist did not reduce amphetamine withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate 5 receptor (mGluR5) antagonist) at the dose 200 and 400mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and a number of open arm entries. mGluR5 selective antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride) and mGluR2/3 agonist, LY354740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), caused effects similar to acamprosate at doses 1.25-5mg/kg and 2.5-5mg/kg, respectively. None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group. Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking, our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian-instrumental transfer task in rats

PubMed Central

Shiflett, Michael W.; Riccie, Meaghan; DiMatteo, RoseMarie

2013-01-01

Rationale Psychostimulant sensitization heightens behavioral and motivational responses to reward-associated stimuli; however, its effects on stimuli associated with reward absence are less understood. Objectives We examined whether amphetamine sensitization alters performance during Pavlovian-instrumental transfer (PIT) to conditioned excitors and inhibitors. We further sought to characterize the effects of amphetamine sensitization on learning versus performance by exposing rats to amphetamine prior to Pavlovian training or between training and test. Methods Adult male Long Evans rats were given conditioned inhibition (A+/AX−) and Pavlovian (B+) training, followed by variable-interval instrumental conditioning. Rats were sensitized to d-amphetamine (2 mg/kg daily injections for seven days), or served as non-exposed controls. Rats were given a PIT test, in which they were presented with stimulus B alone or in compound with the conditioned inhibitor (BX). Results During the PIT test, control rats significantly reduced instrumental responding on BX trials (to approximately 50% of responding to B). Amphetamine sensitization prior to Pavlovian conditioning increased lever-pressing on BX trials and reduced lever-pressing on B trials compared to controls. Amphetamine sensitization between training and test increased lever-pressing on B and BX trials compared to controls. No effects of sensitization were observed on conditioned food-cup approach. Conclusions Amphetamine sensitization increases instrumental responding during PIT to a conditioned inhibitor, by enhancing excitation of conditioned stimuli and reducing inhibition of conditioned inhibitors. PMID:23715640

Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

PubMed

Siegler, Elizabeth Louise; Wang, Pin

2018-05-01

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

21 CFR 868.6175 - Cardiopulmonary emergency cart.

Code of Federal Regulations, 2011 CFR

2011-04-01

... cardiopulmonary resuscitation. (b) Classification. Class I (general controls). The device is exempt from the... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary emergency cart. 868.6175 Section... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6175 Cardiopulmonary emergency cart...

21 CFR 868.6175 - Cardiopulmonary emergency cart.

Code of Federal Regulations, 2010 CFR

2010-04-01

... cardiopulmonary resuscitation. (b) Classification. Class I (general controls). The device is exempt from the... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary emergency cart. 868.6175 Section... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6175 Cardiopulmonary emergency cart...

21 CFR 868.6175 - Cardiopulmonary emergency cart.

Code of Federal Regulations, 2014 CFR

2014-04-01

... cardiopulmonary resuscitation. (b) Classification. Class I (general controls). The device is exempt from the... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiopulmonary emergency cart. 868.6175 Section... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6175 Cardiopulmonary emergency cart...

21 CFR 868.6175 - Cardiopulmonary emergency cart.

Code of Federal Regulations, 2012 CFR

2012-04-01

... cardiopulmonary resuscitation. (b) Classification. Class I (general controls). The device is exempt from the... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiopulmonary emergency cart. 868.6175 Section... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6175 Cardiopulmonary emergency cart...

21 CFR 868.6175 - Cardiopulmonary emergency cart.

Code of Federal Regulations, 2013 CFR

2013-04-01

... cardiopulmonary resuscitation. (b) Classification. Class I (general controls). The device is exempt from the... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiopulmonary emergency cart. 868.6175 Section... (CONTINUED) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6175 Cardiopulmonary emergency cart...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3100 - Amphetamine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Amphetamine test system. 862.3100 Section 862.3100...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

Role of HIV Infection Duration and CD4 Cell Level at Initiation of Combination Anti-Retroviral Therapy on Risk of Failure

PubMed Central

Lodi, Sara; Phillips, Andrew; Fidler, Sarah; Hawkins, David; Gilson, Richard; McLean, Ken; Fisher, Martin; Post, Frank; Johnson, Anne M.; Walker-Nthenda, Louise; Dunn, David; Porter, Kholoud

2013-01-01

Background The development of HIV drug resistance and subsequent virological failure are often cited as potential disadvantages of early cART initiation. However, their long-term probability is not known, and neither is the role of duration of infection at the time of initiation. Methods Patients enrolled in the UK Register of HIV seroconverters were followed-up from cART initiation to last HIV-RNA measurement. Through survival analysis we examined predictors of virologic failure (2HIV-RNA ≥400 c/l while on cART) including CD4 count and HIV duration at initiation. We also estimated the cumulative probabilities of failure and drug resistance (from the available HIV nucleotide sequences) for early initiators (cART within 12 months of seroconversion). Results Of 1075 starting cART at a median (IQR) CD4 count 272 (190,370) cells/mm3 and HIV duration 3 (1,6) years, virological failure occurred in 163 (15%). Higher CD4 count at initiation, but not HIV infection duration at cART initiation, was independently associated with lower risk of failure (p=0.033 and 0.592 respectively). Among 230 patients initiating cART early, 97 (42%) discontinued it after a median of 7 months; cumulative probabilities of resistance and failure by 8 years were 7% (95% CI 4,11) and 19% (13,25), respectively. Conclusion Although the rate of discontinuation of early cART in our cohort was high, the long-term rate of virological failure was low. Our data do not support early cART initiation being associated with increased risk of failure and drug resistance. PMID:24086588

Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma.

PubMed

Feng, Kai-Chao; Guo, Ye-Lei; Liu, Yang; Dai, Han-Ren; Wang, Yao; Lv, Hai-Yan; Huang, Jian-Hua; Yang, Qing-Ming; Han, Wei-Dong

2017-01-05

Cholangiocarcinoma (CCA) is one of the most fatal malignant tumors with increasing incidence, mortality, and insensitivity to traditional chemo-radiotherapy and targeted therapy. Chimeric antigen receptor-modified T cell (CART) immunotherapy represents a novel strategy for the management of many malignancies. However, the potential of CART therapy in treating advanced unresectable/metastatic CCA is uncharted so far. In this case, a 52-year-old female who was diagnosed as advanced unresectable/metastatic CCA and resistant to the following chemotherapy and radiotherapy was treated with CART cocktail immunotherapy, which was composed of successive infusions of CART cells targeting epidermal growth factor receptor (EGFR) and CD133, respectively. The patient finally achieved an 8.5-month partial response (PR) from the CART-EGFR therapy and a 4.5-month-lasting PR from the CART133 treatment. The CART-EGFR cells induced acute infusion-related toxicities such as mild chills, fever, fatigue, vomiting and muscle soreness, and a 9-day duration of delayed lower fever, accompanied by escalation of IL-6 and C reactive protein (CRP), acute increase of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase, and grade 2 lichen striatus-like skin pathological changes. The CART133 cells induced an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release, which needed emergent medical intervention including intravenous methylprednisolone. This case suggests that CART cocktail immunotherapy may be feasible for the treatment of CCA as well as other solid malignancies; however, the toxicities, especially the epidermal/endothelial damages, require a further investigation. ClinicalTrials.gov NCT01869166 and NCT02541370 .

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells.

PubMed

Zhang, Yajing; Zhang, Wenying; Dai, Hanren; Wang, Yao; Shi, Fengxia; Wang, Chunmeng; Guo, Yelei; Liu, Yang; Chen, Meixia; Feng, Kaichao; Zhang, Yan; Liu, Chuanjie; Yang, Qingming; Li, Suxia; Han, Weidong

2016-04-01

Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.

STS-37 crewmembers move CETA electrical cart along rail in JSC's WETF pool

NASA Image and Video Library

1989-12-06

STS-37 Atlantis, Orbiter Vehicle (OV) 104, Mission Specialist (MS) Jerry L. Ross generates electrical power using hand pedals to move crew and equipment translation aid (CETA) cart along a rail during underwater session in JSC's Weightless Environment Training Facility (WETF) Bldg 29. Wearing an extravehicular mobility unit (EMU), Ross operates CETA electrical cart as MS Jerome Apt holds onto the back of the cart. The two crewmembers are practicing a extravehicular activity (EVA) spacewalk they will perform in OV-104's payload bay during STS-37. CETA is a type of railroad hand cart planned as a spacewalker's transportation system along the truss of Space Station Freedom (SSF). SCUBA divers monitor astronauts' underwater activity.

Strategies from a nationwide health information technology implementation: the VA CART story.

PubMed

Box, Tamára L; McDonell, Mary; Helfrich, Christian D; Jesse, Robert L; Fihn, Stephan D; Rumsfeld, John S

2010-01-01

The VA Cardiovascular Assessment, Reporting, and Tracking (CART) system is a customized electronic medical record system which provides standardized report generation for cardiac catheterization procedures, serves as a national data repository, and is the centerpiece of a national quality improvement program. Like many health information technology projects, CART implementation did not proceed without some barriers and resistance. We describe the nationwide implementation of CART at the 77 VA hospitals which perform cardiac catheterizations in three phases: (1) strategic collaborations; (2) installation; and (3) adoption. Throughout implementation, success required a careful balance of technical, clinical, and organizational factors. We offer strategies developed through CART implementation which are broadly applicable to technology projects aimed at improving the quality, reliability, and efficiency of health care.

Genome-wide characterization of monomeric transcriptional regulators in Mycobacterium tuberculosis.

PubMed

Feng, Lipeng; Chen, Zhenkang; Wang, Zhongwei; Hu, Yangbo; Chen, Shiyun

2016-05-01

Gene transcription catalysed by RNA polymerase is regulated by transcriptional regulators, which play central roles in the control of gene transcription in both eukaryotes and prokaryotes. In regulating gene transcription, many regulators form dimers that bind to DNA with repeated motifs. However, some regulators function as monomers, but their mechanisms of gene expression control are largely uncharacterized. Here we systematically characterized monomeric versus dimeric regulators in the tuberculosis causative agent Mycobacterium tuberculosis. Of the >160 transcriptional regulators annotated in M. tuberculosis, 154 transcriptional regulators were tested, 22 % probably act as monomers and most are annotated as hypothetical regulators. Notably, all members of the WhiB-like protein family are classified as monomers. To further investigate mechanisms of monomeric regulators, we analysed the actions of these WhiB proteins and found that the majority interact with the principal sigma factor σA, which is also a monomeric protein within the RNA polymerase holoenzyme. Taken together, our study for the first time globally classified monomeric regulators in M. tuberculosis and suggested a mechanism for monomeric regulators in controlling gene transcription through interacting with monomeric sigma factors.

HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial.

PubMed

Ensoli, Barbara; Nchabeleng, Maphoshane; Ensoli, Fabrizio; Tripiciano, Antonella; Bellino, Stefania; Picconi, Orietta; Sgadari, Cecilia; Longo, Olimpia; Tavoschi, Lara; Joffe, Daniel; Cafaro, Aurelio; Francavilla, Vittorio; Moretti, Sonia; Pavone Cossut, Maria Rosaria; Collacchi, Barbara; Arancio, Angela; Paniccia, Giovanni; Casabianca, Anna; Magnani, Mauro; Buttò, Stefano; Levendal, Elise; Ndimande, John Velaphi; Asia, Bennett; Pillay, Yogan; Garaci, Enrico; Monini, Paolo

2016-06-09

Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa. The ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 μg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4(+) T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4(+) T-cell counts and therapy compliance. Immunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4(+) T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4(+) T-cell numbers over study entry levels as compared to placebo. The data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa. Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012.

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

21 CFR 250.101 - Amphetamine and methamphetamine inhalers regarded as prescription drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Amphetamine and methamphetamine inhalers regarded... DRUGS New Drug or Prescription Status of Specific Drugs § 250.101 Amphetamine and methamphetamine inhalers regarded as prescription drugs. (a) Recurring reports of abuse and misuse of methamphetamine (also...

Amphetamine. Report Series 28, No. 1.

ERIC Educational Resources Information Center

National Inst. on Drug Abuse (DHEW/PHS), Rockville, MD. National Clearinghouse for Drug Abuse Information.

This report, prepared by the National Clearinghouse for Drug Abuse Information, presents substantial information on the use and abuse of the drug "family" known as amphetamines. A brief history of the drug is given, along with its basic pharmacology. The current medical uses for amphetamines include: (1) short-term treatment of obesity,…

Withdrawal from chronic exposure to amphetamine, but not nicotine, leads to an immediate and enduring deficit in motivated behavior without affecting social interaction in rats.

PubMed

Der-Avakian, Andre; Markou, Athina

2010-07-01

Psychostimulant withdrawal leads to depressive symptoms, such as anhedonia and social dysfunction. We determined the effects of withdrawal from chronic exposure to nicotine (9 mg/kg/day salt, 28 days) or amphetamine (10 mg/kg/day salt, 7 days) on the motivated response for a sucrose reward and on social interaction in rats. Both nicotine and amphetamine exposure increased the motivated response for sucrose. However, only spontaneous amphetamine withdrawal led to an immediate and persistent decrease in motivated behavior, which was not correlated with body weight loss. Social interaction was not affected during withdrawal from either drug. These results indicate that withdrawal from chronic amphetamine exposure leads to an immediate and enduring anhedonic state.

A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats.

PubMed

Zovkic, Iva B; McCormick, Cheryl M

2017-11-14

Estradiol moderates the effects of drugs of abuse in both humans and rodents. Estradiol's enhancement of behavioral effects resulting from high (>2.5mg/kg) doses of amphetamine is established in rats; there is less evidence for the role of estradiol in locomotor effects elicited by lower doses, which are less aversive, increase incentive motivation, involve different neural mechanisms than higher doses, and often more readily reveal group differences than do higher doses. Further, the extent to which estradiol is required for the induction versus the expression of sensitization is unknown. To establish a protocol, we replicated the effects of estradiol on locomotor sensitization to amphetamine reported in a previous study that involved a high locomotor-activating dose (1.5mg/kg) of amphetamine, but with a lower dose. Ovariectomized female rats received 5μg of estradiol benzoate (EB) or OIL 30min before each of 5 treatments of 1.0mg/kg amphetamine or saline; all received a 0.5mg/kg challenge dose three days later. Compared with results for OIL, EB enhanced the locomotor-activating effects of repeated 1.0mg/kg amphetamine across treatment days. In contrast, on challenge day, there was no difference between EB-saline and EB-amphetamine to the lower dose (i.e., no sensitization). Experiments 2 and 3 involved a shorter induction (2days) and a lengthier withdrawal (9days) before the challenge test for the expression of sensitization to better differentiate the induction phase from the expression phase. In Expt2, EB-, and not OIL-, treated rats showed sensitization to 0.5mg/kg amphetamine; neither group showed sensitization to 1.5mg/kg amphetamine (ceiling effect?). In Expt3, rats were treated with EB either in both the induction and expression phases, in one of the phases only, or in neither phase. There was an effect of hormone treatment on challenge day and not on induction day; rats given EB on Challenge day showed sensitization to 0.5mg/kg amphetamine; OIL rats did not. The results suggest rapid effects of estradiol on amphetamine sensitization consistent with rapid effects of estradiol reported for other behaviours. Copyright © 2017. Published by Elsevier Inc.

Chimeric peptide-mediated siRNA transduction to inhibit HIV-1 infection.

PubMed

Bivalkar-Mehla, Shalmali; Mehla, Rajeev; Chauhan, Ashok

2017-04-01

Persistent human immunodeficiency virus 1 (HIV-1) infection provokes immune activation and depletes CD4 +  lymphocytes, leading to acquired immunodeficiency syndrome. Uninterrupted administration of combination antiretroviral therapy (cART) in HIV-infected patients suppresses viral replication to below the detectable level and partially restores the immune system. However, cART-unresponsive residual HIV-1 infection and elusive transcriptionally silent but reactivatable viral reservoirs maintain a permanent viral DNA blue print. The virus rebounds within a few weeks after interruption of suppressive therapy. Adjunct gene therapy to control viral replication by ribonucleic acid interference (RNAi) is a post-transcriptional gene silencing strategy that could suppress residual HIV-1 burden and overcome viral resistance. Small interfering ribonucleic acids (siRNAs) are efficient transcriptional inhibitors, but need delivery systems to reach inside target cells. We investigated the potential of chimeric peptide (FP-PTD) to deliver specific siRNAs to HIV-1-susceptible and permissive cells. Chimeric FP-PTD peptide was designed with an RNA binding domain (PTD) to bind siRNA and a cell fusion peptide domain (FP) to enter cells. FP-PTD-siRNA complex entered and inhibited HIV-1 replication in susceptible cells, and could be a candidate for in vivo testing.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

PubMed Central

Barrett, David M.; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.

2016-01-01

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies PMID:27571406

Energy behavior of an electromechanical system with internal impacts and uncertainties

NASA Astrophysics Data System (ADS)

Lima, Roberta; Sampaio, Rubens

2016-07-01

This paper analyzes the maximal energy stored in an elastic barrier due to the impacts of a pendulum fitted within a vibro-impact electromechanical system considering the existence of epistemic uncertainties in the system parameters. The vibro-impact electromechanical system is composed of two subsystems. The first subsystem is the electromechanical system composed by a motor, cart and pendulum, and the second is an elastic barrier. The first will be called striker system. The pendulum is fitted within the cart. Its suspension point is fixed in the cart, so that it may exist a relative motion between cart and pendulum. The influence of the DC motor in the dynamic behavior of the pendulum is considered. The coupling between the motor and the cart is made by a scotch yoke mechanism, so that the motor rotational motion is transformed in horizontal cart motion over a rail. The pendulum is modeled as a mathematical pendulum (bar without mass and particle of mass mp at the end). A flexible barrier, placed inside the cart, constrains the pendulum motion. Due to the relative motion between the cart and the pendulum, impacts may occur between these two elements. The objective of the paper is to analyze the energy stored in the barrier due to impacts as a function of some parameters of the electromechanical system from a deterministic and from a stochastic viewpoint. The system is designed as an aid in drilling. The impacts damage or fracture the rock and facilitate the conventional drilling.

AZ-101 Mixer Pump Demonstration Data Acquisition System and Gamma Cart Data Acquisition Control System Software Configuration Management Plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

WHITE, D.A.

1999-12-29

This Software Configuration Management Plan (SCMP) provides the instructions for change control of the AZ1101 Mixer Pump Demonstration Data Acquisition System (DAS) and the Sludge Mobilization Cart (Gamma Cart) Data Acquisition and Control System (DACS).

The Ballistic Cart on an Incline Revisited.

ERIC Educational Resources Information Center

Serway, Raymond A.; And Others

1995-01-01

Presents the theory behind the mechanics demonstration that involves projecting a ball vertically upward from a ballistic cart moving along an inclined plane. The measured overshoot is believed to be due, in part, to the presence of rolling friction and the inertial properties of the cart wheels. (JRH)

Fan Cart: The Next Generation

ERIC Educational Resources Information Center

Lamore, Brian

2016-01-01

For years the fan cart has provided physics students with an excellent resource for exploring fundamental mechanics concepts such as acceleration, Newton's laws, impulse, momentum, work-energy, and energy conversions. "The Physics Teacher" has even seen some excellent do-it-yourself (DIY) fan carts and activities. If you are interested…

Fatty Acid–Regulated Transcription Factors in the Liver

PubMed Central

Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

2014-01-01

Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

Amphetamine-induced place preference in humans

PubMed Central

Childs, Emma L.; de Wit, Harriet

2009-01-01

Background The conditioned place preference procedure is a widely used animal model of rewarding drug effects that, to date, has not been tested in humans. In this study, we sought to demonstrate that humans, like non-humans, would exhibit a preference for a place previously associated with amphetamine. Further, we investigated the relationship between conditioned place preference and the mood-altering effects of the drug. Methods Thirty-one healthy individuals participated in a five-session procedure during which they experienced the effects of d-amphetamine (20mg) or placebo on two occasions in two distinctive environments (sessions 1 to 4). One group of subjects (paired group, N=19) received amphetamine consistently in one room and placebo in another room, while a second group (unpaired group, N=12) received amphetamine and placebo without regard to the rooms. During the sessions, participants completed questionnaires to rate their mood. On the fifth session, they rated their preference for the two rooms. Results Individuals in the paired group rated their liking of the amphetamine-paired room significantly higher than the placebo-associated room, while there was no difference between ratings of the two rooms for individuals in the unpaired group. In the paired group, drug liking ratings during the conditioning sessions positively predicted preference for the drug-associated room, whereas reports of amphetamine-induced anxiety and dysphoria negatively predicted room liking scores. Conclusions This study demonstrates that humans, like non-humans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning. PMID:19111278

Does COMT genotype influence the effects of d-amphetamine on executive functioning?

PubMed Central

Wardle, Margaret C.; Hart, Amy B.; Palmer, Abraham A.; de Wit, Harriet

2012-01-01

In a widely cited study, Mattay et al. (2003) reported that amphetamine (0.25 mg/kg oral, or 17mg for a 68kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5mg, 10mg, and 20mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions, and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. (Mattay et al., 2003). We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research. PMID:23231539

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction.

PubMed

Simon, Nicholas W; Setlow, Barry

2006-11-01

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.

Preventing growth in amphetamine use: long-term effects of the Midwestern Prevention Project (MPP) from early adolescence to early adulthood.

PubMed

Riggs, Nathaniel R; Chou, Chih-Ping; Pentz, Mary Ann

2009-10-01

The aim of the current study was to examine the long-term effect of an early adolescent substance abuse prevention program on trajectories and initiation of amphetamine use into early adulthood. Eight middle schools were assigned randomly to a program or control condition. The randomized controlled trial followed participants through 15 waves of data, from ages 11-28 years. This longitudinal study design includes four separate periods of development from early adolescence to early adulthood. The intervention took place in middle schools. A total of 1002 adolescents from one large mid-western US city were the participants in the study. The intervention was a multi-component community-based program delivered in early adolescence with a primary emphasis on tobacco, alcohol and marijuana use. At each wave of data collection participants completed a self-report survey that included questions about life-time amphetamine use. Compared to a control group, participants in the Midwestern Prevention Project (MPP) intervention condition had reduced growth (slope) in amphetamine use in emerging adulthood, a lower amphetamine use intercept at the commencement of the early adulthood and delayed amphetamine use initiation. The pattern of results suggests that the program worked first to prevent amphetamine use, and then to maintain the preventive effect into adulthood. Study findings suggest that early adolescent substance use prevention programs that focus initially on the 'gateway' drugs have utility for long-term prevention of amphetamine use. © 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction.

iTAK: A program for genome-wide prediction and classification of plant transcription factors, transcriptional regulators and protein kinases

USDA-ARS?s Scientific Manuscript database

Transcription factors (TFs) are proteins that regulate the expression of target genes by binding to specific elements in their regulatory regions. Transcriptional regulators (TRs) also regulate the expression of target genes; however, they operate indirectly via interaction with the basal transcript...

Engineer pedals STS-37 CETA electrical cart along track in JSC MAIL Bldg 9A

NASA Technical Reports Server (NTRS)

1990-01-01

McDonnell Douglas engineer Gary Peters operates crew and equipment translation aid (CETA) electrical hand pedal cart in JSC's Mockup and Integration Laboratory (MAIL) Bldg 9A. Peters, wearing extravehicular mobility unit (EMU) boots and positioned in portable foot restraint (PFR), is suspended above CETA cart and track via harness to simulate weightlessness. The electrical cart is moved by electricity generated from turning hand pedals. CETA will be tested in orbit in the payload bay of Atlantis, Orbiter Vehicle (OV) 104, during STS-37.

Apparatus and method for servicing an elongated suspended pump motor in an electric power plant with limited access

DOEpatents

Chavez, Rossemary V.; Ekeroth, Douglas E.; Johnson, F. Thomas; Matusz, John M.

1994-01-01

Elongated coolant pumps suspended under steam generators within containment in a power plant with limited access space, are removed and replaced by an elongated maintenance cart with an elongated opening along one side in which the motor is received. Rollers support the cart for conveying the elongated motor in an upright position out from under the steam generator and onto an elevator. The elevator is lowered to transfer support of the cart and motor through trunnions to saddles straddling the elevator for rotation of the cart to a generally horizontal position. The elevator then raises the horizontally disposed cart carrying the motor to a higher floor where it is rolled off the elevator and out through the auxiliary equipment hatch.

Apparatus and method for servicing an elongated suspended pump motor in an electric power plant with limited access

DOEpatents

Chavez, R.V.; Ekeroth, D.E.; Johnson, F.T.; Matusz, J.M.

1994-04-26

Elongated coolant pumps suspended under steam generators within containment in a power plant with limited access space, are removed and replaced by an elongated maintenance cart with an elongated opening along one side in which the motor is received. Rollers support the cart for conveying the elongated motor in an upright position out from under the steam generator and onto an elevator. The elevator is lowered to transfer support of the cart and motor through trunnions to saddles straddling the elevator for rotation of the cart to a generally horizontal position. The elevator then raises the horizontally disposed cart carrying the motor to a higher floor where it is rolled off the elevator and out through the auxiliary equipment hatch. 14 figures.

Nursing perception of the impact of medication carts on patient safety and ergonomics in a teaching health care center.

PubMed

Rochais, Élise; Atkinson, Suzanne; Bussières, Jean-François

2013-04-01

In our Quebec (Canada) University Hospital Center, 68 medication carts have been implemented as part of a nationally funded project on drug distribution technologies. There are limited data published about the impact of medication carts in point-of-care units. Our main objective was to assess nursing staff's perception and satisfaction of medication carts on patient safety and ergonomics. Quantitative and qualitative cross-sectional study. Data were gathered from a printed questionnaire administered to nurses and an organized focus group composed of nurses and pharmacists. A total of 195 nurses completed the questionnaire. Eighty percent of the nurses agreed that medication carts made health care staff's work easier and 64% agreed that it helped to reduce medication incidents/accidents. Only 27% and 43% agreed that carts' location reduces the risk of patients' interruptions and colleagues' interruptions, respectively. A total of 17 suggestions were extracted from the focus group (n = 7 nurses; n = 3 pharmacist) and will be implemented in the next year. This descriptive study confirms the positive perception and satisfaction of nurses exposed to medication carts. However, interruptions are a major concern and source of dissatisfaction. The focus group has revealed many issues which will be improved.

Literature Review: Update on Amphetamine Neurotoxicity and Its Relevance to the Treatment of ADHD

ERIC Educational Resources Information Center

Advokat, Claire

2007-01-01

Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain information on the long-term neurological consequences of this therapy. Method: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed…

Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries.

PubMed

del Amo, Julia; Moreno, Santiago; Bucher, Heiner C; Furrer, Hansjakob; Logan, Roger; Sterne, Jonathan; Pérez-Hoyos, Santiago; Jarrín, Inma; Phillips, Andrew; Lodi, Sara; van Sighem, Ard; de Wolf, Wolf; Sabin, Caroline; Bansi, Loveleen; Justice, Amy; Goulet, Joseph; Miró, José M; Ferrer, Elena; Meyer, Laurence; Seng, Rémonie; Toulomi, Giota; Gargalianos, Panagiotis; Costagliola, Dominique; Abgrall, Sophie; Hernán, Miguel A

2012-05-01

The lower tuberculosis incidence reported in human immunodeficiency virus (HIV)-positive individuals receiving combined antiretroviral therapy (cART) is difficult to interpret causally. Furthermore, the role of unmasking immune reconstitution inflammatory syndrome (IRIS) is unclear. We aim to estimate the effect of cART on tuberculosis incidence in HIV-positive individuals in high-income countries. The HIV-CAUSAL Collaboration consisted of 12 cohorts from the United States and Europe of HIV-positive, ART-naive, AIDS-free individuals aged ≥18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996 through 2007. We estimated hazard ratios (HRs) for cART versus no cART, adjusted for time-varying CD4 cell count and HIV RNA level via inverse probability weighting. Of 65 121 individuals, 712 developed tuberculosis over 28 months of median follow-up (incidence, 3.0 cases per 1000 person-years). The HR for tuberculosis for cART versus no cART was 0.56 (95% confidence interval [CI], 0.44-0.72) overall, 1.04 (95% CI, 0.64-1.68) for individuals aged >50 years, and 1.46 (95% CI, 0.70-3.04) for people with a CD4 cell count of <50 cells/μL. Compared with people who had not started cART, HRs differed by time since cART initiation: 1.36 (95% CI, 0.98-1.89) for initiation <3 months ago and 0.44 (95% CI, 0.34-0.58) for initiation ≥3 months ago. Compared with people who had not initiated cART, HRs <3 months after cART initiation were 0.67 (95% CI, 0.38-1.18), 1.51 (95% CI, 0.98-2.31), and 3.20 (95% CI, 1.34-7.60) for people <35, 35-50, and >50 years old, respectively, and 2.30 (95% CI, 1.03-5.14) for people with a CD4 cell count of <50 cells/μL. Tuberculosis incidence decreased after cART initiation but not among people >50 years old or with CD4 cell counts of <50 cells/μL. Despite an overall decrease in tuberculosis incidence, the increased rate during 3 months of ART suggests unmasking IRIS.

Plasma cytokine profiles in HIV-1 infected patients developing neuropathic symptoms shortly after commencing antiretroviral therapy: a case-control study.

PubMed

Van der Watt, Johan J; Wilkinson, Katalin A; Wilkinson, Robert J; Heckmann, Jeannine M

2014-02-10

In patients infected with human immunodeficiency virus 1 (HIV-1) neuropathic symptoms may develop within weeks of starting combination antiretroviral therapy (cART). This timing coincides with the occurrence of immune reconstitution inflammatory syndrome. Our objective was to investigate the longitudinal association of plasma cytokine and soluble receptor concentrations with incident neuropathic symptoms within 12 weeks of starting programme-based cART in a nested case-control study. One hundred and twenty adults without neuropathic symptoms and about to initiate cART were followed longitudinally for 24 weeks after cART initiation. Subjects were examined for peripheral neuropathy at baseline (pre-cART) and 2-, 4-, 12- and 24 weeks thereafter. Individuals developing neuropathic symptoms within 12 weeks of starting cART were matched in a nested case-control design with those remaining symptom-free for at least 24 weeks. Plasma was collected at each visit. Cytokines and soluble receptors were quantified using multiplex immunometric assays. Incident neuropathic symptoms occurred in 32 (27%) individuals within 12 weeks of starting cART for the first time. Cytokine concentrations increased at 2 weeks, irrespective of symptom-status, returning to baseline concentrations at 12 weeks. Compared to the control group, the symptomatic group had higher baseline levels of interleukin-1 receptor (IL-1R)-antagonist. The symptomatic group also showed greater increases in soluble interleukin-2 receptor-alpha and tumour necrosis factor (TNF) receptor-II levels at week 2 and soluble interleukin-6 receptor levels at week 12. Ratios of pro-inflammatory- vs anti-inflammatory cytokines were higher for TNF-alpha/IL-4 (p = 0.022) and interferon-gamma/IL-10 (p = 0.044) in those developing symptoms. After 24 weeks of cART, the symptomatic group showed higher CD4+ counts (p = 0.002). The initiation of cART in previously treatment naïve individuals was associated with a cytokine 'burst' between 2- and 4 weeks compared with pre-cART levels. Individuals developing neuropathic symptoms within 12 weeks of starting cART showed evidence of altered cytokine concentrations even prior to initiating cART, most notably higher circulating IL-1R-antagonist levels, and altered ratios of "pain-associated" cytokine and soluble receptors shortly after cART initiation.

Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine.

PubMed

Musshoff, F

2000-02-01

The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.

Mechanisms of specificity in neuronal activity-regulated gene transcription

PubMed Central

Lyons, Michelle R.; West, Anne E.

2011-01-01

The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain. PMID:21620929

One day of motor training with amphetamine impairs motor recovery following spinal cord injury.

PubMed

Wong, Jamie K; Steward, Oswald

2012-02-01

It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague-Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury because early training with amphetamine increases lesion severity. Copyright © 2011 Elsevier Inc. All rights reserved.

The stigmatisation of 'ice' and under-reporting of meth/amphetamine use in general population surveys: A case study from Australia.

PubMed

Chalmers, Jenny; Lancaster, Kari; Hughes, Caitlin

2016-10-01

Stigmatisation of illicit drug use is known to discourage people from reporting their use of illicit drugs. In the context of Australia's two recent "ice-epidemics" this study examines whether rapid increases in community concern about meth/amphetamine concurrent with increased stigmatising media reporting about meth/amphetamine "epidemics" are associated with increased under-reporting of its use in population surveys. We examined the relationship between general population trends in self-reported lifetime use of and attitudes towards meth/amphetamine between 2001 and 2013, contextualised against related stimulants and heroin, using five waves of Australia's National Drug Strategy Household Survey (NDSHS), alongside trends in print media reporting on meth/amphetamine from 2001 to 2014. Analysis of NDSHS data showed significant increases in community concern about meth/amphetamine between 2004 and 2007, and 2010 and 2013 in all birth cohorts and age groups. In both periods self-reported lifetime use of meth/amphetamine fell in many birth cohorts. The falls were only statistically significant in the first period, for birth cohorts from 1961-1963 to 1973-1975. Falls in lifetime use within a cohort from one period to the next are incongruous and we did not observe them in the other drugs considered. Equally, increases in concern were specific to meth/amphetamine. We counted substantial and rapid increase in the number of newspaper reports about meth/amphetamine in both periods, particularly reports including the term 'epidemic'. Rapid increases in the quantum of media reporting stigmatising a drug (through its construction as an 'epidemic') accompanying increased general public concerns about the drug may increase the tendency to under-report lifetime use. This may make it difficult to rely upon household surveys to observe trends in patterns of use and suggests that policy makers, media and others in the AOD sector should avoid stigmatisation of drugs, particularly during periods of heightened concern. Copyright © 2016 Elsevier B.V. All rights reserved.

Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release.

PubMed

Carli, Mirjana; Kostoula, Chrysaugi; Sacchetti, Giuseppina; Mainolfi, Pierangela; Anastasia, Alessia; Villani, Claudia; Invernizzi, Roberto William

2015-11-01

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2(-/-) mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2(-/-) mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2(-/-) mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2(-/-) mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2. © 2015 International Society for Neurochemistry.

The Impact of Illicit Use of Amphetamine on Male Sexual Functions.

PubMed

Chou, Nan-Hua; Huang, Yung-Jui; Jiann, Bang-Ping

2015-08-01

Data concerning the impact of amphetamine on male sexual functions are limited, although amphetamine has been used as an aphrodisiac. This cross-sectional study was to assess the impact of illicit use of amphetamine on male sexual functions. Male illicit drug users in a Drug Abstention and Treatment Center were recruited to complete a self-administered questionnaire, and data were compared with age-matched controls. The International Index of Erectile Function (IIEF) and global assessment questions were used to assess sexual functions. Of 1,159 amphetamine mono-illicit drug users, the mean age was 31.9 ± 7.5 (18-57) years, and mean duration of drug use was 30.7 ± 52.2 (median 9, range 0.1-252) months. Half of them reported that drug use had no impact on their sexual functions. The other half reported drug impacts as reduced erectile rigidity and sexual life satisfaction, enhanced orgasmic intensity, and prolonged ejaculation latency time more often than the opposite effects, while they reported enhanced or reduced effect equally on sexual desire. Dosing frequency of amphetamine was associated with its impact on sexual functions, but duration of its use had little association with that. Compared with 211 age-matched controls, the amphetamine mono-illicit drug users had lower IIEF scores in the domains of erectile function, orgasmic function, and overall satisfaction, but there are no significant differences in intercourse satisfaction and sexual desire scores. The prevalence of erectile dysfunction (ED) was significantly higher in the drug users than in the controls (29.3% vs. 11.9%). The odds ratio of ED for amphetamine use was 2.1 (95% confidence interval 1.2-3.6) after adjustment for other risk factors. The impact of illicit use of amphetamine on male sexual functions varied among users, and their ED prevalence was higher than the controls. © 2015 International Society for Sexual Medicine.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

PubMed Central

Hutsell, Blake A.; Blough, Bruce E.; Poklis, Justin L.; Negus, S. Stevens

2015-01-01

Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown. Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction. PMID:25618405

Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Côte d'Ivoire.

PubMed

Pasquet, Armelle; Messou, Eugène; Gabillard, Delphine; Minga, Albert; Depoulosky, Ayeby; Deuffic-Burban, Sylvie; Losina, Elena; Freedberg, Kenneth A; Danel, Christine; Anglaret, Xavier; Yazdanpanah, Yazdan

2010-10-15

To evaluate the type and frequency of antiretroviral drug stock-outs, and their impact on death and interruption in care among HIV-infected patients in Abidjan, Côte d'Ivoire. We conducted a cohort study of patients who initiated combination antiretroviral therapy (cART) in three adult HIV clinics between February 1, 2006 and June 1, 2007. Follow-up ended on February 1, 2008. The primary outcome was cART regimen modification, defined as at least one drug substitution, or discontinuation for at least one month due to drug stock-outs at the clinic pharmacy. The secondary outcome for patients who were on cART for at least six months was interruption in care, or death. A Cox regression model with time-dependent variables was used to assess the impact of antiretroviral drug stock-outs on interruption in care or death. Overall, 1,554 adults initiated cART and were followed for a mean of 13.2 months. During this time, 72 patients discontinued treatment and 98 modified their regimen because of drug stock-outs. Stock-outs involved nevirapine and fixed-dose combination zidovudine/lamivudine in 27% and 51% of cases. Of 1,554 patients, 839 (54%) initiated cART with fixed-dose stavudine/lamivudine/nevirapine and did not face stock-outs during the study period. Among the 975 patients who were on cART for at least six months, stock-out-related cART discontinuations increased the risk of interruption in care or death (adjusted hazard ratio [HR], 2.83; 95%CI, 1.25-6.44) but cART modifications did not (adjusted HR, 1.21; 95%CI, 0.46-3.16). cART stock-outs affected at least 11% of population on treatment. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption in care or death. These stock-outs did not involve the most common first-line regimen. As access to cART continues to increase in sub-Saharan Africa, first-line regimens should be standardized to decrease the probability of drug stock-outs.

Recoverable hearing loss with amphetamines and other drugs.

PubMed

Iqbal, Nayyer

2004-06-01

Prolonged and sustained consumption of alcohol, heroin and volatiles had been reported to impair hearing. Amphetamine related hearing loss is clinically different from the hearing loss seen with other agents. It seems that illicit drug use could result in two clinically different types of hearing losses. In May and June of 2001, 183 men aged 18 and above who met DSM-IV criteria for substance dependence were studied in a hospital in Saudia Arabia. The purpose of the study was to ascertain the prevalence of amphetamine-related recoverable hearing loss, establish whether similar hearing loss also occurred with other drugs of abuse and determine if drug-related psychosis was more prevalent in those amphetamine users who developed this type of hearing loss. Recoverable type of hearing loss was not just seen in amphetamine users but also occurred with cannabis, heroin, alcohol, dextromethorphan and glue use. Drug-induced psychosis was three and a half times more common in those amphetamine users who developed a hearing loss. Major depression and suicidality was also more common in these individuals. This association of major depression and subsequent development of hearing loss was also found in those using other type of drugs. It was concluded that a history of major depression was a good predictor of later development of both drug-induced psychosis and hearing loss in amphetamine users, and hypoperfusion was proposed as the possible explanation.

Brain abnormalities detected on magnetic resonance imaging of amphetamine users presenting to an emergency department: a pilot study.

PubMed

Fatovich, Daniel M; McCoubrie, David L; Song, Swithin J; Rosen, David M; Lawn, Nick D; Daly, Frank F

2010-09-06

To determine the prevalence of occult brain abnormalities in magnetic resonance imaging of active amphetamine users. Prospective convenience study in a tertiary hospital emergency department (ED). Patients presenting to the ED for an amphetamine-related reason were eligible for inclusion. We collected demographic data, drug use data, and performed a mini-mental state examination (MMSE). The proportion of patients with an abnormality on their MRI scan. Of 38 patients enrolled, 30 had MRI scans. Nineteen were male and their mean age was 26.7 +/- 5.4 years (range 19-41 years). The mean age of first amphetamine use was 18 years (range 13-26 years). Sixteen patients used crystal methamphetamine (mean amount 2.5 g/week), nine used amphetamine ("speed") (mean amount 2.9 g/week), and 23 used ecstasy (mean amount 2.3 tablets/week). Marijuana was smoked by 26 (mean amount 5.9 g/week), and 28 drank alcohol (mean amount 207 g/week). The median MMSE score was 27/30 (interquartile range, 26-29). Abnormalities on brain MRI scans were identified in six patients, most commonly an unidentified bright object (n = 4). In this pilot study of brain MRI of young people attending the ED with an amphetamine-related presentation, one in five had an occult brain lesion. While the significance of this is uncertain, it is congruent with evidence that amphetamines cause brain injury.

Caffeine induces differential cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic agonists.

PubMed

Jain, Raka; Holtzman, Stephen G

2005-05-15

The purpose of this study was to determine if caffeine induces cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic drugs that act through distinct mechanisms (e.g., release, uptake inhibition, direct activation of dopamine D(1)- or D(2)-family receptors). Rats were trained to discriminate 1.0 mg/kg d-amphetamine from saline in a two-choice discrete-trial procedure. Stimulus-generalization curves were generated by cumulative dosing for d-amphetamine (0.1-1.0 mg/kg), methylphenidate (0.3-5.6 mg/kg), SKF 81297 (0.3-3.0 mg/kg), and R-(-)-propylnorapomorphine (NPA; 0.001-1.78 mg/kg), as well as for caffeine (3.0-56 mg/kg); curves were re-determined after twice daily injections of caffeine (30 mg/kg) for 3.5 days. The rats generalized dose dependently to the four dopaminergic drugs, but only to a limited extent to caffeine. Twice daily injections of caffeine induced significant cross tolerance (i.e., increased ED(50)) to the amphetamine-like discriminative effects of methylphenidate and SKF 81297, attenuated non-significantly the effects of NPA, and did not alter the effects of amphetamine. Thus, caffeine produces differential cross tolerance to the amphetamine-like discriminative effects of dopaminergic drugs, a phenomenon in which the dopamine D(1) receptor appears to have an important role.

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review].

PubMed

Zuo, Yingxi; Wang, Jingbo; Lu, Aidong; Jia, Yueping; Wu, Jun; Dong, Lujia; Chang, Lungji; Zhang, Leping

2016-02-01

To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL). A relapsed B-ALL child after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was treated with CAR-T, and the related literatures were reviewed. An 11-year-old girl with TEL-AML1 fusion gene positive BALL who suffered a bone marrow relapse 28 months after remission from conventional chemotherapy. During the second remission, the patient received haploidentical allo-HSCT. She relapsed with detectable TEL-AML1 fusion gene even after chemotherapy and donor leukocyte infusions. She received an experimental donor-derived fourth generation CD19 CAR-T therapy. After infusion of 1 × 10(6)/kg CAR-T cells, she experienced only mild or moderate cytokine-release syndrome and the minimal residual disease turned negative. Then three maintenance of CAR-T cell infusions [(0.83-1.65)×10(6)/kg] was administered, and the disease-free survival had lasted for 10 months. However, the TEL-AML1 copies in her blood still increased and she died with leukemia relapse after additional CAR-T cell infusion. Treatment of relapsed B-ALL with the fourth generation CAR-T cells directed against CD19 was effective and safe. CAR-T therapy is a novel therapeutic approach that could be useful for patients with relapsed and refractory B-ALL who have failed all other treatment options.

The PASCO Wireless Smart Cart: A Game Changer in the Undergraduate Physics Laboratory

ERIC Educational Resources Information Center

Shakur, Asif; Connor, Rainor

2018-01-01

With the introduction of the Wireless Smart Cart by PASCO scientific in April 2016, we expect a paradigm shift in undergraduate physics laboratory instruction. We have evaluated the feasibility of using the smart cart by carrying out experiments that are usually performed using traditional PASCO equipment. The simplicity, convenience, and…

CART (Communication Access Realtime Translation). PEPNet Tipsheet

ERIC Educational Resources Information Center

Larson, Judy, Comp.

1999-01-01

Communication Access Realtime Translation--(CART)--is the instant translation of the spoken word into English text performed by a CART reporter using a stenotype machine, notebook computer and realtime software. The text is then displayed on a computer monitor or other display device for the student who is deaf or hard of hearing to read. This…

Boltushka: A Homemade Amphetamine-Type Stimulant and HIV Risk in Odessa, Ukraine

PubMed Central

Chintalova-Dallas, Repsina; Case, Patricia; Kitsenko, Nataliya; Lazzarini, Zita

2009-01-01

Background Homemade amphetamine-type stimulants (ATSs) have been reported in Russia and Eastern Europe for decades. Recipes differ geographically and over time producing differing active ingredients. Vint and jeff (active ingredients methamphetamine and methcathinone, respectively) are two such homemade ATSs originally produced from over-the-counter cold medications and household chemicals. Methods During a Rapid Policy Assessment and Responses (RPAR) project in Odessa, Ukraine, researchers found use of boltushka, a novel homemade ATS. Fourteen supplemental qualitative interviews were conducted, including ten interviews with boltushka injectors and four interviews with pharmacists. We report patterns of boltushka use among local injection drug users (IDUs) as well as the role of laws, regulations, and current pharmacy practices. Results Legal restrictions on over-the-counter cold medicines in Ukraine led to products containing phenypropanolamine (PPA), which oxidized with KMnO4 (potassium permanganate), produces a weak ATS, cathinone, called boltushka. Boltushka’s ingredients are easily available in pharmacies or on the black market. IDUs reported a mean age at first use of 16 years old (range 12–21). While published data are scant, anecdotal evidence reported here include amphetamine-like effects on energy and appetite, binging patterns of use, and some reports of shaking and other neurological damage consistent with earlier reports from exposure to KMnO4. Users reported sharing syringes and other non-sterile injection practices. No users reported specific treatment or prevention programs for boltushka users. Conclusions Although Ukrainian government regulations have limited access to precursor chemicals, IDUs have continued to make and use boltushka. The actual extent and demographics of boltushka use are unknown. Besides risk of bloodborne disease, the health effects of injected homemade ATSs and their constituent chemicals are poorly documented. Interventions beyond available harm reduction efforts may be required. Education/treatment specific to boltushka users and screening for other physical harms are critical interventions. PMID:18976896

Substance use and adherence among people living with HIV/AIDS receiving cART in Latin America

PubMed Central

De Boni, Raquel B.; Shepherd, Bryan E.; Grinsztejn, Beatriz; Cesar, Carina; Cortés, Claudia; Padgett, Denis; Gotuzzo, Eduardo; Belaunzarán-Zamudio, Pablo F.; Rebeiro, Peter F.; Duda, Stephany N.; McGowan, Catherine C.

2016-01-01

This cross-sectional study describes substance use prevalence and its association with cART adherence among 3343 individuals receiving care at HIV clinics in Argentina, Brazil, Chile, Honduras, Mexico, and Peru. A rapid screening tool evaluated self-reported 7-day recall of alcohol, marijuana, cocaine, heroin, and methamphetamine use, and missed cART doses. Overall, 29.3% individuals reported having ≥ 1 alcoholic drinks, 5.0% reported any illicit drug use and 17.0% reported missed cART doses. In the logistic regression model, compared to no substance use, alcohol use (adjusted odds ratio (AOR)=2.46, 95% confidence interval (CI): 1.99–3.05), illicit drug use (AOR=3.57, 95% CI: 2.02–6.30), and using both alcohol and illicit drugs (AOR=4.98, 95% CI: 3.19–7.79) were associated with missed cART doses. The associations between substance use and likelihood of missing cART doses point to the need of targeting alcohol and illicit drug use to improve adherence among people living with HIV in Latin America. PMID:27091028

A novel statistical approach for identification of the master regulator transcription factor.

PubMed

Sikdar, Sinjini; Datta, Susmita

2017-02-02

Transcription factors are known to play key roles in carcinogenesis and therefore, are gaining popularity as potential therapeutic targets in drug development. A 'master regulator' transcription factor often appears to control most of the regulatory activities of the other transcription factors and the associated genes. This 'master regulator' transcription factor is at the top of the hierarchy of the transcriptomic regulation. Therefore, it is important to identify and target the master regulator transcription factor for proper understanding of the associated disease process and identifying the best therapeutic option. We present a novel two-step computational approach for identification of master regulator transcription factor in a genome. At the first step of our method we test whether there exists any master regulator transcription factor in the system. We evaluate the concordance of two ranked lists of transcription factors using a statistical measure. In case the concordance measure is statistically significant, we conclude that there is a master regulator. At the second step, our method identifies the master regulator transcription factor, if there exists one. In the simulation scenario, our method performs reasonably well in validating the existence of a master regulator when the number of subjects in each treatment group is reasonably large. In application to two real datasets, our method ensures the existence of master regulators and identifies biologically meaningful master regulators. An R code for implementing our method in a sample test data can be found in http://www.somnathdatta.org/software . We have developed a screening method of identifying the 'master regulator' transcription factor just using only the gene expression data. Understanding the regulatory structure and finding the master regulator help narrowing the search space for identifying biomarkers for complex diseases such as cancer. In addition to identifying the master regulator our method provides an overview of the regulatory structure of the transcription factors which control the global gene expression profiles and consequently the cell functioning.

Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

PubMed Central

Singer, Bryan F; Neugebauer, Nichole M; Forneris, Justin; Rodvelt, Kelli R; Li, Dongdong; Bubula, Nancy; Vezina, Paul

2014-01-01

Intermittent systemic exposure to psychostimulants such as amphetamine leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying each of these forms of plasticity. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density in this site and enhances the locomotor sensitization normally observed following repeated cocaine. Mice lacking the Kal7 gene display similar phenotypes suggesting that locomotor sensitization and increased NAcc spine density need not be positively correlated. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threoninealanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site. PMID:24939858

Chronic (-)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats.

PubMed

Gorriti, M A; Rodríguez de Fonseca, F; Navarro, M; Palomo, T

1999-01-22

Clinical and basic research studies have linked cannabinoid consumption to the onset of psychosis, specially schizophrenia. In the present study we have evaluated the effects of the natural psychoactive constituent of Cannabis (-)-delta9-tetrahydrocannabinol on the acute actions of the psychostimulant, D-amphetamine, on behaviour displayed by male rats on a hole-board, a proposed animal model of amphetamine-induced psychosis. Cannabinoid-amphetamine interactions were studied (1) 30 min after acute injection of (-)-delta9-tetrahydrocannabinol (0.1 or 6.4 mg/kg, i.p.); (2) 30 min after the last injection of 14-daily treatment with (-)-delta9-tetrahydrocannabinol (0.1 or 6.4 mg/kg) and 3) 24 h after the last injection of 14-daily treatment with (-)-delta9-tetrahydrocannabinol (6.4 mg/kg). Acute cannabinoid exposure antagonized the amphetamine-induced dose-dependent increase in locomotion, exploration and the decrease in inactivity. Chronic treatment with (-)-delta9-tetrahydrocannabinol resulted in tolerance to this antagonistic effect on locomotion and inactivity but not on exploration, and potentiated amphetamine-induced stereotypies. Lastly, 24 h of withdrawal after 14 days of cannabinoid treatment resulted in sensitization to the effects of D-amphetamine on locomotion, exploration and stereotypies. Since (-)-delta9-tetrahydrocannabinol is a cannabinoid CB1 receptor agonist, densely present in limbic and basal ganglia circuits, and since amphetamine enhances monoaminergic inputs (i.e., dopamine, serotonin) in these brain areas, the present data support the hypothesis of a role for the cannabinoid CB1 receptor as a regulatory mechanism of monoaminergic neuron-mediated psychomotor activation. These findings may be relevant for the understanding of both cannabinoid-monoamines interactions and Cannabis-associated psychosis.

Maintaining class, producing gender: enhancement discourses about amphetamine in entertainment media.

PubMed

McKenna, Stacey A

2011-11-01

Since the 1930s, amphetamine has been used for a variety of socially and medically condoned purposes including personal and performance enhancement. In the contemporary U.S., although amphetamine and its derivatives share a history, similar chemical composition, and physiological and psychiatric effects, they are typically treated and researched as two distinct groups: illegally produced methamphetamine and prescription amphetamine. This study is an examination of the social meanings of these categories and their users as represented in popular media. To complement existing research on drug discourses in popular news media, this study analysed entertainment media: ten novels, three seasons of Breaking Bad, six television episodes, and eight movies. Media were coded inductively and deductively using tenets of critical discourse analysis and rhetorical criticism. The author identified discourses about user subject positions and ideologies pertaining to enhancement-related motivations for use. Two important themes emerged from this analysis that construct amphetamine use and users in ways that reflect, legitimize and reproduce class and gender ideologies. First, discourses illustrate that distinct meanings of methamphetamine versus prescription amphetamine are linked to expectations about the respective socioeconomic class and social status of their users. Second, the discourses reflect gendered values and ideals about productivity and sexuality. In reality, American cultural and political-economic contexts may encourage the use of amphetamine to meet a variety of social expectations and economic needs. However, many policy and prevention efforts surrounding amphetamine use disproportionately target methamphetamine users and women. Because policy and prevention efforts can be influenced as much by social values as by data, it is important to examine the many arenas in which social values are produced and disseminated. Copyright © 2011 Elsevier B.V. All rights reserved.

Abuse of Amphetamines and Structural Abnormalities in Brain

PubMed Central

Berman, Steven; O’Neill, Joseph; Fears, Scott; Bartzokis, George; London, Edythe D.

2009-01-01

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse, and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques that include manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common, and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre-existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure. PMID:18991959

Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine.

PubMed

Parkinson, J A; Olmstead, M C; Burns, L H; Robbins, T W; Everitt, B J

1999-03-15

Dopamine release within the nucleus accumbens (NAcc) has been associated with both the rewarding and locomotor-stimulant effects of abused drugs. The functions of the NAcc core and shell were investigated in mediating amphetamine-potentiated conditioned reinforcement and locomotion. Rats were initially trained to associate a neutral stimulus (Pavlovian CS) with food reinforcement (US). After excitotoxic lesions that selectively destroyed either the NAcc core or shell, animals underwent additional CS-US training sessions and then were tested for the acquisition of a new instrumental response that produced the CS acting as a conditioned reinforcer (CR). Animals were infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 microg) before each session. Shell lesions affected neither Pavlovian nor instrumental conditioning but completely abolished the potentiative effect of intra-NAcc amphetamine on responding with CR. Core-lesioned animals were impaired during the Pavlovian retraining sessions but showed no deficit in the acquisition of responding with CR. However, the selectivity in stimulant-induced potentiation of the CR lever was reduced, as intra-NAcc amphetamine infusions dose-dependently increased responding on both the CR lever and a nonreinforced (control) lever. Shell lesions produced hypoactivity and attenuated amphetamine-induced activity. In contrast, core lesions resulted in hyperactivity and enhanced the locomotor-stimulating effect of amphetamine. These results indicate a functional dissociation of subregions of the NAcc; the shell is a critical site for stimulant effects underlying the enhancement of responding with CR and locomotion after intra-NAcc injections of amphetamine, whereas the core is implicated in mechanisms underlying the expression of CS-US associations.

Genetic Variation of the Ghrelin Signalling System in Individuals with Amphetamine Dependence

PubMed Central

Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A.; Franck, Johan

2013-01-01

The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders. PMID:23579732

Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

PubMed

Suchankova, Petra; Jerlhag, Elisabet; Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A; Franck, Johan

2013-01-01

The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels.

PubMed

Assis, María Amparo; Valdomero, Analía; García-Keller, Constanza; Sotomayor, Claudia; Cancela, Liliana Marina

2011-05-01

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level. Copyright © 2011 Elsevier Inc. All rights reserved.

The N Terminus of Monoamine Transporters Is a Lever Required for the Action of Amphetamines*

PubMed Central

Sucic, Sonja; Dallinger, Stefan; Zdrazil, Barbara; Weissensteiner, René; Jørgensen, Trine N.; Holy, Marion; Kudlacek, Oliver; Seidel, Stefan; Cha, Joo Hwan; Gether, Ulrik; Newman, Amy H.; Ecker, Gerhard F.; Freissmuth, Michael; Sitte, Harald H.

2010-01-01

The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). We explored the functional importance of the N terminus in mediating the action of amphetamines by focusing initially on the highly conserved threonine residue at position 81, a candidate site for phosphorylation by protein kinase C. Molecular dynamics simulations of the wild type SERT, compared with its mutations SERTT81A and SERTT81D, suggested structural changes in the inner vestibule indicative of an opening of the inner vestibule. Predictions from this model (e.g. the preferential accumulation of SERTT81A in the inward conformation, its reduced turnover number, and a larger distance between its N and C termini) were verified. Most importantly, SERTT81A (and the homologous mutations in noradrenaline and dopamine) failed to support amphetamine-induced efflux, and this was not remedied by aspartate at this position. Amphetamine-induced currents through SERTT81A were comparable with those through the wild type transporter. Both abundant Na+ entry and accumulation of SERTT81A in the inward facing conformation ought to favor amphetamine-induced efflux. Thus, we surmised that the N terminus must play a direct role in driving the transporter into a state that supports amphetamine-induced efflux. This hypothesis was verified by truncating the first 64 amino acids and by tethering the N terminus to an additional transmembrane helix. Either modification abolished amphetamine-induced efflux. We therefore conclude that the N terminus of monoamine transporters acts as a lever that sustains reverse transport. PMID:20118234

Identification of specific markers for amphetamine synthesised from the pre-precursor APAAN following the Leuckart route and retrospective search for APAAN markers in profiling databases from Germany and the Netherlands.

PubMed

Hauser, Frank M; Rößler, Thorsten; Hulshof, Janneke W; Weigel, Diana; Zimmermann, Ralf; Pütz, Michael

2018-04-01

α-Phenylacetoacetonitrile (APAAN) is one of the most important pre-precursors for amphetamine production in recent years. This assumption is based on seizure data but there is little analytical data available showing how much amphetamine really originated from APAAN. In this study, several syntheses of amphetamine following the Leuckart route were performed starting from different organic compounds including APAAN. The organic phases were analysed using gas chromatography-mass spectrometry (GC-MS) to search for signals caused by possible APAAN markers. Three compounds were discovered, isolated, and based on the performed syntheses it was found that they are highly specific for the use of APAAN. Using mass spectra, high resolution MS and nuclear magnetic resonance (NMR) data the compounds were characterised and identified as 2-phenyl-2-butenenitrile, 3-amino-2-phenyl-2-butenenitrile, and 4-amino-6-methyl-5-phenylpyrimidine. To investigate their significance, they were searched in data from seized amphetamine samples to determine to what extent they were present in illicitly produced amphetamine. Data of more than 580 cases from amphetamine profiling databases in Germany and the Netherlands were used for this purpose. These databases allowed analysis of the yearly occurrence of the markers going back to 2009. The markers revealed a trend that was in agreement with seizure reports and reflected an increasing use of APAAN from 2010 on. This paper presents experimental proof that APAAN is indeed the most important pre-precursor of amphetamine in recent years. It also illustrates how important it is to look for new ways to identify current trends in drug production since such trends can change within a few years. Copyright © 2017 John Wiley & Sons, Ltd.

Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist.

PubMed

Fuller, R W; Hemrick-Luecke, S K; Ornstein, P L

1992-10-01

LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.

Neuroendocrine mechanism of food intake and energy regulation in Japanese quail under differential simulated photoperiodic conditions: Involvement of hypothalamic neuropeptides, AMPK, insulin and adiponectin receptors.

PubMed

Banerjee, Somanshu; Chaturvedi, Chandra Mohini

2018-05-26

Neuroendocrine coordination between the reproductive and energy regulatory hypothalamic circuitries not only tightly regulates food intake and energy expenditure but also maintains the body weight and reproduction. The effect of different simulated photoperiodic conditions on food intake and neuroendocrine mechanism of energy homeostasis in Japanese quail is not investigated till date. Hence, our present study is designed to elucidate the effect of different simulated photoperiodic conditions on food consumption and neuroendocrine mechanism(s) of energy regulation in this poultry species. The alterations in hypothalamic energy balancing neuropeptides (NPY/AgRP/CART), polypeptide hormone precursor (POMC), protein kinase (AMPK-p-AMPK) as well as receptors of insulin and adiponectin [Insulin Receptor (IR), Adiponectin Receptor 1 & 2] have been investigated in photosensitive (PS), scotorefractory (SR),photorefractory (PR) and scotosensitive (SS) quail. Immunofluorescence and western blotting were used to quantify the expression of these peptides and proteins. Results showed increased food consumption and body weight gain, along with increased expression of NPY, AgRP, IR, adiponectin receptors and p-AMPK, decreased CART and POMC in the hypothalamus of photosensitive and scotorefractory quail. While, opposite findings were observed in photorefractory and scotosensitive quail. Hence, this study may suggest the hypothalamic energy channelization towards reproductive axis in photosensitive and scotorefractory quail to support the full breeding conditions, while hypothalamic energy deprivation in photorefractory and scotosensitive quail leads to reproductive quiescence. Copyright © 2018 Elsevier B.V. All rights reserved.

Quantification of CD4 Responses to Combined Antiretroviral Therapy Over 5 Years Among HIV-Infected Children in Kinshasa, Democratic Republic of Congo

PubMed Central

Edmonds, Andrew; Yotebieng, Marcel; Lusiama, Jean; Matumona, Yori; Kitetele, Faustin; Nku, David; Napravnik, Sonia; Cole, Stephen R.; Van Rie, Annelies; Behets, Frieda

2017-01-01

Background The long-term effects of combined antiretroviral therapy (cART) on CD4 percentage in HIV-infected children are incompletely understood, with evidence from resource-deprived areas particularly scarce even though most children with HIV live in such settings. We sought to describe this relationship. Methods Observational longitudinal data from cART-naive children enrolled between December 2004 and May 2010 into an HIV care and treatment program in Kinshasa, Democratic Republic of Congo were analyzed. To estimate the effect of cART on CD4 percentage while accounting for time-dependent confounders affected by prior exposure to cART, a marginal structural linear mean model was used. Results Seven hundred ninety children were active for 2090 person-years and a median of 31 months; 619 (78%) initiated cART. At baseline, 405 children (51%) were in HIV clinical stage 3 or 4; 528 (67%) had advanced or severe immunodeficiency. Compared with no cART, the estimated absolute rise in CD4 percentage was 6.8% [95% confidence interval (CI), 4.7% to 8.9%] after 6 months of cART, 8.6% (95% CI, 7.0% to 10.2%) after 12 months, and 20.5% (95% CI, 16.1% to 24.9%) after 60 months. cART-mediated CD4 percentage gains were slowest but greatest among children with baseline CD4 percentage <15. The cumulative incidence of recovery to “not significant” World Health Organization age-specific immunodeficiency was lower if cART was started when immunodeficiency was severe rather than mild or advanced. Conclusions cART increased CD4 percentages among HIV-infected children in a resource-deprived setting, as previously noted among children in the United States. More gradual and protracted recovery in children with lower baseline CD4 percentages supports earlier initiation of pediatric cART. PMID:22732464

Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study.

PubMed

Balagopal, Ashwin; Asmuth, David M; Yang, Wei-Teng; Campbell, Thomas B; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R; Lalloo, Umesh G; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B; Semba, Richard D; Thomas, David L; Bollinger, Robert C; Gupta, Amita

2015-10-01

Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.

Pre-cART Elevation of CRP and CD4+ T-cell Immune Activation Associated with HIV Clinical Progression in a Multinational Case-Cohort Study

PubMed Central

Balagopal, Ashwin; Asmuth, David M.; Yang, Wei-Teng; Campbell, Thomas B.; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R.; Lalloo, Umesh G.; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B.; Semba, Richard D.; Thomas, David L.; Bollinger, Robert C.; Gupta, Amita

2015-01-01

Background Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. Methods A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm3; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort–36; main cohort–200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Results Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm3. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96–5.21). Conclusions Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm3 at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART. PMID:26017661

Cell-Free and Concentrated Ascites Reinfusion Therapy for Decompensated Liver Cirrhosis.

PubMed

Kozaki, Koichi; IInuma, Masahiro; Takagi, Tomoyuki; Fukuda, Takanori; Sanpei, Takaya; Terunuma, Yusuke; Yatabe, Yoshiharu; Akano, Kazuhiro

2016-08-01

Cell-free and concentrated ascites reinfusion therapy (CART) is expected to improve symptoms associated with refractory ascites of the decompensated liver cirrhosis patients. The aim of this study was to evaluate the safety and efficacy of the CART system performed on the decompensated liver cirrhosis patients. In this retrospective observational study, we evaluated 24 CART processes performed on 11 patients with decompensated liver cirrhosis. We evaluated the effectiveness and adverse events during CART procedures. The amounts of collected and concentrated ascites were 4491.7 ± 2222.8 mL (mean ± SD), respectively, and the concentration ratio was 22.4 ± 15.3 times, respectively. The amount of collected protein in ascites was 2.3 ± 0.5 g/dL, and concentration ratio of protein was 8.2 ± 9.4 times. Serum protein level was not significantly different between before and after CART sessions. Thus, CART allowed for the reduction of doses of albumin preparations (Alb) to be administered. CART has been reported to cause two adverse reactions: elevation of body temperature and decrease in blood pressure. In our study, decreased blood pressure was not observed even in patients with > 5 L of ascites drained. Although a transient elevation in body temperature was seen in only one patient, this febrile patient immediately returned to normal body temperature with the use of NSAIDs. In patients with refractory ascites of decompensated liver cirrhosis in whom complete cure cannot be expected, CART improves their QOL and, in terms of medical economy, allows for the reduction of doses of Alb. CART can be effectively applied as a palliative procedure for refractory ascites of decompensated liver cirrhosis patients. © 2016 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.

Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

PubMed Central

Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortés, Claudia P; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro

2016-01-01

Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings. PMID:27065108

Adaptive Control of a Utility-Scale Wind Turbine Operating in Region 3

NASA Technical Reports Server (NTRS)

Frost, Susan A.; Balas, Mark J.; Wright, Alan D.

2009-01-01

Adaptive control techniques are well suited to nonlinear applications, such as wind turbines, which are difficult to accurately model and which have effects from poorly known operating environments. The turbulent and unpredictable conditions in which wind turbines operate create many challenges for their operation. In this paper, we design an adaptive collective pitch controller for a high-fidelity simulation of a utility scale, variable-speed horizontal axis wind turbine. The objective of the adaptive pitch controller in Region 3 is to regulate generator speed and reject step disturbances. The control objective is accomplished by collectively pitching the turbine blades. We use an extension of the Direct Model Reference Adaptive Control (DMRAC) approach to track a reference point and to reject persistent disturbances. The turbine simulation models the Controls Advanced Research Turbine (CART) of the National Renewable Energy Laboratory in Golden, Colorado. The CART is a utility-scale wind turbine which has a well-developed and extensively verified simulator. The adaptive collective pitch controller for Region 3 was compared in simulations with a bas celliansesical Proportional Integrator (PI) collective pitch controller. In the simulations, the adaptive pitch controller showed improved speed regulation in Region 3 when compared with the baseline PI pitch controller and it demonstrated robustness to modeling errors.

Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.

PubMed

Kraemer, Thomas; Maurer, Hans H

2002-04-01

This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

Innovative Varied-Fidelity Simulation Mobile Teaching Cart and Education Project.

PubMed

Harding, Andrew D; Cullinane Whalen, Kathryn; Silverman, Bradley S

2015-09-01

The use of a varied-fidelity simulation mobile teaching cart is a teaching tool that offers unique advantages in the acute care setting. The cart is used to demonstrate the use of patient monitoring devices, and there are a variety of software tools available with the monitoring technology to ensure that the outputs, including electrocardiographic waves, are analyzed appropriately by nursing staff using this varied-fidelity simulation mobile teaching cart. Bringing varied-fidelity simulation to the nurses' work area is a unique application setting. Copyright © 2015 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.

Les traces matérielles de la Carte du Ciel. Le cas des observatoires d'Alger et de Bordeaux.

NASA Astrophysics Data System (ADS)

Le Guet Tully, F.; Davoigneau, J.; Lamy, J.; de La Noë, J.; Rousseau, J.-M.; Sadsaoud, H.

2008-06-01

Le chapitre évoque les traces matérielles de la Carte du ciel subsistant dans les observatoires d'Alger et de Bordeaux. Les auteurs examinent d'abord l'opération d'inventaire du patrimoine astronomique entreprise à partir du milieu des années 1990. Ils examinent ensuite les éléments concrets constituant aujourd'hui le patrimoine de la Carte du Ciel : lunettes, abris, accessoires, laboratoires, réseaux, plaques de verre, registres, machines à mesurer les clichés, et cartes.

Robust Control Algorithm for a Two Cart System and an Inverted Pendulum

NASA Technical Reports Server (NTRS)

Wilson, Chris L.; Capo-Lugo, Pedro

2011-01-01

The Rectilinear Control System can be used to simulate a launch vehicle during liftoff. Several control schemes have been developed that can control different dynamic models of the rectilinear plant. A robust control algorithm was developed that can control a pendulum to maintain an inverted position. A fluid slosh tank will be attached to the pendulum in order to test robustness in the presence of unknown slosh characteristics. The rectilinear plant consists of a DC motor and three carts mounted in series. Each cart s weight can be adjusted with brass masses and the carts can be coupled with springs. The pendulum is mounted on the first cart and an adjustable air damper can be attached to the third cart if desired. Each cart and the pendulum have a quadrature encoder to determine position. Full state feedback was implemented in order to develop the control algorithm along with a state estimator to determine the velocity states of the system. A MATLAB program was used to convert the state space matrices from continuous time to discrete time. This program also used a desired phase margin and damping ratio to determine the feedback gain matrix that would be used in the LabVIEW program. This experiment will allow engineers to gain a better understanding of liquid propellant slosh dynamics, therefore enabling them to develop more robust control algorithms for launch vehicle systems

Perceptions regarding barriers and facilitators to combination antiretroviral therapy adherence among people living with HIV/AIDS in Gujarat, India: A qualitative study

PubMed Central

Patel, Sangita; Baxi, Rajendra K.; Patel, Shilpa N.; Golin, Carol E; Mehta, Mansi; Bakshi, Harsh; Shingrapure, Kalpita; Modi, Ekta; Coonor, Priyanka; Mehta, Kedar

2012-01-01

Objectives: To know the perceptions regarding barriers and facilitators to cART adherence among people living with HIV/AIDS Materials and Methods: To adapt U.S. based SAFETALK “prevention with positives” intervention to be culturally relevant in Gujarat, India in assisting PLWHA, a formative study was conducted. We conducted 30 in-depth interviews with PLWHA in the local language, assessing the experiences, perceived barriers, and facilitators to combination antiretroviral therapy (cART) among PLWHA in Gujarat. PLWHA were selected from the Voluntary Counseling and Testing Centre (VCTC) in Gujarat. To triangulate interview findings, we conducted two focus group discussions (FGDs) with medical and non-medical providers, respectively. Results: Travel and commuting to clinic, fear of possible physical reactions, high cost of ART from private practitioners, CD4 count being in normal limits and resistance to medication acted as barriers to cART adherence. Initiation of cART was facilitated by family members′ suggestion, advice of treating doctors and counselors, appropriate counseling before starting cART, belief that cART would aid in living a better and longer life and due to lowering of the CD4 count. Interpretation and Conclusions: Our study suggests that several issues need to be considered when providing cART. Further research is needed to study interactions between patients and their health care providers. PMID:23188935

The Csr system regulates genome-wide mRNA stability and transcription and thus gene expression in Escherichia coli.

PubMed

Esquerré, Thomas; Bouvier, Marie; Turlan, Catherine; Carpousis, Agamemnon J; Girbal, Laurence; Cocaign-Bousquet, Muriel

2016-04-26

Bacterial adaptation requires large-scale regulation of gene expression. We have performed a genome-wide analysis of the Csr system, which regulates many important cellular functions. The Csr system is involved in post-transcriptional regulation, but a role in transcriptional regulation has also been suggested. Two proteins, an RNA-binding protein CsrA and an atypical signaling protein CsrD, participate in the Csr system. Genome-wide transcript stabilities and levels were compared in wildtype E. coli (MG1655) and isogenic mutant strains deficient in CsrA or CsrD activity demonstrating for the first time that CsrA and CsrD are global negative and positive regulators of transcription, respectively. The role of CsrA in transcription regulation may be indirect due to the 4.6-fold increase in csrD mRNA concentration in the CsrA deficient strain. Transcriptional action of CsrA and CsrD on a few genes was validated by transcriptional fusions. In addition to an effect on transcription, CsrA stabilizes thousands of mRNAs. This is the first demonstration that CsrA is a global positive regulator of mRNA stability. For one hundred genes, we predict that direct control of mRNA stability by CsrA might contribute to metabolic adaptation by regulating expression of genes involved in carbon metabolism and transport independently of transcriptional regulation.

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction.

PubMed

Bossi, Flavia; Fan, Jue; Xiao, Jun; Chandra, Lilyana; Shen, Max; Dorone, Yanniv; Wagner, Doris; Rhee, Seung Y

2017-06-26

The molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. To identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation. We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.

Automatic State Space Aggregation Using a Density Based Technique

DTIC Science & Technology

2012-05-01

learner: the position of the cart X , the velocity of the cart X ′, the angle each beam makes with the cart, θ1 and θ2, and the angular velocities of the...ulation of 100 neural networks per generation, with a maximum of 200 generations of learning. Neuroevolution is provided by Another NEAT Java Implementation

Rolling Friction on a Wheeled Laboratory Cart

ERIC Educational Resources Information Center

Mungan, Carl E.

2012-01-01

A simple model is developed that predicts the coefficient of rolling friction for an undriven laboratory cart on a track that is approximately independent of the mass loaded onto the cart and of the angle of inclination of the track. The model includes both deformation of the wheels/track and frictional torque at the axles/bearings. The concept of…

Treatment of Attention Deficit/Hyperactivity Disorder with Amphetamine: Short-Term Effects on Family Interaction

ERIC Educational Resources Information Center

Gustafsson, Peik; Hansson, Kjell; Eidevall, Lena; Thernlund, Gunilla; Svedin, Carl Goran

2008-01-01

Objective: This research seeks to study the impact on family function after 3 months of treatment with amphetamine. Method: A total of 43 children, 6 to 11 years of age, with ADHD were treated with amphetamine for 3 months. Family function was studied before and after treatment by parent self-rating and independent observer ratings of videotaped…

[Epileptic insults, cerebral infarction and rhabdomyolysis as complications of amphetamine use].

PubMed

Roebroek, R M; Korten, J J

1996-01-27

In a 16-year-old boy with acute generalised epileptic convulsions, cerebral infarction and rhabdomyolysis were diagnosed. The urine was positive for amphetamine. Until that moment the patient had denied using drugs. He recovered and was discharged after nine days. Recreational use of ecstasy (methylenedioxymethamphetamine) and other amphetamine derivatives is gaining popularity worldwide. This drug abuse is rarely reported spontaneously.

HIV Risk Behavior among Amphetamine Injectors at U.S. Syringe Exchange Programs

ERIC Educational Resources Information Center

Braine, Naomi; Des Jarlais, Don C.; Goldblatt, Cullen; Zadoretzky, Cathy; Turner, Charles

2005-01-01

The goal of this study was to compare HIV risk behaviors of amphetamine and non-amphetamine injectors at syringe exchange programs (SEP) in the United States and to identify factors associated with injection risk. This analysis is based on data from a random cross-section of participants at 13 SEPs in different parts of the country. All interviews…

[Urine levels of fenethylline and amphetamine after administration of Captagon].

PubMed

Iffland, R

1982-01-01

The limit for detecting fenethylline and its metabolite amphetamine in GLC with N-FID is in the range of nanograms. The elimination of these substances in urine was measured after giving different quantities of Captagon to six volunteers. The concentrations of fenethylline and amphetamine in urine allow to estimate with some limitations time and amount of consuming Captagon for forensic purposes.

Dopaminergic Actions of D-Amphetamine on Schedule-Induced Polydipsia in Rats

ERIC Educational Resources Information Center

Pellon, Ricardo; Ruiz, Ana; Rodriguez, Cilia; Flores, Pilar

2007-01-01

Schedule-induced polydipsia in rats was developed by means of a fixed-time 60-s schedule of food presentation. The acute administration of d-amphetamine sulfate (0.1-3.0 mg/kg) produced a dose-dependent decrease in the rate of licking. D-Amphetamine shifted to the left the temporal distribution of adjunctive drinking within interfood intervals.…

[Hallucinogens, amphetamines and entactogens].

PubMed

Vollenweider, F X; Vollenweider-Scherpenhuyzen, M F

2003-06-01

MDMA ("Ecstasy") and its analogues such as MDE and MDA are amphetamine derivatives reported to produce an altered state with emotional overtones. Since more than ten years, ecstasy is after cannabis the most frequently used recreational drug by young adults, particularly in the so-called techno-scene. However, according to a recent survey there is an increasing trend for a revival of classic amphetamine and hallucinogen abuse, possibly due to the concern about the potential neurotoxicity and somatic risks associated with ecstasy use. Of the hallucinogens consumed, psilocybin containing mushroom ("magic mushrooms"), but also LSD are at the forefront. The present contribution summarizes the psychological and somatic effects of hallucinogens, amphetamines, and entactogens.

Sensitive and selective determination of methylenedioxylated amphetamines by high-performance liquid chromatography with fluorimetric detection.

PubMed

Sadeghipour, F; Veuthey, J L

1997-11-07

A rapid, sensitive and selective liquid chromatographic method with fluorimetric detection was developed for the separation and quantification of four methylenedioxylated amphetamines without interference of other drugs of abuse and common substances found in illicit tablets. The method was validated by examining linearity, precision and accuracy as well as detection and quantification limits. Methylenedioxylated amphetamines were quantified in eight tablets from illicit drug seizures and results were quantitatively compared to HPLC-UV analyses. To demonstrate the better sensitivity of the fluorimetric detection, methylenedioxylated amphetamines were analyzed in serum after a liquid-liquid extraction procedure and results were also compared to HPLC-UV analyses.

The effect of antimotion sickness drugs on habituation to motion

NASA Technical Reports Server (NTRS)

Wood, C. D.; Manno, J. E.; Manno, B. R.; Odenheimer, R. C.; Bairnsfather, L. E.

1986-01-01

The mechanism which allows for increased exposure to motion and accelerates habituation is investigated. The responses of 12 male and female subjects between 18-30 years rotated once a day for 5 days on the Contraves Goerz rotating chair after receiving placebo, 10 mg d-amphetamine, 0.6 mg scopolamine with 5 mg d-amphetamine, and 1.0 mg scopolamine are studied. It is observed that with placebo the subjects performed 48 more head movements than untreated subjects, 118 more movements with d-amphetamine, 176 more with 0.6 mg scopolamine with d-amphetamine, and 186 more with 1.0 scopolamine. The data reveal that exposure to rotation increases tolerance from 88 head movements on day 2 to 159 on day 4 at 17.4 rpm and with placebo; 96 to 186 at 19.9 rpm with 10 mg d-amphetamine; 111 to 273 at 20.2 rpm with scopolamine with d-amphetamine, and 141 to 279 at 22.4 rpm with 1.0 mg scopolamine. It is noted that a combination of cholinergic blocking and norepinephrine activation action is most effective in preventing the development of motion sickness and habituation is due to the greater exposure to vestibular simulation permitted by the drugs.

Tracing methamphetamine and amphetamine sources in wastewater and receiving waters via concentration and enantiomeric profiling.

PubMed

Xu, Zeqiong; Du, Peng; Li, Kaiyang; Gao, Tingting; Wang, Zhenglu; Fu, Xiaofang; Li, Xiqing

2017-12-01

Wastewater analysis is a promising approach to monitor illicit drug abuse of a community. However, drug use estimation via wastewater analysis may be biased by sources other than abuse. This is especially true for methamphetamine and amphetamine as their presence in wastewater may come from many sources, such as direct disposal or excretion following administration of prescription drugs. Here we traced methamphetamine and amphetamine sources via concentration and enantiomeric profiling of the two compounds from black market to receiving waters. Methamphetamine in wastewater was found to predominantly arise from abuse, proving the feasibility of using wastewater analysis for estimating its consumption in China. Amphetamine abuse was previously considered negligible in East and Southeast Asia. However, we found that amphetamine was abused considerably (up to 90.7mg/1000inh/day) in a significant number (>20%) of major cities in China. Combined concentration and enantiomeric profiling also revealed direct disposal into receiving waters of methamphetamine manufactured by different processes. These findings have important implications for monitoring of and law enforcement against methamphetamine/amphetamine abuse and related crimes in China and abroad. Copyright © 2017. Published by Elsevier B.V.

The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities.

PubMed

Faraone, Stephen V

2018-04-01

Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD). This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions. A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system-level effects of amphetamine and methylphenidate. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function. Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2. There is also evidence for interactions with glutamate and opioid systems. Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed. Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved.

Retention of sequential drug discriminations under fixed-interval schedules for long time periods without training.

PubMed

Li, Mi; McMillan, Donald E

2003-08-22

The experiments showed that sequential drug discriminations can be learned and retained under a fixed-interval (FI) schedule for more than 18 months without additional training under a complex three-choice procedure. Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg D-amphetamine, and saline. After responding stabilized, dose-response curves were determined for other drugs. Subsequently, pentobarbital was replaced with 5 mg/kg morphine as a training drug, and D-amphetamine was replaced with 30 mg/kg caffeine. After the pigeons learned these new discriminations, dose-response curves were redetermined. Initially, chlordiazepoxide substituted for pentobarbital, cocaine substituted for D-amphetamine, and nicotine partially substituted for D-amphetamine. Morphine, Delta9-tetrahydrocannabinol, and caffeine did not substitute for either drug. After retraining with morphine and caffeine, responding occurred on the pentobarbital/morphine key after pentobarbital, chlordiazepoxide and morphine and on the D-amphetamine/caffeine key after D-amphetamine, cocaine and caffeine. After nicotine and Delta9-tetrahyrdocannabinol, responding occurred on the saline key. These data show that drug discriminations learned under fixed-interval schedules are retained for long time periods, even when discrimination training with other drugs occurs during the retention period.

Maternal Combination Antiretroviral Therapy is Associated with Improved Retention of HIV-Exposed Infants in Kinshasa, Democratic Republic of Congo

PubMed Central

FEINSTEIN, Lydia; EDMONDS, Andrew; OKITOLONDA, Vitus; COLE, Stephen R; VAN RIE, Annelies; CHI, Benjamin H; NDJIBU, Papy; LUSIAMA, Jean; CHALACHALA, Jean Lambert; BEHETS, Frieda

2015-01-01

Background Programs to prevent mother-to-child HIV transmission (PMTCT) are plagued by loss to follow-up (LTFU) of HIV-exposed infants. We assessed if providing combination antiretroviral therapy (cART) to HIV-infected mothers was associated with reduced LTFU of their HIV-exposed infants in Kinshasa, DR Congo. Methods We constructed a cohort of mother-infant pairs using routinely collected clinical data. Maternal cART eligibility was based on national guidelines in effect at the time. Infants were considered LTFU following three failed tracking attempts after a missed visit or if more than six months passed since they were last seen in clinic. Statistical methods accounted for competing risks (e.g. death). Results 1318 infants enrolled at a median age of 2.6 weeks (interquartile range [IQR]: 2.1-6.9), at which point 24% of mothers were receiving cART. Overall, 5% of infants never returned to care following enrollment and 18% were LTFU by 18 months. The 18-month cumulative incidence of LTFU was 8% among infants whose mothers initiated cART by infant enrollment and 20% among infants whose mothers were not yet on cART. Adjusted for baseline factors, infants whose mothers were not on cART were over twice as likely to be LTFU, with a subdistribution hazard ratio of 2.75 (95% confidence limit: 1.81, 4.16). The association remained strong regardless of maternal CD4 count at infant enrollment. Conclusion Increasing access to cART for pregnant women could improve retention of HIV-exposed infants, thereby increasing the clinical and population-level impacts of PMTCT interventions and access to early cART for HIV-infected infants. PMID:25886922

CD4+ cell count recovery in naïve patients initiating cART, who achieved and maintained plasma HIV-RNA suppression.

PubMed

Costagliola, Dominique; Lacombe, Jean-Marc; Ghosn, Jade; Delaugerre, Constance; Pialoux, Gilles; Cuzin, Lise; Launay, Odile; Ménard, Amélie; de Truchis, Pierre; Mary-Krause, Murielle; Weiss, Laurence; Delfraissy, Jean-François

2014-01-01

A key objective of combined antiretroviral therapy (cART) is to reach and maintain high CD4 cell counts to provide long-term protection against AIDS-defining opportunistic infections and malignancies, as well as other comorbidities. However, a high proportion of patients present late for care. Our objective was to assess CD4 cell count recovery up to seven years in naïve patients initiating cART with at least three drugs in usual clinical care. From the French Hospital Database on HIV, we selected naïve individuals initiating cART from 2000 with at least two years of follow-up. Participants were further required to have achieved viral load suppression by six months after initiating cART and were censored in case of virological failure. We calculated the proportion of patients (Kaplan-Meier estimates) who achieved CD4 recovery to >500/mm(3) according to baseline CD4 cell count. A total of 15,025 patients were analyzed with a median follow-up on ART of 65.5 months (IQR: 42.3-96.0). At cART initiation, the median age was 38.6 years (IQR: 32.2-46.0), 9734 (64.8%) were men, median CD4 cell count was 239 (IQR: 130-336) and 2668 (17.8%) had a prior AIDS event. RESULTS are presented in the Table 1. This study shows that CD4 cell counts continue to increase seven years after cART initiation, whatever the baseline CD4 cell count. Failing to achieve CD4 recovery with continuous viral load suppression is rare for naïve patients initiating cART in routine clinical practice, but takes substantially longer in patients who initiate antiretroviral therapy at low CD4 cell counts.

Effect of combination antiretroviral therapy on Chinese rhesus macaques of simian immunodeficiency virus infection.

PubMed

Ling, Binhua; Rogers, Linda; Johnson, Ann-Marie; Piatak, Michael; Lifson, Jeffrey; Veazey, Ronald S

2013-11-01

Definitive treatment of HIV infection remains a critical but elusive goal, with persistence of residual virus even in the face of prolonged administration of suppressive combination antiretroviral treatment (cART) providing a source for recrudescent infection if treatment is stopped. Characterization of the residual virus and devising strategies to target it for eradication are key goals in HIV treatment research. Indian rhesus macaques (In-RM) infected with SIVmac have been widely used in such research. However, it has proven challenging to achieve and sustain clinically relevant levels of suppression (<30 vRNA copies/ml plasma) with cART in such models. As ease of viral suppression by cART is related to pretreatment levels of viral replication, and levels of replication of SIVmac239/251 are lower in Chinese rhesus macaques (Ch-RM) than in In-RM, we evaluated cART administration to SIVmac-infected Ch-RM as a potential model for studies of residual virus and eradication strategies. Four SIVmac239-infected Ch-RM received cART including reverse transcriptase inhibitors PMPA/FTC and integrase inhibitor L-870812 daily for 8 weeks. Plasma viral loads were promptly reduced to <30 copies/ml upon initiation of cART. Cell-associated SIV DNA levels in lymphocytes from the gut were also significantly reduced. Jejunal and colonic CCR5(+)CD4(+) mucosal memory T cells increased significantly; restoration of these cells was associated with reductions in immune activation. In conclusion, cART effectively suppressed viral replication to <30 vRNA copies/ml in SIVmac239-infected Ch-RM, reducing immune activation and restoring mucosal immune cell populations. SIVmac239-infected Ch-RM may be a useful model for studying responses to cART and persistent tissue reservoirs and evaluating candidate eradication strategies to cure HIV infection.

Ejection of a rear facing, golf cart passenger.

PubMed

Schau, Kyle; Masory, Oren

2013-10-01

The following report details the findings of a series of experiments and simulations performed on a commercially available, shuttle style golf cart during several maneuvers involving rapid accelerations of the vehicle. It is determined that the current set of passive restraints on these types of golf carts are not adequate in preventing ejection of a rear facing passenger during rapid accelerations in the forward and lateral directions. Experimental data and simulations show that a hip restraint must be a minimum of 13 in. above the seat in order to secure a rear facing passenger during sharp turns, compared to the current restraint height of 5 in. Furthermore, it is determined that a restraint directly in front of the rear facing passenger is necessary to prevent ejection. In addressing these issues, golf cart manufacturers could greatly reduce the likelihood of injury due to ejection of a rear facing, golf cart passenger. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chimeric Antigen Receptor T Cells and Hematopoietic Cell Transplantation: How Not to Put the CART Before the Horse

PubMed Central

Kenderian, Saad S.; Porter, David L.; Gill, Saar

2016-01-01

Hematopoietic cell transplantation (HCT) remains an important and potentially curative option in most hematological malignancies. As a form of immunotherapy, allogeneic HCT offers the potential for durable remissions but is limited by transplant related morbidity and mortality due to organ toxicity, infection and graft versus host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematological malignancies. Clinical trials will now need to address the relative roles of CART cells and HCT in the context of transplant-eligible patients. In this review we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT. PMID:27638367

The Communities Advancing Resilience Toolkit (CART): an intervention to build community resilience to disasters.

PubMed

Pfefferbaum, Rose L; Pfefferbaum, Betty; Van Horn, Richard L; Klomp, Richard W; Norris, Fran H; Reissman, Dori B

2013-01-01

Community resilience has emerged as a construct to support and foster healthy individual, family, and community adaptation to mass casualty incidents. The Communities Advancing Resilience Toolkit (CART) is a publicly available theory-based and evidence-informed community intervention designed to enhance community resilience by bringing stakeholders together to address community issues in a process that includes assessment, feedback, planning, and action. Tools include a field-tested community resilience survey and other assessment and analytical instruments. The CART process encourages public engagement in problem solving and the development and use of local assets to address community needs. CART recognizes 4 interrelated domains that contribute to community resilience: connection and caring, resources, transformative potential, and disaster management. The primary value of CART is its contribution to community participation, communication, self-awareness, cooperation, and critical reflection and its ability to stimulate analysis, collaboration, skill building, resource sharing, and purposeful action.

Individual vulnerabilities relative for potential pathological conditions.

PubMed

Moal, Michel Le

2016-08-15

It is not a usual venture to review experiments conducted decades ago in the context of interests of that time and replace them in a long-term historical perspective. These investigations were the product of a long-standing interest for individual differences in vulnerabilities relative to coping with stressful situations and for potential pathological conditions such as drug abuse. The rationale was, and still is, to decipher the psychobiological characteristics of these complex traits. STRESS- AND PHARMACOLOGICALLY-INDUCED BEHAVIORAL SENSITIZATION INCREASES VULNERABILITY TO ACQUISITION OF AMPHETAMINE SELF-ADMINISTRATION: Individual vulnerability to drug addiction may be an important factor in the prognosis of pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we use a self-administration (SA) acquisition paradigm showing that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine increases the locomotor response to this drug (behavioral sensitization) and enhances vulnerability to amphetamine SA. These results show that vulnerability to developing amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may also enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (a behavior also modulated by DA activity), stress may influence SA via an action on the DA system. © 1990. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

Amphetamine increases schedule-induced drinking reduced by negative punishment procedures.

PubMed

Pérez-Padilla, Angeles; Pellón, Ricardo

2003-05-01

d-Amphetamine has been reported to increase schedule-induced drinking punished by lick-dependent signalled delays in food delivery. This might reflect a drug-behaviour interaction dependent on the type of punisher, because no such effect has been found when drinking was reduced by lick-contingent electric shocks. However, the anti-punishment effect of amphetamine could be mediated by other behavioural processes, such as a loss of discriminative control or an increase in the value of delayed reinforcers. To test the effects of d-amphetamine on the acquisition and maintenance of schedule-induced drinking reduced by unsignalled delays in food delivery. Rats received 10-s unsignalled delays initiated by each lick after polydipsia was induced by a fixed-time 30-s food reinforcement schedule or from the outset of the experiment. Yoked-control rats received these same delays but independently of their own behaviour. d-Amphetamine (0.1-3.0 mg/kg) was then tested IP. d-Amphetamine dose-dependently increased and then decreased punished schedule-induced drinking. The drug led to dose-dependent reductions when the delays were not contingent or when they were applied from the outset of training. These results support the contention that d-amphetamine has an increasing effect on schedule-induced drinking that has been previously reduced by a negative punishment procedure. This effect cannot be attributed to other potentially involved processes, and therefore support the idea that drug effects on punished behaviour depend on punishment being delays in food or shock deliveries.

Individual behavioural predictors of amphetamine-induced emission of 50 kHz vocalization in rats.

PubMed

Mulvihill, Kevin G; Brudzynski, Stefan M

2018-05-11

Measurement of ultrasonic vocalizations (USVs) produced by adult rats represents a highly useful index of emotional arousal. The associations found between 50 kHz USV production and a variety of behavioural and pharmacological protocols increasingly suggests they serve as a marker of positive motivational states. This study used a powerful within-subjects design to investigate the relationships among individual differences in approach to a sweet-food reward, predisposition to emit 50 kHz USVs spontaneously, and 50 kHz USVs emission following acute systemic administration of amphetamine. Both approach motivation and predisposition to call were found to not correlate with each other but did predict 50 kHz USV response to acute amphetamine. These two behavioural phenotypes appear to represent dissociable predictors of acute amphetamine-induced emission of 50 kHz USVs in a non-sensitization paradigm. In contrast to that, a measure of sucrose preference was not found to predict 50 kHz USV emission following amphetamine. Acute amphetamine was also found to increase average sound frequency of emitted USVs and selectively increase the proportion of Trill subtype 50 kHz USVs. Together, these data demonstrate that acute amphetamine-induced 50 kHz USVs in the adult rat represent more than just a univariate motivational state and may represent the product of dissociable subsystems of emotional behavior. Copyright © 2018. Published by Elsevier B.V.

Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors.

PubMed

Sirohi, Sunil; Schurdak, Jennifer D; Seeley, Randy J; Benoit, Stephen C; Davis, Jon F

2016-07-01

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders. Copyright © 2016. Published by Elsevier Inc.

Post-transcriptional Regulation of Genes Related to Biological Behaviors of Gastric Cancer by Long Noncoding RNAs and MicroRNAs

PubMed Central

Liu, Wenjing; Ma, Rui; Yuan, Yuan

2017-01-01

Noncoding RNAs play critical roles in regulating protein-coding genes and comprise two major classes: long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). LncRNAs regulate gene expression at transcriptional, post-transcriptional, and epigenetic levels via multiple action modes. LncRNAs can also function as endogenous competitive RNAs for miRNAs and indirectly regulate gene expression post-transcriptionally. By binding to the 3'-untranslated regions (3'-UTR) of target genes, miRNAs post-transcriptionally regulate gene expression. Herein, we conducted a review of post-transcriptional regulation by lncRNAs and miRNAs of genes associated with biological behaviors of gastric cancer. PMID:29187891

A Go-to-Market Strategy: Promoting Private Sector Solutions to the Threat of Proliferation

DTIC Science & Technology

2013-04-01

indicators reveal that these problems, often subsumed under the seemingly innocuous heading of “transnational threats,” are a growing cancer on the...trade is worth an estimated $322 billion annually with 52,356 metric tons of opium, cannabis , cocaine, and amphetamine-type stimulant (ATS...of medical isotopes to the sites that secure the material. 30 Regulators are also now starting to consider another critical component in the

Integration of light and circadian signals that regulate chloroplast transcription by a nuclear-encoded sigma factor.

PubMed

Belbin, Fiona E; Noordally, Zeenat B; Wetherill, Sarah J; Atkins, Kelly A; Franklin, Keara A; Dodd, Antony N

2017-01-01

We investigated the signalling pathways that regulate chloroplast transcription in response to environmental signals. One mechanism controlling plastid transcription involves nuclear-encoded sigma subunits of plastid-encoded plastid RNA polymerase. Transcripts encoding the sigma factor SIG5 are regulated by light and the circadian clock. However, the extent to which a chloroplast target of SIG5 is regulated by light-induced changes in SIG5 expression is unknown. Moreover, the photoreceptor signalling pathways underlying the circadian regulation of chloroplast transcription by SIG5 are unidentified. We monitored the regulation of chloroplast transcription in photoreceptor and sigma factor mutants under controlled light regimes in Arabidopsis thaliana. We established that a chloroplast transcriptional response to light intensity was mediated by SIG5; a chloroplast transcriptional response to the relative proportions of red and far red light was regulated by SIG5 through phytochrome and photosynthetic signals; and the circadian regulation of chloroplast transcription by SIG5 was predominantly dependent on blue light and cryptochrome. Our experiments reveal the extensive integration of signals concerning the light environment by a single sigma factor to regulate chloroplast transcription. This may originate from an evolutionarily ancient mechanism that protects photosynthetic bacteria from high light stress, which subsequently became integrated with higher plant phototransduction networks. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Field Research Validation Sites | Wind | NREL

Science.gov Websites

, independent pitch control of the Controls Advanced Research Turbine (CART) blades Variable-speed or constant CART2 600-kW Turbine Model: Westinghouse Blades: 2 Hub height: 36.6 m Rotor diameter: 42.6 m Extensively instrumented CART3 600-kW Turbine Model: Westinghouse Blades: 3 Hub height: 36.6 m Rotor diameter: 42.6 m

75 FR 4769 - Hand Trucks and Certain Parts Thereof From The People's Republic of China: Notice of Decision of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-29

...''), requested the Department to determine whether two of the welding carts that it imported, models 93851 and... Ruling for Central Purchasing, LLC's Two Models of Welding Carts,'' dated February 15, 2006 (``Final... reevaluated its position and determined that both models of welding carts were subject to the Order. The trial...

The Retarding Force on a Fan-Cart Reversing Direction

ERIC Educational Resources Information Center

Aurora, Tarlok S.; Brunner, Bernard J.

2011-01-01

In introductory physics, students learn that an object tossed upward has a constant downward acceleration while going up, at the highest point and while falling down. To demonstrate this concept, a self-propelled fan cart system is used on a frictionless track. A quick push is given to the fan cart and it is allowed to move away on a track under…

The inhibition of amine oxidase and the central stimulating action of the stereoisomeric amphetamines and 1-phenylethylamines

PubMed Central

Grana, E.; Lilla, L.

1959-01-01

The stereoisomers of amphetamine and 1-phenylethylamine have been studied in the rat both as central stimulants and as inhibitors of amine oxidase from brain, liver, and kidney. There was no correlation between these two effects; thus it is unlikely that the central stimulating action of amphetamine is due to inhibition of amine oxidase. PMID:13828860

Effects of Amphetamine-CNS Depressant Combinations and of Other CNS Stimulants in Four-Choice Drug Discriminations

ERIC Educational Resources Information Center

Li, Mi; Wessinger, William D.; McMillan, D. E.

2005-01-01

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine--pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs…

Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects.

PubMed

Di, Shengmeng; Li, Zonghai

2016-04-01

Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed.

[Consensus Statement by GeSIDA/National AIDS Plan Secretariat on antiretroviral treatment in adults infected by the human immunodeficiency virus (Updated January 2013)].

PubMed

2013-11-01

This consensus document is an update of combined antiretroviral therapy (cART) guidelines for HIV-1 infected adult patients. To formulate these recommendations a panel composed of members of the GeSIDA/National AIDS Plan Secretariat (Grupo de Estudio de Sida and the Secretaría del Plan Nacional sobre el Sida) reviewed the efficacy and safety advances in clinical trials, cohort and pharmacokinetic studies published in medical journals (PubMed and Embase) or presented in medical scientific meetings. The strength of the recommendations and the evidence which support them are based on a modification of the criteria of Infectious Diseases Society of America. cART is recommended in patients with symptoms of HIV infection, in pregnant women, in serodiscordant couples with high risk of transmission, in hepatitisB co-infection requiring treatment, and in HIV nephropathy. cART is recommended in asymptomatic patients if CD4 is <500cells/μl. If CD4 are >500cells/μl cART should be considered in the case of chronic hepatitisC, cirrhosis, high cardiovascular risk, plasma viral load >100.000 copies/ml, proportion of CD4 cells <14%, neurocognitive deficits, and in people aged >55years. The objective of cART is to achieve an undetectable viral load. The first cART should include 2 reverse transcriptase inhibitors (RTI) nucleoside analogs and a third drug (a non-analog RTI, a ritonavir boosted protease inhibitor, or an integrase inhibitor). The panel has consensually selected some drug combinations, for the first cART and specific criteria for cART in acute HIV infection, in tuberculosis and other HIV related opportunistic infections, for the women and in pregnancy, in hepatitisB or C co-infection, in HIV-2 infection, and in post-exposure prophylaxis. These new guidelines update previous recommendations related to first cART (when to begin and what drugs should be used), how to monitor, and what to do in case of viral failure or adverse drug reactions. cART specific criteria in comorbid patients and special situations are similarly updated. Copyright © 2013 Elsevier España, S.L. All rights reserved.

High Fat Diet Augments Amphetamine Sensitization in Mice: Role of Feeding Pattern, Obesity, and Dopamine Terminal Changes

PubMed Central

Fordahl, Steve C.; Locke, Jason L.; Jones, Sara R.

2016-01-01

High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3d/week) or extended (24h 7d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations. PMID:27267686

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bossi, Flavia; Fan, Jue; Xiao, Jun

Here, the molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. As a result, to identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation.more » We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.« less

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

DOE PAGES

Bossi, Flavia; Fan, Jue; Xiao, Jun; ...

2017-06-26

Here, the molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. As a result, to identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation.more » We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.« less

An Optogenetic Platform for Real-Time, Single-Cell Interrogation of Stochastic Transcriptional Regulation.

PubMed

Rullan, Marc; Benzinger, Dirk; Schmidt, Gregor W; Milias-Argeitis, Andreas; Khammash, Mustafa

2018-05-17

Transcription is a highly regulated and inherently stochastic process. The complexity of signal transduction and gene regulation makes it challenging to analyze how the dynamic activity of transcriptional regulators affects stochastic transcription. By combining a fast-acting, photo-regulatable transcription factor with nascent RNA quantification in live cells and an experimental setup for precise spatiotemporal delivery of light inputs, we constructed a platform for the real-time, single-cell interrogation of transcription in Saccharomyces cerevisiae. We show that transcriptional activation and deactivation are fast and memoryless. By analyzing the temporal activity of individual cells, we found that transcription occurs in bursts, whose duration and timing are modulated by transcription factor activity. Using our platform, we regulated transcription via light-driven feedback loops at the single-cell level. Feedback markedly reduced cell-to-cell variability and led to qualitative differences in cellular transcriptional dynamics. Our platform establishes a flexible method for studying transcriptional dynamics in single cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Highly efficient gene transfer using a retroviral vector into murine T cells for preclinical chimeric antigen receptor-expressing T cell therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kusabuka, Hotaka; Fujiwara, Kento; Tokunaga, Yusuke

Adoptive immunotherapy using chimeric antigen receptor-expressing T (CAR-T) cells has attracted attention as an efficacious strategy for cancer treatment. To prove the efficacy and safety of CAR-T cell therapy, the elucidation of immunological mechanisms underlying it in mice is required. Although a retroviral vector (Rv) is mainly used for the introduction of CAR to murine T cells, gene transduction efficiency is generally less than 50%. The low transduction efficiency causes poor precision in the functional analysis of CAR-T cells. We attempted to improve the Rv gene transduction protocol to more efficiently generate functional CAR-T cells by optimizing the period ofmore » pre-cultivation and antibody stimulation. In the improved protocol, gene transduction efficiency to murine T cells was more than 90%. In addition, almost all of the prepared murine T cells expressed CAR after puromycin selection. These CAR-T cells had antigen-specific cytotoxic activity and secreted multiple cytokines by antigen stimulation. We believe that our optimized gene transduction protocol for murine T cells contributes to the advancement of T cell biology and development of immunotherapy using genetically engineered T cells. - Highlights: • We established highly efficient gene transduction protocols for murine T cells. • CD8{sup +} CAR-T cells had antigen-specific cytotoxic activity. • CD4{sup +} CAR-T cells secreted multiple cytokines by antigen stimulation. • This finding can contribute to the development of T-cell biology and immunotherapy.« less

Executive summary of the Consensus Document of GeSIDA and Spanish Secretariat for the National Plan on AIDS on combined antiretroviral treatment in adults infected by the human immunodeficiency virus (January 2013).

PubMed

2013-11-01

In the present update of the guidelines, a starting combination antiretroviral treatment (cART) is recommended in symptomatic patients, in pregnant women, in serodiscordant couples with a high risk of transmission, in patients co-infected with hepatitis B virus requiring treatment, and in patients with HIV-related nephropathy. Guidelines on cART are included in the event of a concurrent diagnosis of HIV infection with an AIDS-defining event. In asymptomatic naïve patients, cART is recommended if the CD4(+) lymphocyte count is <500cells/μL; if the CD4(+) lymphocyte count is >500cells/μL, cART can be delayed, although it may be considered in patients with liver cirrhosis, chronic infection due to hepatitis C virus, high cardiovascular risk, plasma viral load (PVL) >10(5)copies/mL, CD4(+) lymphocyte percentage <14%, cognitive impairment, and age >55 years. cART in naïve patients requires a combination of 3 drugs, and its aim is to achieve undetectable PVL. Treatment adherence plays a key role in sustaining a favorable response. cART can, and should be, changed if virological failure occurs, in order to return to undetectable PVL. Approaches to cART in acute HIV infection, in women, in pregnancy, in tuberculosis, and post-exposure prophylaxis are also examined. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Using decision trees to understand structure in missing data

PubMed Central

Tierney, Nicholas J; Harden, Fiona A; Harden, Maurice J; Mengersen, Kerrie L

2015-01-01

Objectives Demonstrate the application of decision trees—classification and regression trees (CARTs), and their cousins, boosted regression trees (BRTs)—to understand structure in missing data. Setting Data taken from employees at 3 different industrial sites in Australia. Participants 7915 observations were included. Materials and methods The approach was evaluated using an occupational health data set comprising results of questionnaires, medical tests and environmental monitoring. Statistical methods included standard statistical tests and the ‘rpart’ and ‘gbm’ packages for CART and BRT analyses, respectively, from the statistical software ‘R’. A simulation study was conducted to explore the capability of decision tree models in describing data with missingness artificially introduced. Results CART and BRT models were effective in highlighting a missingness structure in the data, related to the type of data (medical or environmental), the site in which it was collected, the number of visits, and the presence of extreme values. The simulation study revealed that CART models were able to identify variables and values responsible for inducing missingness. There was greater variation in variable importance for unstructured as compared to structured missingness. Discussion Both CART and BRT models were effective in describing structural missingness in data. CART models may be preferred over BRT models for exploratory analysis of missing data, and selecting variables important for predicting missingness. BRT models can show how values of other variables influence missingness, which may prove useful for researchers. Conclusions Researchers are encouraged to use CART and BRT models to explore and understand missing data. PMID:26124509

America’s First Amphetamine Epidemic 1929–1971

PubMed Central

Rasmussen, Nicolas

2008-01-01

Using historical research that draws on new primary sources, I review the causes and course of the first, mainly iatrogenic amphetamine epidemic in the United States from the 1940s through the 1960s. Retrospective epidemiology indicates that the absolute prevalence of both nonmedical stimulant use and stimulant dependence or abuse have reached nearly the same levels today as at the epidemic’s peak around 1969. Further parallels between epidemics past and present, including evidence that consumption of prescribed amphetamines has also reached the same absolute levels today as at the original epidemic’s peak, suggest that stricter limits on pharmaceutical stimulants must be considered in any efforts to reduce amphetamine abuse today. PMID:18445805

Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus.

PubMed

Hori, Takanori; Barnor, Jacob; Huu, Tung Nguyen; Morinaga, Osamu; Hamano, Akiko; Ndzinu, Jerry; Frimpong, Angela; Minta-Asare, Keren; Amoa-Bosompem, Mildred; Brandful, James; Odoom, John; Bonney, Joseph; Tuffour, Isaac; Owusu, Baffour-Awuah; Ofosuhene, Mark; Atchoglo, Philip; Sakyiamah, Maxwell; Adegle, Richard; Appiah-Opong, Regina; Ampofo, William; Koram, Kwadwo; Nyarko, Alexander; Okine, Laud; Edoh, Dominic; Appiah, Alfred; Uto, Takuhiro; Yoshinaka, Yoshiyuki; Uota, Shin; Shoyama, Yukihiro; Yamaoka, Shoji

2015-04-03

Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs. Copyright © 2015 Elsevier Inc. All rights reserved.

Cross-reactivity of amphetamine analogues with Roche Abuscreen radioimmunoassay reagents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cody, J.T.

1990-01-01

Cross-reactivity of amphetamine analogues with the Abuscreen amphetamine radioimmunoassay reagents was determined for both the standard and high specificity antibody systems. Compounds tested included 2-methoxyamphetamine, 4-hydroxymethamphetamine, 2,5-dimethoxyamphetamine (DMA), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-bromo-2,5-dimethoxy-beta-phenethylamine (BDMPEA), 3,4,5-trimethoxyamphetamine (TMA), 3,4-methylenedioxyamphetamine (MDA), N,N-dimethyl-3,4-methylenedioxyamphetamine and N-hydroxy-3,4-methylenedioxyamphetamine (N-OH MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-methylamphetamine (DOM), and 3,4,5-trimethoxyphenethylamine (mescaline). Blank negative reference material was spiked with 1,000 to 100,000 ng/mL of the amphetamine analogue and used as sample in the assays. MDA was the only analogue that showed cross reactivity equal to or greater than that of amphetamine. None of the other analogue compounds demonstrated a positive resultmore » at even the highest concentration; however several showed depressed counts at various concentration levels.« less

Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents.

PubMed

Slezak, Jonathan M; Mueller, Melanie; Ricaurte, George A; Katz, Jonathan L

2018-06-02

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug-plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations. We sought to determine whether acute drug-plasma concentrations that enhance performance in the 5-CSRT procedure are similar to those found to be therapeutic in patients diagnosed with ADHD. Results from the pharmacokinetic/pharmacodynamic assessment indicate that d-amphetamine plasma concentrations associated with improved performance on the 5-CSRT procedure overlap with those that have been reported to be therapeutic in clinical trials. The current findings suggest that the 5-CSRT procedure may be a useful preclinical model for predicting the utility of novel ADHD therapeutics and their effective concentrations.

Transcriptomic Analysis of Grapevine (cv. Summer Black) Leaf, Using the Illumina Platform

PubMed Central

Pervaiz, Tariq; Haifeng, Jia; Salman Haider, Muhammad; Cheng, Zhang; Cui, Mengjie; Wang, Mengqi; Cui, Liwen; Wang, Xicheng; Fang, Jinggui

2016-01-01

Proceeding to illumina sequencing, determining RNA integrity numbers for poly RNA were separated from each of the four developmental stages of cv. Summer Black leaves by using Illumina HiSeq™ 2000. The sums of 272,941,656 reads were generated from vitis vinifera leaf at four different developmental stages, with more than 27 billion nucleotides of the sequence data. At each growth stage, RNA samples were indexed through unique nucleic acid identifiers and sequenced. KEGG annotation results depicted that the highest number of transcripts in 2,963 (2Avs4A) followed by 1Avs4A (2,920), and 3Avs4A (2,294) out of 15,614 (71%) transcripts were recorded. In comparison, a total of 1,532 transcripts were annotated in GOs, including Cellular component, with the highest number in “Cell part” 251 out of 353 transcripts (71.1%), followed by intracellular organelle 163 out of 353 transcripts (46.2%), while in molecular function and metabolic process 375 out of 525 (71.4%) transcripts, multicellular organism process 40 out of 525 (7.6%) transcripts in biological process were most common in 1Avs2A. While in case of 1Avs3A, cell part 476 out of 662 transcripts (71.9%), and membrane-bounded organelle 263 out of 662 transcripts (39.7%) were recorded in Cellular component. In the grapevine transcriptome, during the initial stages of leaf development 1Avs2A showed single transcript was down-regulated and none of them were up-regulated. While in comparison of 1A to 3A showed one up-regulated (photosystem II reaction center protein C) and one down regulated (conserved gene of unknown function) transcripts, during the hormone regulating pathway namely SAUR-like auxin-responsive protein family having 2 up-regulated and 7 down-regulated transcripts, phytochrome-associated protein showed 1 up-regulated and 9 down-regulated transcripts, whereas genes associated with the Leucine-rich repeat protein kinase family protein showed 7 up-regulated and 1 down-regulated transcript, meanwhile Auxin Resistant 2 has single up-regulated transcript in second developmental stage, although 3 were down-regulated at lateral growth stages (3A and 4A). In the present study, 489 secondary metabolic pathways related genes were identified during leaf growth, which mainly includes alkaloid (40), anthocyanins (21), Diterpenoid (144), Monoterpenoid (90) and Flavonoids (93). Quantitative real-time PCR was applied to validate 10 differentially expressed transcripts patterns from flower, leaf and fruit metabolic pathways at different growth stages. PMID:26824474

Impact of Portion-Size Control for School a la Carte Items: Changes in Kilocalories and Macronutrients Purchased by Middle School Students

USDA-ARS?s Scientific Manuscript database

We assessed the impact of a pilot middle school a la carte intervention on food and beverage purchases, kilocalories, fat, carbohydrate, and protein sold per student, and nutrient density of the foods sold. A la carte sales were obtained from six middle schools in three states for 1 baseline week an...

Detection of Delta9-tetrahydrocannabinol and amphetamine-type stimulants in oral fluid using the Rapid Stat point-of-collection drug-testing device.

PubMed

Röhrich, J; Zörntlein, S; Becker, J; Urban, R

2010-04-01

The Rapid Stat assay, a point-of-collection drug-testing device for detection of amphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines in oral fluid, was evaluated for cannabis and amphetamine-type stimulants. The Rapid Stat tests (n = 134) were applied by police officers in routine traffic checks. Oral fluid and blood samples were analyzed using gas chromatography-mass spectrometry (GC-MS) for Delta(9)-tetrahydrocannabinol, amphetamine, methamphetamine, methylenedioxymethamphetamine, methylenedioxyethylamphetamine, and methylenedioxyamphetamine. The comparison of GC-MS analysis of oral fluid with the Rapid Stat results for cannabis showed a sensitivity of 85%, a specificity of 87%, and a total confirmation rate of 87%. When compared with serum, the sensitivity of the cannabis assay decreased to 71%, the specificity to 60%, and the total confirmation rate to 66%. These findings were possibly caused by an incorrect reading of the THC test results. Comparison of the Rapid Stat amphetamine assay with GC-MS in oral fluid showed a sensitivity of 94%, a specificity of 97%, and a total confirmation rate of 97%. Compared with serum, a sensitivity of 100%, a specificity of 90%, and a total confirmation rate of 92% was found. The amphetamine assay must, therefore, be regarded as satisfactory.

Pathology of deaths associated with "ecstasy" and "eve" misuse.

PubMed

Milroy, C M; Clark, J C; Forrest, A R

1996-02-01

To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia.

The amphetamine sensitization model of schizophrenia symptoms and its effect on schedule-induced polydipsia in the rat.

PubMed

Hawken, Emily R; Beninger, Richard J

2014-05-01

Amphetamine enhances dopamine (DA) transmission and induces psychotic states or exacerbates psychosis in at-risk individuals. Amphetamine sensitization of the DA system has been proposed as a rodent model of schizophrenia-like symptoms. In humans, excessive nonphysiologic drinking or primary polydipsia is significantly associated with a diagnosis of schizophrenia. In rodents, nonphysiologic drinking can be induced by intermittent presentation of food in the presence of a drinking spout to a hungry animal; this phenomenon is termed, "schedule-induced polydipsia" (SIP). This study aims to determine the effects of amphetamine sensitization on SIP. We injected rats with amphetamine (1.5 mg/kg) daily for 5 days. Following 4 weeks of withdrawal, animals were food restricted and exposed to the SIP protocol (noncontingent fixed-time 1-min food schedule) for daily 2-h sessions for 24 days. Results showed that previously amphetamine-injected animals drank more in the SIP protocol and drank more than controls when the intermittent food presentation schedule was removed. These findings suggest that hyperdopaminergia associated with schizophrenia may contribute to the development of polydipsia in this population. Whether animals that develop SIP have DA dysfunction or aberrant activity of other circuits that modulate DA activity has yet to be clearly defined.

Catecholaminergic consolidation of motor cortical neuroplasticity in humans.

PubMed

Nitsche, Michael A; Grundey, Jessica; Liebetanz, David; Lang, Nicolas; Tergau, Frithjof; Paulus, Walter

2004-11-01

Amphetamine, a catecholaminergic re-uptake-blocker, is able to improve neuroplastic mechanisms in humans. However, so far not much is known about the underlying physiological mechanisms. Here, we study the impact of amphetamine on NMDA receptor-dependent long-lasting excitability modifications in the human motor cortex elicited by weak transcranial direct current stimulation (tDCS). Amphetamine significantly enhanced and prolonged increases in anodal, tDCS-induced, long-lasting excitability. Under amphetamine premedication, anodal tDCS resulted in an enhancement of excitability which lasted until the morning after tDCS, compared to approximately 1 h in the placebo condition. Prolongation of the excitability enhancement was most pronounced for long-term effects; the duration of short-term excitability enhancement was only slightly increased. Since the additional application of the NMDA receptor antagonist dextromethorphane blocked any enhancement of tDCS-driven excitability under amphetamine, we conclude that amphetamine consolidates the tDCS-induced neuroplastic effects, but does not initiate them. The fact that propanolol, a beta-adrenergic antagonist, diminished the duration of the tDCS-generated after-effects suggests that adrenergic receptors play a certain role in the consolidation of NMDA receptor-dependent motor cortical excitability modifications in humans. This result may enable researchers to optimize neuroplastic processes in the human brain on the rational basis of purpose-designed pharmacological interventions.

The HIV-Brazil Cohort Study: Design, Methods and Participant Characteristics

PubMed Central

Grangeiro, Alexandre; Escuder, Maria Mercedes; Cassanote, Alex Jones Flores; Souza, Rosa Alencar; Kalichman, Artur O.; Veloso, Valdiléa; Ikeda, Maria Letícia Rodrigues; Barcellos, Nêmora Tregnago; Brites, Carlos; Tupinanbás, Unai; Lucena, Noaldo O.; da Silva, Carlos Lima; Lacerda, Heloisa Ramos; Grinsztejn, Beatriz; Castilho, Euclides Ayres

2014-01-01

Background The HIV-Brazil Cohort Study was established to analyze the effectiveness of combination antiretroviral therapy (cART) and the impact of this treatment on morbidity, quality of life (QOL) and mortality. The study design, patients’ profiles and characteristics of cART initiation between 2003 and 2010 were described. Methodology/Principal Findings Since 2003, the HIV-Brazil Cohort has been following HIV-infected adults receiving cART at 26 public health care facilities, using routine clinical care data and self-reported QOL questionnaires. When not otherwise available, data are obtained from national information systems. The main outcomes of interest are diseases related or unrelated to HIV; suppression of viral replication; adverse events; virological, clinical and immunological failures; changes in the cART; and mortality. For the 5,061 patients who started cART between 2003 and 2010, the median follow-up time was 4.1 years (IQR 2.2–5.9 years) with an 83.4% retention rate. Patient profiles were characterized by a predominance of men (male/female ratio 1.7∶1), with a mean age of 36.9 years (SD 9.9 years); 55.2% had been infected with HIV via heterosexual contact. The majority of patients (53.4%) initiated cART with a CD4+ T-cell count ≤200 cells/mm3. The medications most often used in the various treatment regimens were efavirenz (59.7%) and lopinavir/ritonavir (18.2%). The proportion of individuals achieving viral suppression within the first 12 months of cART use was 77.4% (95% CI 76.1–78.6). Nearly half (45.4%) of the patients presented HIV-related clinical manifestations after starting cART, and the AIDS mortality rate was 13.9 per 1,000 person-years. Conclusions/Significance Results from cART use in the daily practice of health services remain relatively unknown in low- and middle-income countries, and studies with the characteristics of the HIV-Brazil Cohort contribute to minimizing these shortcomings, given its scope and patient profile, which is similar to that of the AIDS epidemic in the country. PMID:24789106

Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada.

PubMed

Samji, H; Taha, T E; Moore, D; Burchell, A N; Cescon, A; Cooper, C; Raboud, J M; Klein, M B; Loutfy, M R; Machouf, N; Tsoukas, C M; Montaner, J S G; Hogg, R S

2015-02-01

Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/μL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/μL at cART initiation. Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART. © 2014 British HIV Association.

Technical Performance and Clinical Effectiveness of Drop Type With Adjustable Concentrator-Cell Free and Concentrated Ascites Reinfusion Therapy.

PubMed

Yamada, Yosuke; Harada, Makoto; Yamaguchi, Akinori; Kobayashi, Yasuko; Chino, Takashi; Minowa, Takashi; Kosuge, Takashi; Tsukada, Wataru; Hashimoto, Koji; Kamijo, Yuji

2017-12-01

Cell-free and concentrated ascites reinfusion therapy (CART) is a very useful treatment method for refractory ascites but is difficult for many hospitals to employ due to its need for specialized equipment. We have therefore developed drop-type with adjustable concentrator CART (DC-CART) that uses a drop-type filtration mechanism and requires only a simple pump and pressure monitor for its concentration process. Easy adjustment of ascites concentration is possible through a recirculation loop, and filter membrane washing is aided by DC-CART's external pressure-type filtration to enable the processing of any quality or quantity of ascites. Moreover, the absence of a roller pump before filtration avoids inflammatory substance release from compressed cells. A total of 268 sessions of DC-CART using ascites from 98 patients were performed with good clinical results at our hospitals between January 2012 and June 2016. This report presents the detailed methods of DC-CART and summarizes its clinical effectiveness using patient ascites and blood data obtained from 59 sessions between March 2015 and February 2016. This novel technique successfully processed refractory ascites in numerous diseases with no serious adverse events. DC-CART could concentrate large amounts of ascites (from median weight: 4900 g [max: 20 200 g] to median weight: 695 g; median concentration ratio: 7.4), and a high amount of protein (median weight: 73 g [max: 294 g]) could be reinfused. Serum albumin levels were significantly increased (P = 0.010) and kidney function and systemic hemodynamics were well maintained in treated subjects. Additional concentration of ascites and adjustment of ascites volume were easily performed by recirculation (from median weight: 615 g to median weight: 360 g; median concentration ratio: 1.5). Time was needed during DC-CART for filter membrane cleaning, especially for viscous ascites. Overall, DC-CART represents a safe and useful treatment method for various forms of refractory ascites that can be performed at a wide range of health care institutions. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Effects of amphetamine on reactivity to emotional stimuli

PubMed Central

Wardle, Margaret C.; de Wit, Harriet

2011-01-01

Rationale Most studies of the reinforcing effects of stimulants have focused on the drugs’ capacity to induce positive mood (i.e., euphoria). However, recent findings suggest drugs may also alter emotional reactivity to external stimuli, and that this may occur independently of direct effects on mood. Objectives We aimed to examine effects of d-amphetamine, a prototypic stimulant, on self-reported and psychophysiological reactivity to emotional stimuli as well as overall subjective mood. We predicted that amphetamine would enhance reactivity to pleasant stimuli, particularly, stimuli with social content and that these effects would be independent of the drug’s direct effects on mood. Methods Over three sessions, 36 healthy normal adults received placebo, d-amphetamine 10 and 20 mg under counterbalanced double-blind conditions. At each session, emotional reactivity to standardized positive, neutral, and negative pictures with and without social content was measured in self-reports and facial muscles sensitive to emotional state. Drug effects on cardiovascular variables and subjective mood were also measured. Results Amphetamine produced euphoria, feelings of drug effect, and increased blood pressure. Most notably, amphetamine enhanced self-reported positive reactions to all pictures and psychophysiological reactions to positive pictures. These effects were not significantly related to drug-induced mood changes. Contrary to our hypothesis, effects of amphetamine on emotional reactivity were not moderated by social content. Conclusions This study demonstrates a previously unexamined and potentially reinforcing effect of stimulant drugs in humans, distinct from more typically measured euphorigenic effects, and suggests new areas of research in stimulant abuse risk and adaptations occurring during drug dependence. PMID:21947316

The predictors and consequences of adolescent amphetamine use: findings from the Victoria Adolescent Health Cohort Study.

PubMed

Degenhardt, Louisa; Coffey, Carolyn; Moran, Paul; Carlin, John B; Patton, George C

2007-07-01

Previous work has highlighted the adverse consequences of early-onset cannabis use. However, little is known about the predictors and effects of early-onset amphetamine use. We set out to examine these issues using a representative cohort of young people followed-up over 11 years in Victoria, Australia. A stratified, random sample of 1943 adolescents was recruited from secondary schools across Victoria at age 14-15 years. This cohort was interviewed on eight occasions until the age of 24-25 years (78% follow-up at that age). Cross-sectional associations were assessed using logistic regression with allowance for repeated measures. Both proportional hazards models and logistic regression models were used to assess prospective associations. Approximately 7% of the sample had used amphetamines by the age of 17 years. Amphetamine use by this age was associated with poorer mental health and other drug use. The incidence of amphetamine use during the teenage years was predicted by heavier drug use and by mental health problems. By young adulthood (age 24-25 years), adolescent amphetamine users were more likely to meet criteria for dependence upon a range of drugs, to have greater psychological morbidity and to have some limitations in educational attainment. Most of these associations were not sustained after adjustment for early-onset cannabis use. Young people in Australia who begin amphetamine use by age 17 years are at increased risk for a range of mental health, substance use and psychosocial problems in young adulthood. However, these problems are largely accounted for by their even earlier-onset cannabis use.

Sweet taste liking is associated with subjective response to amphetamine in women but not men.

PubMed

Weafer, Jessica; Lyon, Nicholas; Hedeker, Donald; de Wit, Harriet

2017-11-01

Preference for sweet taste rewards has been linked to the propensity for drug use in both animals and humans. Here, we tested the association between sweet taste liking and sensitivity to amphetamine reward in healthy adults. We hypothesized that sweet likers would report greater euphoria and stimulation following D-amphetamine (20 mg) compared to sweet dislikers. Men (n = 36) and women (n = 34) completed a sweet taste test in which they rated their liking of various concentrations of sucrose and filtered water (0.05, 0.10, 0.21, 0.42, and 0.83 M). Participants who preferred the highest concentration were classified as "sweet likers." All others were classified as "sweet dislikers." They then completed four sessions in which they received D-amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and stimulation on the Addiction Research Center Inventory (ARCI) at regular intervals. We conducted linear mixed effects models to examine relationships between sweet liking and drug-induced euphoria and stimulation. Sweet likers reported significantly greater amphetamine-induced euphoria than did sweet dislikers among women. By contrast, sweet liking was not associated with amphetamine response in men. No associations with stimulation were observed. The association between sweet preference and amphetamine response in women is consistent with animal studies linking sweet taste preference and drug reward and also fits with observations that individuals who use drugs show a preference for sweet tastes. Whether the sex difference is related to circulating hormones, or other variables, remains to be determined.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

PubMed

Ferris, Mark J; Calipari, Erin S; Rose, Jamie H; Siciliano, Cody A; Sun, Haiguo; Chen, Rong; Jones, Sara R

2015-07-01

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants.

PubMed

Dopheide, Marsha M; Morgan, Russell E; Rodvelt, Kelli R; Schachtman, Todd R; Miller, Dennis K

2007-07-30

Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (<100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.

Amphetamine reward in food restricted mice lacking the melanin-concentrating hormone receptor-1.

PubMed

Geuzaine, Annabelle; Tyhon, Amélie; Grisar, Thierry; Brabant, Christian; Lakaye, Bernard; Tirelli, Ezio

2014-04-01

Chronic food restriction (FR) and maintenance of low body weight have long been known to increase the rewarding and motor-activating effects of addictive drugs. However, the neurobiological mechanisms through which FR potentiates drug reward remain largely unknown. Melanin-concentrating hormone (MCH) signaling could be one of these mechanisms since this peptide is involved in energy homeostasis and modulates mesolimbic dopaminergic transmission. The purpose of the present study was to test this hypothesis by investigating the impact of FR on amphetamine reward in wild-type (WT) and knockout mice lacking the melanin-concentrating hormone receptor-1 (MCHR1-KO). The rewarding effects of amphetamine (0.75-2.25 mg/kg, i.p.) were measured with the conditioned place preference (CPP) technique. The food of the mice was restricted to maintain their body weight at 80-85% of their free-feeding (FF) weight throughout the entire CPP experiment. Locomotor activity of the animals was recorded during the conditioning sessions. Our results show that locomotion of all the food-restricted mice treated with saline or amphetamine increased over the sessions whatever the genotype. On the place preference test, the amplitude of CPP induced by 0.75 mg/kg amphetamine was higher in food restricted WT mice than in free-fed WT mice and food restricted MCHR1-KO mice. However, FR did not affect amphetamine reward in MCHR1-KO mice. The present results indicate that MCH signaling could be involved in the ability of FR to increase amphetamine-induced CPP. Copyright © 2014 Elsevier B.V. All rights reserved.

Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines.

PubMed

McBride, Shawna M; Culver, Bruce; Flynn, Francis W

2006-10-01

Acute sodium deficiency sensitizes adult rats to psychomotor effects of amphetamine. This study determined whether prenatal and early life manipulation of dietary sodium sensitized adult offspring to psychomotor effects of amphetamine (1 or 3 mg/kg ip) in two strains of rats. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) dams were fed chow containing low NaCl (0.12%; LN), normal NaCl (1%; NN), or high NaCl (4%; HN) throughout breeding, gestation, and lactation. Male offspring were maintained on the test diet for an additional 3 wk postweaning and then fed standard chow thereafter until testing began. Overall, blood pressure (BP), total fluid intake, salt preference, and adrenal gland weight were greater in SHR than in WKY. WKY LN offspring had greater water intake and adrenal gland weight than did WKY NN and HN offspring, whereas WKY HN offspring had increased BP, salt intake, and salt preference compared with other WKY offspring. SHR HN offspring also had increased BP compared with other SHR offspring; all other measures were similar for SHR offspring. The low-dose amphetamine increased locomotor and stereotypical behavior compared with baseline and saline injection in both WKY and SHR offspring. Dietary sodium history affected the rats' psychomotor response to the higher dose of amphetamine. Injections of 3 mg/kg amphetamine in both strains produced significantly more behavioral activity in the LN offspring than in NN and HN offspring. These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine.

Psychostimulants and forced swim stress interaction: how activation of the hypothalamic-pituitary-adrenal axis and stress-induced hyperglycemia are affected.

PubMed

Gagliano, Humberto; Ortega-Sanchez, Juan Antonio; Nadal, Roser; Armario, Antonio

2017-10-01

We recently reported that simultaneous exposure to amphetamine and various stressors resulted in reduced hypothalamic-pituitary-adrenal (HPA) and glycemic responses to the stressors. Since this is a new and relevant phenomenon, we wanted to further explore this interaction. This study aims (i) to characterize the effect of various doses of amphetamine on the physiological response to a predominantly emotional stressor (forced swim) when the drug was given immediately before stress; (ii) to study if an interaction appears when the drug was given 30 min or 7 days before swim; and (iii) to know whether cocaine causes similar effects when given just before stress. Adult male rats were used and plasma levels of ACTH, corticosterone, and glucose were the outcomes. Amphetamine caused a dose-dependent activation of the HPA axis, but all doses reduced HPA and glycemic responses to swim when given just before the stressor. Importantly, during the post-swim period, the stressor potently inhibited the ACTH response to amphetamine, demonstrating mutual inhibition between the two stimuli. The highest dose of amphetamine also reduced the response to swim when given 30 min before stress, whereas it caused HPA sensitization when given 7 days before. Cocaine also reduced stress-induced HPA activation when given just before swim. The present results demonstrate a negative synergy between psychostimulants (amphetamine and cocaine) and stress regarding HPA and glucose responses when rats were exposed simultaneously to both stimuli. The inhibitory effect of amphetamine is also observed when given shortly before stress, but not some days before.

Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine.

PubMed

Pedrazzi, J F C; Issy, A C; Gomes, F V; Guimarães, F S; Del-Bel, E A

2015-08-01

The information processing appears to be deficient in schizophrenia. Prepulse inhibition (PPI), which measures the inhibition of a motor response by a weak sensory event, is considered particularly useful to understand the biology of information processing in schizophrenia patients. Drugs that facilitate dopaminergic neurotransmission such as amphetamine induce PPI disruption in human and rodents. Clinical and neurobiological findings suggest that the endocannabinoid system and cannabinoids may be implicated in the pathophysiology and treatment of schizophrenia. Cannabidiol (CBD), a non-psychotomimetic constituent of the Cannabis sativa plant, has also been reported to have potential as an antipsychotic. Our aim was to investigate if CBD pretreatment was able to prevent PPI disruption induced by amphetamine. Since one possible mechanism of CBD action is the facilitation of endocannabinoid-mediated neurotransmission through anandamide, we tested the effects of an anandamide hydrolysis inhibitor (URB597) in the amphetamine-induced PPI disruption. Male Swiss mice were treated with CBD systemic or intra-accumbens, or URB597 (systemic) prior to amphetamine and were exposed to PPI test. Amphetamine (10 mg/kg) disrupted PPI while CBD (15-60 mg/kg) or URB597 (0.1-1 mg/kg) administered alone had no effect. Pretreatment with CBD attenuated the amphetamine-disruptive effects on PPI test after systemic or intra-accumbens administration. Similar effects were also found with the inhibitor of anandamide hydrolysis. These results corroborate findings indicating that CBD induces antipsychotic-like effects. In addition, they pointed to the nucleus accumbens as a possible site of these effects. The increase of anandamide availability may be enrolled in the CBD effects.

Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos

PubMed Central

Joseph, Shai R; Pálfy, Máté; Hilbert, Lennart; Kumar, Mukesh; Karschau, Jens; Zaburdaev, Vasily; Shevchenko, Andrej; Vastenhouw, Nadine L

2017-01-01

Upon fertilization, the genome of animal embryos remains transcriptionally inactive until the maternal-to-zygotic transition. At this time, the embryo takes control of its development and transcription begins. How the onset of zygotic transcription is regulated remains unclear. Here, we show that a dynamic competition for DNA binding between nucleosome-forming histones and transcription factors regulates zebrafish genome activation. Taking a quantitative approach, we found that the concentration of non-DNA-bound core histones sets the time for the onset of transcription. The reduction in nuclear histone concentration that coincides with genome activation does not affect nucleosome density on DNA, but allows transcription factors to compete successfully for DNA binding. In agreement with this, transcription factor binding is sensitive to histone levels and the concentration of transcription factors also affects the time of transcription. Our results demonstrate that the relative levels of histones and transcription factors regulate the onset of transcription in the embryo. DOI: http://dx.doi.org/10.7554/eLife.23326.001 PMID:28425915

Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos.

PubMed

Joseph, Shai R; Pálfy, Máté; Hilbert, Lennart; Kumar, Mukesh; Karschau, Jens; Zaburdaev, Vasily; Shevchenko, Andrej; Vastenhouw, Nadine L

2017-04-20

Upon fertilization, the genome of animal embryos remains transcriptionally inactive until the maternal-to-zygotic transition. At this time, the embryo takes control of its development and transcription begins. How the onset of zygotic transcription is regulated remains unclear. Here, we show that a dynamic competition for DNA binding between nucleosome-forming histones and transcription factors regulates zebrafish genome activation. Taking a quantitative approach, we found that the concentration of non-DNA-bound core histones sets the time for the onset of transcription. The reduction in nuclear histone concentration that coincides with genome activation does not affect nucleosome density on DNA, but allows transcription factors to compete successfully for DNA binding. In agreement with this, transcription factor binding is sensitive to histone levels and the concentration of transcription factors also affects the time of transcription. Our results demonstrate that the relative levels of histones and transcription factors regulate the onset of transcription in the embryo.

Psychotic disorders among inpatients with abuse of cannabis, amphetamine and opiates. Do dopaminergic stimulants facilitate psychiatric illness?

PubMed

Dalmau, A; Bergman, B; Brismar, B

1999-11-01

We have studied the occurrence of dual diagnoses (psychoses as well as abuse of either amphetamine, cannabis or opiates) during a 15-year period, among patients treated at Huddinge Hospital, Stockholm, Sweden. The purpose of the study is to evaluate if the different drugs were coupled to different rates of psychiatric co-morbidity. During the period in question, 461, 425 and 371 different patients respectively had been admitted at least once due to dependency on amphetamine, cannabis and opiates. Approximately 30% of the patients with a pure abuse of amphetamine or cannabis and less than 6% of the opiate abusers had been diagnosed at least once with any of the psychoses studied. Comparing the frequency of psychoses among mixed and pure abusers of illegal drugs, with and without a concomitant abuse of alcohol, we found that the co-morbidity rate for mixed opiate abusers increased significantly from 7.2 to 20.2% when alcohol abuse was also present. For abusers of amphetamine and cannabis (both pure and mixed), no differences in co-morbidity rates were seen when an abuse of alcohol was added to that of the drugs. It is difficult to find an explanation for the significant difference between the co-morbidity of pure abuse of amphetamine or cannabis on the one hand and opiates on the other. In conclusion, our findings show that the distribution of psychotic illness is high among abusers of amphetamine and cannabis, in contrast to the generally lower co-morbidity among abusers of opiates. Although these findings are consistent with earlier studies that have shown a propensity for developing psychoses among abusers of amphetamine and cannabis, one should bear in mind that this study is based on inpatients, and is not necessarily representative for all abusers of the drugs in question.

An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis.

PubMed

Dias da Silva, Diana; Carmo, Helena; Lynch, Adam; Silva, Elisabete

2013-12-01

The liver is a vulnerable target for amphetamine toxicity, but the mechanisms involved in the drug's hepatotoxicity remain poorly understood. The purpose of the current research was to characterize the mode of death elicited by four amphetamines and to evaluate whether their combination triggered similar mechanisms in immortalized human HepG2 cells. The obtained data revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy; 1.3 mM), methamphetamine (3 mM), 4-methylthioamphetamine (0.5 mM) and D-amphetamine (1.7 mM), alone or combined (1.6 mM mixture). At physiological temperature (37 °C), 24-h exposures caused HepG2 death preferentially by apoptosis, while a rise to 40.5 °C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5 °C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels, with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels was also seen. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. The cell dismantling was confirmed by poly(ADP-ribose)polymerase proteolysis. Overall, for all evaluated parameters, no relevant differences were detected between individual amphetamines and the mixture (all tested at equieffective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually, when eliciting HepG2 cell death.

Evidence for Fibroblast Growth Factor-2 as a Mediator of Amphetamine-Enhanced Motor Improvement following Stroke

PubMed Central

Wolf, William A.; Martin, Jody L.; Kartje, Gwendolyn L.; Farrer, Robert G.

2014-01-01

Previously we have shown that addition of amphetamine to physical therapy results in enhanced motor improvement following stroke in rats, which was associated with the formation of new motor pathways from cortical projection neurons of the contralesional cortex. It is unclear what mechanisms are involved, but amphetamine is known to induce the neuronal release of catecholamines as well as upregulate fibroblast growth factor-2 (FGF-2) expression in the brain. Since FGF-2 has been widely documented to stimulate neurite outgrowth, the present studies were undertaken to provide evidence for FGF-2 as a neurobiological mechanism underlying amphetamine-induced neuroplasticity. In the present study rats that received amphetamine plus physical therapy following permanent middle cerebral artery occlusion exhibited significantly greater motor improvement over animals receiving physical therapy alone. Amphetamine plus physical therapy also significantly increased the number of FGF-2 expressing pyramidal neurons of the contralesional cortex at 2 weeks post-stroke and resulted in significant axonal outgrowth from these neurons at 8 weeks post-stroke. Since amphetamine is a known releaser of norepinephrine, in vitro analyses focused on whether noradrenergic stimulation could lead to neurite outgrowth in a manner requiring FGF-2 activity. Primary cortical neurons did not respond to direct stimulation by norepinephrine or amphetamine with increased neurite outgrowth. However, conditioned media from astrocytes exposed to norepinephrine or isoproterenol (a beta adrenergic agonist) significantly increased neurite outgrowth when applied to neuronal cultures. Adrenergic agonists also upregulated FGF-2 expression in astrocytes. Pharmacological analysis indicated that beta receptors and alpha1, but not alpha2, receptors were involved in both effects. Antibody neutralization studies demonstrated that FGF-2 was a critical contributor to neurite outgrowth induced by astrocyte-conditioned media. Taken together the present results suggest that noradrenergic activation, when combined with physical therapy, can improve motor recovery following ischemic damage by stimulating the formation of new neural pathways in an FGF-2-dependent manner. PMID:25229819

Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation

PubMed Central

Amelio, Antonio L; Caputi, Massimo; Conkright, Michael D

2009-01-01

The CREB regulated transcription co-activators (CRTCs) regulate many biological processes by integrating and converting environmental inputs into transcriptional responses. Although the mechanisms by which CRTCs sense cellular signals are characterized, little is known regarding how CRTCs contribute to the regulation of cAMP inducible genes. Here we show that these dynamic regulators, unlike other co-activators, independently direct either pre-mRNA splice-site selection or transcriptional activation depending on the cell type or promoter context. Moreover, in other scenarios, the CRTC co-activators coordinately regulate transcription and splicing. Mutational analyses showed that CRTCs possess distinct functional domains responsible for regulating either pre-mRNA splicing or transcriptional activation. Interestingly, the CRTC1–MAML2 oncoprotein lacks the splicing domain and is incapable of altering splice-site selection despite robustly activating transcription. The differential usage of these distinct domains allows CRTCs to selectively mediate multiple facets of gene regulation, indicating that co-activators are not solely restricted to coordinating alternative splicing with increase in transcriptional activity. PMID:19644446

Post-transcriptional regulation tends to attenuate the mRNA noise and to increase the mRNA gain

NASA Astrophysics Data System (ADS)

Shi, Changhong; Wang, Shuqiang; Zhou, Tianshou; Jiang, Yiguo

2015-10-01

Post-transcriptional regulation is ubiquitous in prokaryotic and eukaryotic cells, but how it impacts gene expression remains to be fully explored. Here, we analyze a simple gene model in which we assume that mRNAs are produced in a constitutive manner but are regulated post-transcriptionally by a decapping enzyme that switches between the active state and the inactive state. We derive the analytical mRNA distribution governed by a chemical master equation, which can be well used to analyze the mechanism of how post-transcription regulation influences the mRNA expression level including the mRNA noise. We demonstrate that the mean mRNA level in the stochastic case is always higher than that in the deterministic case due to the stochastic effect of the enzyme, but the size of the increased part depends mainly on the switching rates between two enzyme states. More interesting is that we find that in contrast to transcriptional regulation, post-transcriptional regulation tends to attenuate noise in mRNA. Our results provide insight into the role of post-transcriptional regulation in controlling the transcriptional noise.

NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines.

PubMed

2005-07-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).

Participation of ghrelin signalling in the reciprocal regulation of hypothalamic NPY/POMC-mediated appetite control in amphetamine-treated rats.

PubMed

Yu, Ching-Han; Chu, Shu-Chen; Chen, Pei-Ni; Hsieh, Yih-Shou; Kuo, Dong-Yih

2017-06-01

Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) have been documented to participate in amphetamine (AMPH)-induced appetite suppression. This study investigated whether ghrelin signalling is associated with changes in NPY/POMC-mediated appetite control. Rats were given AMPH daily for four days, and changes in food intake, body weight, plasma ghrelin, hypothalamic NPY, melanocortin 3 receptor (MC3R), ghrelin O-acyltransferase (GOAT), acyl ghrelin (AG) and ghrelin receptor (GHSR1a) were examined and compared. Food intake, body weight and NPY expression decreased, while MC3R expression increased and expressed reciprocally to NPY expression during AMPH treatment. Plasma ghrelin and hypothalamic AG/GOAT/GHSR1a expression decreased on Day 1 and Day 2, which was associated with the positive energy metabolism, and returned to normal levels on Day 3 and Day 4, which was associated with the negative energy metabolism; this expression pattern was similar to that of NPY. Infusion with a GHSR1a antagonist or an NPY antisense into the brain enhanced the decrease in NPY and AG/GOAT/GHSR1a expression and the increase in MC3R expression compared to the AMPH-treated group. Peripheral ghrelin and the central ghrelin system participated in the regulation in AMPH-induced appetite control. These results shed light on the involvement of ghrelin signalling in reciprocal regulation of NPY/POMC-mediated appetite control and may prove useful for the development of anti-obesity drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

STS-37 crewmembers test CETA hand cart during training session in JSC's WETF

NASA Technical Reports Server (NTRS)

1989-01-01

STS-37 Atlantis, Orbiter Vehicle (OV) 104, Mission Specialist (MS) Jerry L. Ross and MS Jerome Apt test crew and equipment translation aid (CETA) manual hand over hand cart during underwater session in JSC's Weightless Environment Training Facility (WETF) Bldg 29. Wearing an extravehicular mobility unit (EMU), Ross pulls the CETA manual cart along the rail while Apt holds onto the back of the cart. The test will determine how difficult it is to maneuver cargo in such a manner when it is done in space on STS-37. The goal is to find the best method for astronauts to move around the exterior of Space Station Freedom (SSF).

Object Transportation by Two Mobile Robots with Hand Carts

PubMed Central

Hara, Tatsunori

2014-01-01

This paper proposes a methodology by which two small mobile robots can grasp, lift, and transport large objects using hand carts. The specific problems involve generating robot actions and determining the hand cart positions to achieve the stable loading of objects onto the carts. These problems are solved using nonlinear optimization, and we propose an algorithm for generating robot actions. The proposed method was verified through simulations and experiments using actual devices in a real environment. The proposed method could reduce the number of robots required to transport large objects with 50–60%. In addition, we demonstrated the efficacy of this task in real environments where errors occur in robot sensing and movement. PMID:27433499

Object Transportation by Two Mobile Robots with Hand Carts.

PubMed

Sakuyama, Takuya; Figueroa Heredia, Jorge David; Ogata, Taiki; Hara, Tatsunori; Ota, Jun

2014-01-01

This paper proposes a methodology by which two small mobile robots can grasp, lift, and transport large objects using hand carts. The specific problems involve generating robot actions and determining the hand cart positions to achieve the stable loading of objects onto the carts. These problems are solved using nonlinear optimization, and we propose an algorithm for generating robot actions. The proposed method was verified through simulations and experiments using actual devices in a real environment. The proposed method could reduce the number of robots required to transport large objects with 50-60%. In addition, we demonstrated the efficacy of this task in real environments where errors occur in robot sensing and movement.

The 5th Symposium on Post-Transcriptional Regulation of Plant Gene Expression (PTRoPGE)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karen S. Browning; Marie Petrocek; Bonnie Bartel

2006-06-01

The 5th Symposium on Post-Transcriptional Regulation of Plant Gene Expression (PTRoPGE) will be held June 8-12, 2005 at the University of Texas at Austin. Exciting new and ongoing discoveries show significant regulation of gene expression occurs after transcription. These post-transcriptional control events in plants range from subtle regulation of transcribed genes and phosphorylation, to the processes of gene regulation through small RNAs. This meeting will focus on the regulatory role of RNA, from transcription, through translation and finally degradation. The cross-disciplinary design of this meeting is necessary to encourage interactions between researchers that have a common interest in post-transcriptional genemore » expression in plants. By bringing together a diverse group of plant molecular biologist and biochemists at all careers stages from across the world, this meeting will bring about more rapid progress in understanding how plant genomes work and how genes are finely regulated by post-transcriptional processes to ultimately regulate cells.« less

Chimeric Antigen Receptor T Cells and Hematopoietic Cell Transplantation: How Not to Put the CART Before the Horse.

PubMed

Kenderian, Saad S; Porter, David L; Gill, Saar

2017-02-01

Hematopoietic cell transplantation (HCT) remains an important and potentially curative option for most hematologic malignancies. As a form of immunotherapy, allogeneic HCT (allo-HCT) offers the potential for durable remissions but is limited by transplantation- related morbidity and mortality owing to organ toxicity, infection, and graft-versus-host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematologic malignancies as well. Clinical trials are now needed to address the relative roles of CART cells and HCT in the context of transplantation-eligible patients. In this review, we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma, and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Amphetamines

MedlinePlus

... site Sitio para adolescentes Body Mind Sexual Health Food & Fitness Diseases & ... español Anfetaminas What It Is: Amphetamines are very addictive stimulants. They speed up functions in the brain and ...

Second Servings and a La Carte Sales to Elementary Children in the National School Lunch Program and Potential Implications for Childhood Obesity

ERIC Educational Resources Information Center

Wilder, Amanda J.

2012-01-01

The sale of second servings and/or a la carte purchases made by elementary students participating in the National School Lunch Program (NSLP) was investigated in this mixed methods case study. The percentage of elementary students in one school district who purchase second servings and/or a la carte items, in addition to the regularly purchased…

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

PubMed Central

Steinkellner, Thomas; Freissmuth, Michael; Sitte, Harald H.; Montgomery, Therese

2015-01-01

Amphetamine (‘Speed’), methamphetamine (‘Ice’) and its congener 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity. PMID:21194370

Towards an HIV cure based on targeted killing of infected cells: different approaches against acute versus chronic infection.

PubMed

Dey, Barna; Berger, Edward A

2015-05-01

Current regimens of combination antiretroviral therapy (cART) offer effective control of HIV infection, with maintenance of immune health and near-normal life expectancy. What will it take to progress beyond the status quo, whereby infectious virus can be eradicated (a 'sterilizing cure') or fully controlled without the need for ongoing cART (a 'functional cure')? On the basis of therapeutic advances in the cancer field, we propose that targeted cytotoxic therapy to kill HIV-infected cells represents a logical complement to cART for achieving an HIV cure. This concept is based on the fact that cART effectively blocks replication of the virus, but does not eliminate cells that are already infected; targeted cytotoxic therapy would contribute precisely this missing component. We suggest that different modalities are suited for curing primary acute versus established chronic infection. For acute infection, relatively short-acting potent agents such as recombinant immunotoxins might prove sufficient for HIV eradication, whereas for chronic infection, a long-lasting (lifelong?) modality is required to maintain full virus control, as might be achieved with genetically modified autologous T cells. We present perspectives for complementing cART with targeted cytotoxic therapy, whereby HIV infection is either eradicated or fully controlled, thereby eliminating the need for lifelong cART.

Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma

PubMed Central

Gilmore, Sarah A.; Voorhies, Mark; Gebhart, Dana; Sil, Anita

2015-01-01

Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5’ leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature. PMID:26177267

Genome-Wide Reprogramming of Transcript Architecture by Temperature Specifies the Developmental States of the Human Pathogen Histoplasma.

PubMed

Gilmore, Sarah A; Voorhies, Mark; Gebhart, Dana; Sil, Anita

2015-07-01

Eukaryotic cells integrate layers of gene regulation to coordinate complex cellular processes; however, mechanisms of post-transcriptional gene regulation remain poorly studied. The human fungal pathogen Histoplasma capsulatum (Hc) responds to environmental or host temperature by initiating unique transcriptional programs to specify multicellular (hyphae) or unicellular (yeast) developmental states that function in infectivity or pathogenesis, respectively. Here we used recent advances in next-generation sequencing to uncover a novel re-programming of transcript length between Hc developmental cell types. We found that ~2% percent of Hc transcripts exhibit 5' leader sequences that differ markedly in length between morphogenetic states. Ribosome density and mRNA abundance measurements of differential leader transcripts revealed nuanced transcriptional and translational regulation. One such class of regulated longer leader transcripts exhibited tight transcriptional and translational repression. Further examination of these dually repressed genes revealed that some control Hc morphology and that their strict regulation is necessary for the pathogen to make appropriate developmental decisions in response to temperature.

Pediatric head and neck injuries due to golf cart trauma.

PubMed

Miller, Brandon; Yelverton, Eden; Monico, Jesus; Replogle, William; Jordan, J Randall

2016-09-01

Golf carts are increasingly used off the golf course and are often viewed as innocuous modes of transportation. However, research has shown they can cause significant injuries, particularly to children. Analyze golf cart related head and neck injuries in children and adults from a national database. The National Electronic Injury Surveillance System (NEISS) was queried for golf cart injuries. The NEISS tracks consumer product related injuries from a sampling of approximately 100 emergency departments across the United States. Age, general diagnosis (concussion, fracture, laceration), body-part injured, disposition (hospitalized, discharged), location injury occurred, and mechanism of injury were analyzed. Over an 11-year period, a total of 3433 total patients were identified. There were 1471 children (16 years old or younger), which compromised 42.9% of the cohort. Children were injured at home or on the road 44.7% of the time compared to only 16.6% of adults (p < 0.003). Children injured their head or neck 42.6% of the time compared to 28.6% of adults (p < 0.0001). Adults who were hit by a car while riding a golf cart or were ejected from the golf cart 44.6% of the time compared to 61.7% of children (p < 0.0001). There were 3.9% of children with a face, head, or neck fracture compared to only 2.4% of adults (p = 0.01). Children are more vulnerable to golf cart related injuries, specifically to the head and neck. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.