The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.

PubMed

De Gregorio, Danilo; Posa, Luca; Ochoa-Sanchez, Rafael; McLaughlin, Ryan; Maione, Sabatino; Comai, Stefano; Gobbi, Gabriella

2016-11-01

d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT 1 and 5-HT 2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT 2A and D 2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D 2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1 ) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT 1A, D 2 and TAAR 1 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Caffeine's Attenuation of Cocaine-Induced Dopamine Release by Inhibition of Adenosine.

PubMed

Malave, Lauren B; Broderick, Patricia A

2014-06-01

Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE ® was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo , in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction.

Caffeine's Attenuation of Cocaine-Induced Dopamine Release by Inhibition of Adenosine

PubMed Central

Malave, Lauren B.

2014-01-01

Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE® was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo, in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction. PMID:25054079

High Doses of Amphetamine Augment, Rather Than Disrupt, Exocytotic Dopamine Release in the Dorsal and Ventral Striatum of the Anesthetized Rat

PubMed Central

Ramsson, Eric S.; Howard, Christopher D.; Covey, Dan P.; Garris, Paul A.

2011-01-01

High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata. An equivalent high dose of cocaine (40 mg/kg) was also examined for comparison to psychostimulants acting preferentially by DAT inhibition. Parameters describing exocytotic DA release and neuronal DA uptake were determined from dynamic DA signals evoked by mild electrical stimulation previously established to be reinforcing. High-sensitivity FSCV with nanomolar detection was used to monitor changes in the background voltammetric signal as an index of DA efflux. Both doses of AMPH and cocaine markedly elevated evoked DA levels over the entire 2-h time course in the dorsal and ventral striatum. These increases were mediated by augmented vesicular DA release and diminished DA uptake typically acting concurrently. AMPH, but not cocaine, induced a slow, DA-like rise in some baseline recordings. However, this effect was highly variable in amplitude and duration, modest, and generally not present at all. These data thus describe a mechanistically similar activation of action potential-dependent dopaminergic neurotransmission by AMPH and cocaine in vivo. Moreover, DA efflux appears to be a unique, but secondary, AMPH action. PMID:21806614

Domoic acid toxicokinetics in Dungeness crabs: new insights into mechanisms that regulate bioaccumulation.

PubMed

Schultz, Irvin R; Skillman, Ann; Sloan-Evans, Siobhan; Woodruff, Dana

2013-09-15

Domoic acid (DA) is an excitatory neurotoxic amino acid produced by several marine algal species and is the causative agent of amnesic shellfish poisoning. Profound differences in the toxicokinetics of DA have been identified in a wide variety of shellfish. We characterized the toxicokinetics of DA in Dungeness crabs (Metacarcinus magister) after oral and intravascular dosing (IV) using a variety of doses ranging from 0.1 to 20mg/kg. After a 1mg/kg oral dose, DA disappeared from the foregut within 2h and largely accumulated in the hepatopancreas, with hemolymph and other tissues having 100-1000 times lower concentrations. After IV dosing, hemolymph concentrations of DA were unexpectedly high and toxicokinetic analysis indicated the steady-state volume of distribution (Vss) was 123-197 ml/kg, which is well below the hemolymph volume of 350 ml/kg for crabs. This indicated only limited extravascular distribution of DA was occurring after IV injection, which is surprising considering the capacity of the hepatopancreas to sequester DA after oral dosing. Additional studies measured the partitioning of DA in hepatopancreas cellular and subcellular fractions. The subcellular distribution of DA was primarily associated with the S8 fraction and could be filtered through a 30,000 MW cut-off filter, indicating DA was not appreciably bound to macromolecules. Interestingly, very little (<0.4%) of the total hepatopancreas DA tissue content was associated with the cellular fraction isolated after dissociation and separation from tissue fragments. The in vivo and in vitro results led us to hypothesize that DA uptake and distribution is regulated by crustacean orthologs of ATP-binding cassette (ABC) type transporters. We tested this hypothesis by co-exposing crabs to DA and known inhibitors of ABC transporters (verapamil, cyclosporine A and MK-571) and through in vitro studies using isolated hepatopancreas tissue and mixed cell suspensions prepared from hepatopancreas tissue. The in vivo results were inconclusive in that the toxicokinetics of DA was not consistently altered by co-administration of the inhibitors. Two exceptions were MK-571, which significantly increased the total body clearance of DA and co-administration of verapamil, which significantly increased the hepatopancreas tissue content of DA 24h after IV injection. Isolated pieces of hepatopancreas tissue were able to readily absorb DA from incubation media, but mixed cell suspensions did not. The absorption of DA or lack thereof was largely unaffected by co-incubation with verapamil although cell suspensions appeared to accumulate small quantities of DA in the presence of verapamil. Collectively, the results of this study suggest DA accumulates in the extracellular spaces of the hepatopancreas, such as the tubular lumen. Under natural circumstances, crabs feeding on contaminated shellfish would be expected to readily absorb DA, which is then stored and slowly eliminated in urine. If the DA exposure level exceeds the storage capacity of the tissue (as occurred with the 20mg/kg dose), breakthrough occurs resulting in much higher systemic exposure and potential for DA toxicity. Copyright © 2013 Elsevier B.V. All rights reserved.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

PubMed

Galle, Jan-Christoph; Addison, Janet; Suranyi, Michael G; Claes, Kathleen; Di Giulio, Salvatore; Guerin, Alain; Herlitz, Hans; Kiss, István; Farouk, Mourad; Manamley, Nick; Wirnsberger, Gerhard; Winearls, Christopher

2016-12-01

Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

PubMed

Volkow, N D; Wang, G; Fowler, J S; Logan, J; Gerasimov, M; Maynard, L; Ding, Y; Gatley, S J; Gifford, A; Franceschi, D

2001-01-15

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.

Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats.

PubMed

Jung, Ji Won; Kwon, Yong Sam; Jeong, Jin Seok; Son, Miwon; Kang, Hee Eun

2015-01-01

DA-9701, a new botanical gastroprokinetic agent, has potential for the management of delayed gastric emptying in Parkinson's disease if it has no central anti-dopaminergic activity. Therefore, we examined the pharmacokinetics of DA-9701 components having dopamine D2 receptor antagonizing activity, tetrahydropalmatine (THP) and tetrahydroberberine (THB), following various oral doses (80-328 mg/kg) of DA-9701. The distribution of THP and THB to the brain and/or other tissues was also evaluated after single or multiple oral administrations of DA-9701. Oral administration of DA-9701 yielded dose-proportional area under the plasma concentration-time curve (AUC0-8 h) and maximum plasma concentration (Cmax) values for THP and THB, indicating linear pharmacokinetics (except for THB at the lowest dose). THP and THB's large tissue-to-plasma concentration ratios indicated considerable tissue distribution. High concentrations of THP and THB in the stomach and small intestine suggest an explanation for DA-9701's potent gastroprokinetic activity. The maximum concentrations of THP and THB in brain following multiple oral DA-9701 for 7 d (150 mg/kg/d) was observed at 30 min after the last oral DA-9701 treatment: 131±67.7 ng/g for THP and 6.97±4.03 ng/g for THB. Although both THP and THB pass through the blood-brain barrier, as indicated by brain-to-plasma concentration ratios greater than unity (approximately 2-4), oral administration of DA-9701 at the effective dose in humans is not expected to lead to sufficient brain concentrations to exert central dopamine D2 receptor antagonism.

Modafinil Activates Phasic Dopamine Signaling in Dorsal and Ventral Striata

PubMed Central

Bobak, Martin J.; Weber, Matthew W.; Doellman, Melissa A.; Schuweiler, Douglas R.; Athens, Jeana M.; Juliano, Steven A.

2016-01-01

Modafinil (MOD) exhibits therapeutic efficacy for treating sleep and psychiatric disorders; however, its mechanism is not completely understood. Compared with other psychostimulants inhibiting dopamine (DA) uptake, MOD weakly interacts with the dopamine transporter (DAT) and modestly elevates striatal dialysate DA, suggesting additional targets besides DAT. However, the ability of MOD to induce wakefulness is abolished with DAT knockout, conversely suggesting that DAT is necessary for MOD action. Another psychostimulant target, but one not established for MOD, is activation of phasic DA signaling. This communication mode during which burst firing of DA neurons generates rapid changes in extracellular DA, the so-called DA transients, is critically implicated in reward learning. Here, we investigate MOD effects on phasic DA signaling in the striatum of urethane-anesthetized rats with fast-scan cyclic voltammetry. We found that MOD (30–300 mg/kg i.p.) robustly increases the amplitude of electrically evoked phasic-like DA signals in a time- and dose-dependent fashion, with greater effects in dorsal versus ventral striata. MOD-induced enhancement of these electrically evoked amplitudes was mediated preferentially by increased DA release compared with decreased DA uptake. Principal component regression of nonelectrically evoked recordings revealed negligible changes in basal DA with high-dose MOD (300 mg/kg i.p.). Finally, in the presence of the D2 DA antagonist, raclopride, low-dose MOD (30 mg/kg i.p.) robustly elicited DA transients in dorsal and ventral striata. Taken together, these results suggest that activation of phasic DA signaling is an important mechanism underlying the clinical efficacy of MOD. PMID:27733628

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

Fox, Donald A., E-mail: dafox@uh.edu; Department of Biology and Biochemistry, University of Houston, Houston, TX; Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was {<=} 1,more » {<=} 10, {approx} 25 and {approx} 40 {mu}g/dL, respectively, on PN10 and by PN30 all were {<=} 1 {mu}g/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. -- Highlights: Black-Right-Pointing-Pointer Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: {<=} 1, {<=} 10, 25 and 40 {mu}g/dL Black-Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased the number of TH-immunoreactive dopaminergic amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure selectively decreased dopaminergic, but not GABAergic, glycinergic or cholinergic, amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased retinal dopamine content, its metabolites and dopamine utilization Black-Right-Pointing-Pointer A decrease in dopamine can alter ERG amplitudes, circadian rhythms, dark/light adaptation and spatial contrast sensitivity.« less

Preservation of anemia control and weekly ESA dosage after conversion from PEG-Epoetin beta to darbepoetin alfa in adult hemodialysis patients: the TRANSFORM study.

PubMed

Donck, Jan; Gonzalez-Tabares, Lourdes; Chanliau, Jacques; Martin, Heike; Stamatelou, Kyriaki; Manamley, Nick; Farouk, Mourad; Addison, Janet

2014-11-01

There is scant real-world information on switching treatment for anemia associated with chronic kidney disease (CKD) from methoxy polyethylene glycol-epoetin beta (PEG-Epo) to darbepoetin alfa (DA). TRANSFORM was a multi-center, observational study designed to describe the time course of hemoglobin (Hb) concentration (primary outcome measure) and other parameters of clinical management of anemia in European hemodialysis patients in clinical practice before and after a switch from PEG-Epo to DA. Eligible subjects were adult patients with CKD dialyzed at European dialysis centers for ≥26 weeks and treated with PEG-Epo for ≥14 weeks immediately prior to being switched to DA and no earlier than January 2011. Erythropoiesis-stimulating agent doses and Hb values were recorded for the 14-week pre-switch and 26-week post-switch periods. Of the 1,027 eligible patients enrolled at 42 hemodialysis centers in 7 European countries, 785 were included in analyses. Mean (95% confidence interval [CI]) Hb was generally stable: 11.19 (11.11, 11.26), 11.48 (11.40, 11.57), and 11.29 (11.20, 11.37) g/dL at month -1 pre-switch and months 3 and 6 post-switch, respectively. The geometric mean (95% CI) PEG-Epo dose at month -1 was 27.4 (26.0, 28.8) µg/week; DA dose was 29.4 (27.9, 30.9), 23.3 (21.9, 24.9), and 25.6 (24.1, 27.1) µg/week at months 1, 4, and 6, respectively. The geometric mean (95% CI) dose ratio at switching was 1.06 (1.01, 1.11). When stratifying by dose-ratio categories <0.8, 0.8-1.2, and >1.2 at switching, mean DA dose and Hb converged within narrow ranges by month 6 post-switch: 23.9-27.0 µg/week and 11.1-11.5 g/dL, respectively. Hb excursions <10 g/dL were less frequent post-switch versus pre-switch. Mean Hb values remained within a narrow range following switching from PEG-Epo to DA in this population of hemodialysis patients. Time trends of mean Hb and DA dose indicate that physicians titrated DA doses post-switch, to attain Hb concentrations comparable to those attained pre-switch with PEG-Epo.

Costs Associated With Intravenous Darbepoetin Versus Epoetin Therapy in Hemodialysis Patients: A Randomized Controlled Trial

PubMed Central

Woodland, Andrea L.; Murphy, Sean W.; Curtis, Bryan M.; Barrett, Brendan J.

2017-01-01

Background: Anemia of chronic kidney disease is associated with adverse outcomes and a reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have improved anemia management, and 2 agents are available in Canada, epoetin alfa (EPO) and darbepoetin alfa (DA). EPO and DA are considered equally effective in achieving target hemoglobin (Hb), but it is not clear whether there is a cost difference. There have been few head-to-head comparisons; most published studies are observational switch studies. Objective: To compare the cost of DA and EPO and to determine the dose conversion ratio over a 12-month period. Design: Randomized controlled trial. Setting: Canadian outpatient hemodialysis center. Patients: Eligible patients were adult hemodialysis patients requiring ESA therapy. Measurements: The primary outcome was ESA cost (Can$) per patient over 12 months. Secondary outcomes included the dose conversion ratio, deviation from target ranges in anemia indices, iron dose and cost, and time and number of dose changes. Methods: An open-label randomized controlled trial of intravenous (IV) DA versus EPO was conducted in 50 hemodialysis patients. Participants underwent a minimum 6-week run-in phase followed by a 12-month active study phase. ESA and iron were dosed using a study algorithm. Results: The median cost was $4179 (interquartile range [IQR]: $2416-$5955) for EPO and $2303 (IQR: $1178-$4219) for DA with a difference of $1876 (P = .02). The dose conversion ratio was 280:1 (95% confidence interval [CI]: 197-362:1) at the end of the run-in phase, 360:1 (95% CI: 262-457:1) at the 3-month point of the active phase, and 382:1 (95% CI: 235-529:1) at the 6-month point of the active phase. There were no significant differences between the 2 groups in weekly iron dose, Hb, serum ferritin, or transferrin saturation. The number of dose changes and the time to Hb stability were similar. Limitations: Results may not be generalizable to hemodialysis units without algorithm-based anemia management, with subcutaneous ESA administration, or to the nondialysis chronic kidney disease population. The effective conversion ratio between EPO and DA is known to increase at higher doses; the Hb targets used in the study were slightly higher than those recommended today so it is possible that the doses used were also higher. Because of this, the cost savings estimated for DA could differ somewhat from the savings realizable in current practice. Conclusions: In this study of hemodialysis patients with comparable anemia management, IV DA cost $1876 less per year per patient than IV EPO. The dose conversion ratio was greater than 350:1 by the 3-month point. Trial registration: ClinicalTrials.gov (NCT02817555). PMID:28717516

Dosimetric Comparison between Single and Dual Arc-Volumetric Modulated Arc Radiotherapy and Intensity Modulated Radiotherapy for Nasopharyngeal Carcinoma Using a Simultaneous Integrated Boost Technique

PubMed Central

Radhakrishnan, Sivakumar; Chandrasekaran, Anuradha; Sarma, Yugandhar; Balakrishnan, Saranganathan; Nandigam, Janardhan

2017-01-01

Backround: Plan quality and performance of dual arc (DA) volumetric modulated arc therapy (VMAT), single arc (SA) VMAT and nine field (9F) intensity modulated radiotherapy were compared using a simultaneous integrated boost (SIB) technique. Methods: Twelve patients treated in Elekta Synergy Platform (mlci2) by 9F-IMRT were replanned with SA/DA-VMAT using a CMS Monaco Treatment Planning System (TPS) with Monte Carlo simulation. Target delineation was conducted as per Radiation Therapy Oncology Protocols (RTOG0225 and 0615). A 70Gy dose prescribed to PTV70 and 61Gy to PTV61 in 33 fractions was applied for the SIB technique. The conformity index (CI) and homogeneity index (HI) for targets and the mean dose and maximum dose for OAR’s, treatment delivery time (min), monitor units (MUs) per fraction, normal tissue integral dose and patient specific quality assurance were analysed. Results: Acceptable target coverage was achieved for PTV70 and PTV61 with all the planning techniques. No significant differences were observed except for D98 (PTV61), CI(PTV70) and HI(PTV61). Maximum dose (Dmax) to the spinal cord was lower in DA-VMAT than 9F-IMRT (p=0.002) and SA-VMAT (p=0.001). D50 (%) of parotid glands was better controlled by 9F-IMRT (p=0.001) and DA-VMAT (p=0.001) than SA-VMAT. A lower mean dose to the larynx was achieved with 9F-IMRT (P=0.001) and DA-VMAT (p=0.001) than with SA-VMAT. DA-VMAT achieved higher CI of PTV70 (P= 0.005) than SA-VMAT. For PTV61, DA-VMAT (P=0.001) and 9F-IMRT (P=0.001) achieved better HI than SA-VMAT. The average treatment delivery times were 7.67mins, 3.35 mins, 4.65 mins for 9F-IMRT, SA-VMAT and DA-VMAT, respectively. No significant difference were observed in MU/fr (p=0.9) and NTID (P=0.90) and the patient quality assurance pass rates were >95% (gamma analysis I3mm, 3%). Conclusion: DA-VMAT showed better conformity over target dose and spared the OARs better or equal to IMRT. SA-VMAT could not spare the OARs well. DA-VMAT offered shorter delivery time than IMRT without compromising the plan quality. PMID:28612593

Dosimetric Comparison between Single and Dual Arc-Volumetric Modulated Arc Radiotherapy and Intensity Modulated Radiotherapy for Nasopharyngeal Carcinoma Using a Simultaneous Integrated Boost Technique

PubMed

Radhakrishnan, Sivakumar; Chandrasekaran, Anuradha; Sarma, Yugandhar; Balakrishnan, Saranganathan; Nandigam, Janardhan

2017-05-01

Backround: Plan quality and performance of dual arc (DA) volumetric modulated arc therapy (VMAT) , single arc (SA) VMAT and nine field (9F) intensity modulated radiotherapy were compared using a simultaneous integrated boost (SIB) technique. Methods: Twelve patients treated in Elekta Synergy Platform (mlci2) by 9F-IMRT were replanned with SA/DA-VMAT using a CMS Monaco Treatment Planning System (TPS) with Monte Carlo simulation. Target delineation was conducted as per Radiation Therapy Oncology Protocols (RTOG0225 and 0615). A 70Gy dose prescribed to PTV70 and 61Gy to PTV61 in 33 fractions was applied for the SIB technique. The conformity index (CI) and homogeneity index (HI) for targets and the mean dose and maximum dose for OAR’s, treatment delivery time (min), monitor units (MUs) per fraction, normal tissue integral dose and patient specific quality assurance were analysed. Results: Acceptable target coverage was achieved for PTV70 and PTV61 with all the planning techniques. No significant differences were observed except for D98 (PTV61), CI(PTV70) and HI(PTV61). Maximum dose (Dmax) to the spinal cord was lower in DA-VMAT than 9F-IMRT (p=0.002) and SA-VMAT (p=0.001). D50 (%) of parotid glands was better controlled by 9F-IMRT (p=0.001) and DA-VMAT (p=0.001) than SA-VMAT. A lower mean dose to the larynx was achieved with 9F-IMRT (P=0.001) and DA-VMAT (p=0.001) than with SA-VMAT. DA-VMAT achieved higher CI of PTV70 (P= 0.005) than SA-VMAT. For PTV61, DA-VMAT (P=0.001) and 9F-IMRT (P=0.001) achieved better HI than SA-VMAT. The average treatment delivery times were 7.67mins, 3.35 mins, 4.65 mins for 9F- IMRT, SA-VMAT and DA-VMAT, respectively. No significant difference were observed in MU/fr (p=0.9) and NTID (P=0.90) and the patient quality assurance pass rates were >95% (gamma analysis Ґ3mm, 3%). Conclusion: DA-VMAT showed better conformity over target dose and spared the OARs better or equal to IMRT. SA-VMAT could not spare the OARs well. DA-VMAT offered shorter delivery time than IMRT without compromising the plan quality. Creative Commons Attribution License

Trichinella spiralis: strong antibody response to a 49 kDa newborn larva antigen in infected rats.

PubMed

Salinas-Tobon, Maria Del Rosario; Navarrete-Leon, Anaid; Mendez-Loredo, Blanca Esther; Esquivel-Aguirre, Dalia; Martínez-Abrajan, Dulce Maria; Hernandez-Sanchez, Javier

2007-02-01

In this work, we analyzed the kinetics of anti-Trichinella spiralis newborn larva (NBL) antibodies (Ab) and the antigenic recognition pattern of NBL proteins and its dose effects. Wistar rats were infected with 0, 700, 2000, 4000 and 8000 muscle larvae (ML) and bled at different time intervals up to day 31 post infection (p.i.). Ab production was higher with 2000 ML dose and decreased with 8000, 4000 and 700 ML. Abs were not detected until day 10, peaked on day 14 for the 2000 ML dose and on day 19 for the other doses and thereafter declined slowly from 19 to 31 days p.i. In contrast, Abs to ML increased from day 10, peaked on day 19 and remained high until the end of the study. Abs bound strongly at least to three NBL components of 188, 205 and 49 kDa. NBL antigen of 188 and 205 kDa were recognized 10-26 days p.i. and that of 49 kDa from day 10 to day 31 p.i. A weak recognition towards antigens of 52, 54, 62 and 83 kDa was also observed during the infection. An early recognition of 31, 43, 45, 55, 68 and 85 kDa ML antigens was observed whereas the response to those of 43, 45, 48, 60, 64 and 97 kDa (described previously as TSL-1 antigens) occurred late in the infection. A follow-up of antigen recognition up to day 61 with the optimal immunization dose (2000 ML) evidenced a decline of Ab production to the 49 kDa NBL antigen 42 days p.i., which suggested antigenic differences with the previously reported 43 kDa ML antigen strongly recognized late in the infection. To analyze the stage-specificity of the 49 kDa NBL antigen, polyclonal antibodies (PoAb) were obtained in rats immunized with 49 kDa NBL antigen. PoAb reacted strongly with the 49 kDa NBL component in NBL total soluble extract but no reactivity was observed with soluble antigen of the other T. spiralis stages. Albeit with less intensity, the 49 kDa component was also recognized by PoAb together with other antigens of 53, 97 and 107 kDa, in NBL excretory-secretory products (NBL-ESP). Thus, our results reveal differences in the kinetics of anti-NBL and ML Ab responses. While anti-NBL Abs declined slowly from day 19 until the end of the experiment, Abs to ML antigen remained high in the same period. It is remarkable the optimal Ab response to NBL antigens with 2000 ML infective dose and the reduced number of NBL antigens identified throughout the experimental T. spiralis infection, standing out the immunodominant 49 kDa antigen. Interestingly, this antigen, which was prominently expressed in NBL somatic proteins, was also detected in NBL-ESP.

Gestational Lead Exposure Selectively Decreases Retinal Dopamine Amacrine Cells and Dopamine Content in Adult Mice

PubMed Central

Fox, Donald A.; Hamilton, W. Ryan; Johnson, Jerry E.; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B.; O’Callaghan, James P.

2011-01-01

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤1, ≤10, ~25 and ~40 µg/dL, respectively, on PN10 and by PN30 all were ≤1 µg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. PMID:21703292

Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice.

PubMed

Fox, Donald A; Hamilton, W Ryan; Johnson, Jerry E; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B; O'Callaghan, James P

2011-11-01

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤ 1, ≤ 10, ~25 and ~40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. Copyright © 2011 Elsevier Inc. All rights reserved.

Widespread Increases in Malondialdehyde Immunoreactivity in Dopamine-Rich and Dopamine-Poor Regions of Rat Brain Following Multiple, High Doses of Methamphetamine

PubMed Central

Horner, Kristen A.; Gilbert, Yamiece E.; Cline, Susan D.

2011-01-01

Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system. PMID:21602916

Prostate Cancer Xenograft Inhibitory Activity and Pharmacokinetics of Decursinol, a Metabolite of Angelica gigas Pyranocoumarins, in Mouse Models.

PubMed

Wu, Wei; Tang, Su-Ni; Zhang, Yong; Puppala, Manohar; Cooper, Timothy K; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2017-01-01

We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5[Formula: see text]mg decursinol per mouse with equi-molar dose of 6[Formula: see text]mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3[Formula: see text]h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.

Dopamine modulates male sexual behavior in Japanese quail in part via actions on noradrenergic receptors.

PubMed

Cornil, Charlotte A; Dejace, Christel; Ball, Gregory F; Balthazart, Jacques

2005-08-30

In rats, dopamine (DA) facilitates male sexual behavior through its combined action on D1- and D2-like receptors, in the medial preoptic area (MPOA) as well as other brain areas. In Japanese quail, systemic injections of dopaminergic drugs suggested a similar pharmacology but central injections have never been performed. Recent electrophysiological experiments demonstrated that DA effects in the MPOA of quail are mediated mainly through the activation of alpha2-noradrenergic receptors. Previous studies of DA action on behavior used specific dopaminergic agonists/antagonists and therefore unintentionally avoided the potential cross-reaction with alpha2-receptors. The present study was thus designed to investigate directly the effects of DA on male sexual behavior and to test whether the interaction of DA with heterologous receptors affects this behavior. Intracerebroventricular (i.c.v.) injection of DA or NE inhibited copulation in a dose-dependent manner. Systemic injections of yohimbine, an alpha2-noradrenergic antagonist, modulated copulation in a bimodal manner depending on the dose injected. Interestingly, a behaviorally ineffective dose of yohimbine markedly reduced the inhibitory effects of DA when injected 15min before. Together, these results show for the first time that i.c.v. injections of DA itself inhibit male sexual behavior in quail and suggest that the interaction of DA with alpha2-receptors has behavioral significance.

Effect of DA-9701 on Colorectal Distension-Induced Visceral Hypersensitivity in a Rat Model

PubMed Central

Kim, Eun Ran; Min, Byung-Hoon; Lee, Tae Ho; Son, Miwon; Rhee, Poong-Lyul

2014-01-01

Background/Aims DA-9701 is a newly developed drug made from the vegetal extracts of Pharbitidis semen and Co-rydalis tuber. The aim of this study was to evaluate the effect of DA-9701 on colorectal distension (CRD)-induced visceral hypersensitivity in a rat model. Methods Male Sprague-Dawley rats were subjected to neonatal colon irritation (CI) using CRD at 1 week after birth (CI group). At 6 weeks after birth, CRD was applied to these rats with a pressure of 20 to 90 mm Hg, and changes in the mean arterial pressure (MAP) were measured at baseline (i.e., without any drug administration) and after the administration of different doses of DA-9701. Results In the absence of DA-9701, the MAP changes after CRD were significantly higher in the CI group than in the control group at all applied pressures. In the control group, MAP changes after CRD were not significantly affected by the administration of DA-9701. In the CI group, however, the administration of DA-9701 resulted in a significant decrease in MAP changes after CRD. The administration of DA-9701 at a dose of 1.0 mg/kg produced a more significant decrease in MAP changes than the 0.3 mg/kg dose. Conclusions The administration of DA-9701 resulted in a significant increase in pain threshold in rats with CRD-induced visceral hypersensitivity. PMID:25071903

Effect of DA-9701 on colorectal distension-induced visceral hypersensitivity in a rat model.

PubMed

Kim, Eun Ran; Min, Byung-Hoon; Lee, Tae Ho; Son, Miwon; Rhee, Poong-Lyul

2014-07-01

DA-9701 is a newly developed drug made from the vegetal extracts of Pharbitidis semen and Co-rydalis tuber. The aim of this study was to evaluate the effect of DA-9701 on colorectal distension (CRD)-induced visceral hypersensitivity in a rat model. Male Sprague-Dawley rats were subjected to neonatal colon irritation (CI) using CRD at 1 week after birth (CI group). At 6 weeks after birth, CRD was applied to these rats with a pressure of 20 to 90 mm Hg, and changes in the mean arterial pressure (MAP) were measured at baseline (i.e., without any drug administration) and after the administration of different doses of DA-9701. In the absence of DA-9701, the MAP changes after CRD were significantly higher in the CI group than in the control group at all applied pressures. In the control group, MAP changes after CRD were not significantly affected by the administration of DA-9701. In the CI group, however, the administration of DA-9701 resulted in a significant decrease in MAP changes after CRD. The administration of DA-9701 at a dose of 1.0 mg/kg produced a more significant decrease in MAP changes than the 0.3 mg/kg dose. The administration of DA-9701 resulted in a significant increase in pain threshold in rats with CRD-induced visceral hypersensitivity.

Effects of omeprazole or cola beverage on the pharmacokinetics of oral DA-8159, a new erectogenic, in rats.

PubMed

Lee, Joo H; Bae, Soo K; Kwon, Jong W; Kim, Won B; Lee, Myung G

2005-12-01

The changes in pharmacokinetics of DA-8159 by omeprazole with respect to inhibition of CYP3A1/2 in rats were evaluated. After oral administration of DA-8159 at dose of 30 mg/kg to rats pretreated with oral omeprazole at 30 mg/kg for 1 week, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 was significantly greater (37.5% increase) than that in control rats. This could be due to inhibition of metabolism of DA-8159 by inhibition of CYP3A1/2 by omeprazole. The AUC(DA-8164 (a metabolite of DA-8159))/AUC(DA-8159) ratio was also smaller (32.4% decrease) with omeprazole. After oral administration of DA-8159 at a dose of 30 mg/kg to rats without or with cola beverage, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that cola beverage did not have any considerable effects on CYP3A1/2 in rats.

Experiences in the Family Health Strategy: demands and vulnerabilities in the territory.

PubMed

Pinto, Antonio Germane Alves; Jorge, Maria Salete Bessa; Marinho, Mirna Neyara Alexandre de Sá Barreto; Vidal, Emery Ciana Figueirêdo; Aquino, Priscila de Souza; Vidal, Eglídia Carla Figueirêdo

2017-01-01

To understand the daily demands of Family Health Strategy in clinical practice of the team and social vulnerabilities of community territory. Research with qualitative approach, in a critical-reflexive perspective, held with two teams of the Family Health Strategy, in the city of Fortaleza, State of Ceará, Brazil. The participants were 22 users and 19 health professionals from the basic health network. Data from the interviews and observation were analyzed under the assumptions of critical hermeneutics. We highlight the unveiling of sufferings and daily clashes, the influence of social determinants on health and psychosocial demands, limits and possibilities of everyday clinical practice. The clinic attention must recognize the perceptions and living conditions by listening and promoting health in the community. Compreender as demandas cotidianas da Estratégia Saúde da Família na prática clínica da equipe e as vulnerabilidades sociais do território comunitário. Pesquisa com abordagem qualitativa, numa perspectiva crítico-reflexiva, realizada com duas equipes da Estratégia Saúde da Família, no município de Fortaleza, Estado do Ceará, Brasil. Os participantes foram 22 usuários e 19 profissionais de saúde da rede básica de saúde. Os dados das entrevistas e observação foram analisados sob os pressupostos da hermenêutica crítica. Evidenciam-se o desvelamento de sofrimentos e enfrentamentos cotidianos, a influência dos determinantes sociais na saúde e as demandas psicossociais, limites e possibilidades da prática clínica cotidiana. Considera-se que a atenção clínica deve reconhecer as percepções e condições de vida pela escuta e ações de promoção de saúde na comunidade.

D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure.

PubMed

Venkataraman, Sidish; Claussen, Catherine; Dafny, Nachum

2017-02-01

The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0 mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4 mg/kg SCH-23390 selective D1 DA antagonist or a 0.3 mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30 min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.

Monoaminergic Psychomotor Stimulants: Discriminative Stimulus Effects and Dopamine Efflux

PubMed Central

Desai, Rajeev I.; Paronis, Carol A.; Martin, Jared; Desai, Ramya

2010-01-01

The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3–3 mg/kg), COC (3–56 mg/kg), and GBR 12909 (3–30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants. PMID:20190012

Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients.

PubMed

Röllig, C; Kramer, M; Gabrecht, M; Hänel, M; Herbst, R; Kaiser, U; Schmitz, N; Kullmer, J; Fetscher, S; Link, H; Mantovani-Löffler, L; Krümpelmann, U; Neuhaus, T; Heits, F; Einsele, H; Ritter, B; Bornhäuser, M; Schetelig, J; Thiede, C; Mohr, B; Schaich, M; Platzbecker, U; Schäfer-Eckart, K; Krämer, A; Berdel, W E; Serve, H; Ehninger, G; Schuler, U S

2018-04-01

The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.

Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels

PubMed Central

Steffensen, Scott C.; Taylor, Seth R.; Horton, Malia L.; Barber, Elise N.; Lyle, Laura T.; Stobbs, Sarah H.; Allison, David W.

2010-01-01

The aim of this study was to evaluate the effects of cocaine on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. PMID:19046384

Determinação de regiões de órbitas diretas estáveis ao redor da Lua

NASA Astrophysics Data System (ADS)

de Melo, C. F.; Winter, O. C.; Vieira Neto, E.

2003-08-01

Neste Trabalho estamos investigando regiões do sistema Terra-Lua que contêm órbitas diretas estáveis ao redor da Lua visando a utilização destas órbitas em futuras missões de veículos espaciais como alternativas de trajetórias com baixo custo de manutenção. Adotando-se o problema restrito de três corpos, Terra-Lua-partícula, a localização e a extensão destas regiões de estabilidade foram investigadas numericamente considerando como estável toda órbita que permanece ao redor a Lua por, no mínimo, 1000 dias com energia de dois corpos da partícula em relação à Lua negativa. A estabilidade de tais regiões está associada a duas famílias de órbitas periódicas simples H1 e H2 e a órbitas quase-periódicas associadas a elas. Uma vez identificadas as regiões de estabilidade passamos a analisá-las introduzindo, paulatinamente, outras interações relevantes ao sistema como as perturbações do Sol (via problema restrito de quatro corpos), das marés, da pressão de radiação e do achatamento terrestre. Os resultados encontrados até o momento mostram que a perturbação do Sol é a única que reduz significativamente o tamanho das regiões de estabilidade. Também estamos investigando o comportamento de tais regiões quando características intrínsecas do sistema como as excentricidades das órbitas da Terra e da Lua e a inclinação da órbita Lua são consideradas. Com este estudo estamos reunindo informações que nos permitirão compreender a evolução das regiões de estabilidade no sistema Terra-Lua, bem como estabelecer parâmetros adequados para a utilização das trajetórias estáveis em futuras missões espaciais. Agradecimentos: Este projeto conta com o apoio do CNPq, da Capes e da Fapesp.

Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD).

PubMed

Moon, Su Jin; Kim, Chang Ju; Lee, Yeon Jung; Hong, Minha; Han, Juhee; Bahn, Geon Ho

2014-01-01

Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD). To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.

Effect of Atomoxetine on Hyperactivity in an Animal Model of Attention-Deficit/Hyperactivity Disorder (ADHD)

PubMed Central

Moon, Su Jin; Kim, Chang Ju; Lee, Yeon Jung; Hong, Minha; Han, Juhee; Bahn, Geon Ho

2014-01-01

Background Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD). Purpose To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. Methods Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. Results The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. Conclusion Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway. PMID:25271814

Characterization of low molecular weight fragments from gamma irradiated κ-carrageenan used as plant growth promoter

NASA Astrophysics Data System (ADS)

Abad, Lucille V.; Aurigue, Fernando B.; Relleve, Lorna S.; Montefalcon, Djowel Recto V.; Lopez, Girlie Eunice P.

2016-01-01

Radiation degraded κ-carrageenan (1% solution at absorbed doses of 20 kGy and 30 kGy) were tested for its plant growth promoter (PGP) effect on pechay plants under hydroponics condition. Results revealed that higher PGP effects were found in κ-carrageenan irradiated at an absorbed dose of 30 kGy. Mw of irradiated κ-carrageenan as measured by GPC were determined to be 7362 Da and 6762 Da for 20 kGy and 30 kGy, respectively. Fractionation of the irradiated κ-carrageenan (30 kGy) was done to separate different Mw fractions using Mw cut-off filters of 1 kDa, 3 kDa, and 5 kDa. The PGP effect of the different retentates showed that biological activity in plants followed the order of 5 kDa>3 kDa>1 kDa using hydroponics condition but the reverse was observed in the order of 1 kDa>3 kDa>5 kDa when absorbed in plants by foliar spraying. GPC chromatogram indicated at least three (3) low molecular weight (LMW) fragments from radiation modified κ-carrageenan solution with an Mw<2000 Da. A fragment has also been identified with an Mw of as low as 160 Da which was produced under acidic (un-neutralized) condition. This may be attributed to the formation of 5-hydroxymethylfurfural (5-HMF).

Domoic acid excretion in dungeness crabs, razor clams and mussels.

PubMed

Schultz, Irvin R; Skillman, Ann; Woodruff, Dana

2008-07-01

Domoic acid (DA) is a neurotoxic amino acid produced by several marine algal species of the Pseudo-nitzschia (PN) genus. We studied the elimination of DA from hemolymph after intravascular (IV) injection in razor clams (Siliqua patula), mussels (Mytilus edulis) and Dungeness crabs (Cancer magister). Crabs were also injected with two other organic acids, dichloroacetic acid (DCAA) and kainic acid (KA). For IV dosing, hemolymph was repetitively sampled and DA concentrations measured by HPLC-UV. Toxicokinetic analysis of DA in crabs suggested most of the injected dose remained within hemolymph compartment with little extravascular distribution. This observation is in sharp contrast to results obtained from clams and mussels which exhibited similarly large apparent volumes of distribution despite large differences in overall clearance. These findings suggest fundamentally different storage and elimination processes are occurring for DA between bivalves and crabs.

GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

PubMed

Engberg, G; Kling-Petersen, T; Nissbrandt, H

1993-11-01

Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

Perfil dos Professores de Ciências Naturais do Recôncavo da Bahia - Alunos da Disciplina Terra e Universo no Curso de Ciências Naturais do Parfor

NASA Astrophysics Data System (ADS)

Lima, S. R.; Cerqueira Júnior, W.; Dutra, G.

2011-12-01

Este trabalho foi desenvolvido pelo projeto Astronomia no Recôncavo da Bahia, no Centro de Formação de Professores da Universidade Federal do Recôncavo da Bahia. Traçamos o perfil de um grupo de professores que lecionam conteúdos de Ciências Naturais no recôncavo, alunos do curso de Licenciatura em Ciências Naturais, oferecido dentro do Plano Nacional de Formação de Professores da Educação Básica. Nosso objetivo era avaliar se eles estão preparados para trabalhar conteúdos de Astronomia e identificar suas dificuldades. Os resultados serviram para orientar o professor da disciplina “Terra e Universo”, oferecida no segundo semestre de 2010. Durante a primeira aula da disciplina Terra e Universo, os alunos responderam a um questionário contendo questões abertas e fechadas, divididas em duas partes. A primeira procurando caracterizar profissionalmente os alunos enquanto professores da rede pública da região do Recôncavo Sul da Bahia e uma segunda parte procurando identificar conhecimentos básicos em Astronomia. Os resultados indicam uma predominância de professores do sexo feminino, com idade superior aos 40 anos, pardos e sem formação específica para o ensino de ciências. A maioria leciona há mais de 15 anos para turmas do 1º ao 5º ano, alguns lecionam para turmas de 6º ao 9º ano. Quase todos nunca participaram de um curso de formação continuada em Astronomia. Além disso, não estão habituados a ler revistas especializadas e nem livros com esta temática. Os que procuram ensinar temas voltados para a Astronomia têm, no livro didático, a maior fonte de informação sobre o assunto. As respostas também indicam uma deficiência em conteúdos básicos como a compreensão da esfericidade da Terra, noções de verticalidade e gravidade, incapacidade de identificar a Terra como um planeta, no Sistema Solar, em uma galáxia, no Universo. Estes resultados ressaltam a importância de disciplinas de Astronomia básica na formação dos professores da região.

A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice.

PubMed

Demars, Fanny; Clark, Kristen; Wyeth, Megan S; Abrams, Emily; Buckmaster, Paul S

2018-05-01

Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study's in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1-11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice. Copyright © 2018 Elsevier B.V. All rights reserved.

SU-E-T-309: Dosimetric Comparison of Simultaneous Integrated Boost Treatment Plan Between Intensity Modulated Radiotherapies (IMRTs), Dual Arc Volumetric Modulated Arc Therapy (DA-VMAT) and Single Arc Volumetric Modulated Arc Therapy (SA-VMAT) for Nasopharyngeal Carcinoma (NPC)

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

Sivakumar, R; Janardhan, N; Bhavani, P

Purpose: To compare the plan quality and performance of Simultaneous Integrated Boost (SIB) Treatment plan between Seven field (7F) and Nine field(9F) Intensity Modulated Radiotherapies and Single Arc (SA) and Dual Arc (DA) Volumetric Modulated Arc Therapy( VMAT). Methods: Retrospective planning study of 16 patients treated in Elekta Synergy Platform (mlci2) by 9F-IMRT were replanned with 7F-IMRT, Single Arc VMAT and Dual Arc VMAT using CMS, Monaco Treatment Planning System (TPS) with Monte Carlo simulation. Target delineation done as per Radiation Therapy Oncology Protocols (RTOG 0225&0615). Dose Prescribed as 70Gy to Planning Target Volumes (PTV70) and 61Gy to PTV61 inmore » 33 fraction as a SIB technique. Conformity Index(CI), Homogeneity Index(HI) were used as analysis parameter for Target Volumes as well as Mean dose and Max dose for Organ at Risk(OAR,s).Treatment Delivery Time(min), Monitor unit per fraction (MU/fraction), Patient specific quality assurance were also analysed. Results: A Poor dose coverage and Conformity index (CI) was observed in PTV70 by 7F-IMRT among other techniques. SA-VMAT achieved poor dose coverage in PTV61. No statistical significance difference observed in OAR,s except Spinal cord (P= 0.03) and Right optic nerve (P=0.03). DA-VMAT achieved superior target coverage, higher CI (P =0.02) and Better HI (P=0.03) for PTV70 other techniques (7F-IMRT/9F-IMRT/SA-VMAT). A better dose spare for Parotid glands and spinal cord were seen in DA-VMAT. The average treatment delivery time were 5.82mins, 6.72mins, 3.24mins, 4.3mins for 7F-IMRT, 9F-IMRT, SA-VMAT and DA-VMAT respectively. Significance difference Observed in MU/fr (P <0.001) and Patient quality assurance pass rate were >95% (Gamma analysis (Γ3mm, 3%). Conclusion: DA-VAMT showed better target dose coverage and achieved better or equal performance in sparing OARs among other techniques. SA-VMAT offered least Treatment Time than other techniques but achieved poor target coverage. DA-VMAT offered shorter delivery time than 7F-IMRT and 9F-IMRT without compromising the plan quality.« less

QUALIS PERIODIC EVALUATION: ANALYSIS OF QUALIS UPGRADE IN MEDICINE III.

PubMed

Jukemura, José; Diniz, Márcio Augusto

2015-01-01

To evaluate the preliminary results related to journals up-grade that was used by Medicine III, through opportunity offered by Capes to all agency areas programs. Were used area document of Medicine I, II and III, besides other relevant topics available online at Capes site, between 2009 and 2013. The research was focused to answer two questions: 1) the stratification of Qualis is similar in the three areas of medicine? and 2) the evolution of Qualis in Medicine III was higher? Medicine III showed an increase in its Qualis classification and is publishing in journals with higher impact factors, virtually the same as the Medicine I and II. The area showed the strongest growth in recent three-year periods. Avaliar os resultados preliminares sobre a Medicina III do up-grade oportunizado pela Capes para todas as áreas. Foram utilizados os documentos de áreas e os relevantes ao tema disponíveis online no site da Capes entre 2009 e 2013. Procurou-se focar a pesquisa em dois aspectos para responder duas perguntas: 1) a estratificação do Qualis é semelhante nas três áreas da medicina? e 2) a evolução do Qualis da Medicina III foi maior? A Medicina III apresentou evolução em sua classificação Qualis e está publicando em revistas com maior fator de impacto e é praticamente igual ao da Medicina I e II. A área foi a que apresentou maior evolução nestes últimos triênios.

Study of heat and salt transport processes in the Espinheiro Channel (Ria de Aveiro)

NASA Astrophysics Data System (ADS)

Vaz, Nuno Alexandre Firmino

O principal objectivo deste trabalho consistiu no estudo da dinâmica termohalina do Canal do Espinheiro em funcao de dois forcamentos principais: mare e caudal fluvial, usando duas abordagens distintas: trabalho experimental e modelacao numerica. A propagacao da mare e o caudal fluvial do Rio Vouga sao determinantes no estabelecimento da estrutura horizontal da salinidade ao longo do canal. A estrutura termica horizontal ao longo do canal e, em grande parte, determinada pela variacao sazonal da temperatura da agua do Rio Vouga, bem como, pela variacao sazonal das condicoes meteorologicas devido a reduzida profundidade. Foi observada a formacao de fortes gradientes de salinidade (relacionados com a formacao de frentes estuarinas) numa regiao a cerca de 7-8 km da embocadura do canal, observando-se a sua migracao numa regiao de aproximadamente 1 km, dependendo do regime de mare. O balanco entre o transporte de sal de natureza advectiva e difusiva foi calculado, revelando que junto a embocadura os processos fisicos que mais contribuem para o transporte de sal sao a circulacao residual e o aprisionamento da agua em canais secundarios. Junto a foz do Rio Vouga os termos devidos a descarga fluvial e a circulacao gravitacional dominam o transporte de sal. Foi calibrado e validado um modelo numerico (Mohid, em modo 2D e 3D), sendo posteriormente utilizado para estudar a hidrologia do canal. Foi concedida particular atencao ao estudo da hidrologia em condicoes extremas de caudal fluvial e de mare. Os resultados da modelacao numerica permitiram numa primeira fase avaliar o bom desempenho do Mohid na reproducao dos escoamentos barotropicos na Ria de Aveiro, bem como na evolucao temporal das propriedades termohalinas da agua. Sob condicoes de caudal fluvial reduzido, a dinâmica do canal e essencialmente dominada pela mare. Com o aumento do caudal fluvial, a influencia da agua doce estende-se para jusante, estratificando a coluna de agua. As simulacoes 3D do Canal do Espinheiro foram efectuadas para periodos marcadamente diferentes de caudal fluvial e de mare. O modelo reproduziu qualitativamente/quantitativamente as observacoes de alturas de agua, velocidade e distribuicoes longitudinais de salinidade e temperatura sob um regime fraco a medio de caudal fluvial. Sob condicoes de caudal fluvial elevado, os resultados mostram que o modelo subestima a estratificacao. Este estudo contribuiu para o aumento do conhecimento da dinâmica do Canal do Espinheiro, bem como para o desenvolvimento de um sistema numerico capaz de reproduzir e prever os processos de transporte de sal e calor. None

Dose conversion ratio in hemodialysis patients switched from darbepoetin alfa to PEG-epoetin beta: AFFIRM study.

PubMed

Choi, Peter; Farouk, Mourad; Manamley, Nick; Addison, Janet

2013-11-01

There is limited information published on switching erythropoiesis-stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo. Eligible patients had received hemodialysis for ≥ 12 months and DA for ≥ 7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified. Of 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 μg DA in the pre-switch EP and 28.6 μg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35). In these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately threefold from the pre-switch to the post-switch period.

Nicotine- and methamphetamine-induced dopamine release evaluated with in-vivo binding of radiolabelled raclopride to dopamine D2 receptors: comparison with in-vivo microdialysis data.

PubMed

Kim, Sang Eun; Han, Seung-Moo

2009-07-01

The effect of substances which alter extracellular dopamine (DA) concentration has been studied by measuring changes in the binding of radiolabelled raclopride, a DA D2 receptor ligand that is sensitive to endogenous DA. To better characterize the relationship between extracellular DA concentration and DA D2 receptor binding of raclopride, we compared the changes of extracellular DA concentration (measured using in-vivo microdialysis) and in-vivo [3H]raclopride binding induced by different doses of methamphetamine (Meth) and nicotine, drugs that enhance DA release with and without blocking DA transporters (DATs), respectively, in rat striatum. Nicotine elicited a modest increase of striatal extrasynaptic extracellular DA, while Meth produced a marked increase of striatal extrasynaptic DA in a dose-dependent manner. There was a close correlation between the decrease in [3H]raclopride in-vivo binding and the increase in extrasynaptic DA concentration induced by both nicotine (r2=0.95, p<0.001) and Meth (r2=0.98, p=0.001), supporting the usefulness of the radiolabelled raclopride-binding measurement for the non-invasive assessment of DA release following interventions in the living brain. However, the linear regression analysis revealed that the ratio of percent DA increase to percent [3H]raclopride binding reduction was 25-fold higher for Meth (34.8:1) than for nicotine (1.4:1). The apparent discrepancy in the extrasynaptic DA-[3H]raclopride binding relationship between the DA-enhancing drugs with and without DAT-blocking property indicates that the competition between endogenous DA and radiolabelled raclopride takes place at the intrasynaptic rather than extrasynaptic DA D2 receptors and reflects synaptic concentration of DA.

Effects of developmental methylphenidate (MPH) treatment on monoamine neurochemistry of male and female rats.

PubMed

Panos, John J; O'Callaghan, James P; Miller, Diane B; Ferguson, Sherry A

2014-01-01

Attention Deficit Hyperactivity Disorder (ADHD) is estimated to affect 4-5% of the adult human population (Kessler et al., 2006; Willcutt, 2012). Often prescribed to attenuate ADHD symptoms (Nair and Moss, 2009), methylphenidate hydrochloride (MPH) can have substantial positive effects. However, there is a paucity of literature regarding its use during pregnancy. Thus, adult women with ADHD face a difficult decision when contemplating pregnancy. In this study, pregnant Sprague-Dawley rats were orally treated a total of 0 (water), 6 (low), 18 (medium), or 42 (high) mg MPH/kg body weight/day (divided into three doses) on gestational days 6-21 (i.e., the low dose received 2 mg MPH/kg body weight 3×/day). Offspring were orally treated with the same daily dose as their dam (divided into two doses) on postnatal days (PNDs) 1-21. One offspring/sex/litter was sacrificed at PND 22 or PND 104 (n=6-7/age/sex/treatment group) and the striatum was quickly dissected and frozen. High Performance Liquid Chromatography (HPLC) coupled to a Photo Diode Array detector (PDA) was used to analyze monoamine content in the striatum of one side while a sandwich ELISA was used to analyze tyrosine hydroxylase (TH) from the other side. Age significantly affected monoamine and metabolite content as well as turnover ratios (i.e., DA, DOPAC, HVA, DOPAC/DA, HVA/DA, 5-HT and 5-HIAA); however, there were no significant effects of sex. Adult rats of the low MPH group had higher DA levels than control adults (p<0.05). At both ages, subjects of the low MPH group had higher TH levels than controls (p<0.05), although neither effect (i.e., higher DA or TH levels) exhibited an apparent dose-response. PND 22 subjects of the high MPH treatment group had higher ratios of HVA/DA and DOPAC/DA than same-age control subjects (p<0.05). The increased TH levels of the low MPH group may be related to the increased DA levels of adult rats. While developmental MPH treatment appears to have some effects on monoamine system development, further studies are required to determine if these alterations manifest as functional changes in behavior. Published by Elsevier Inc.

Protection by GDNF and other trophic factors against the dopamine-depleting effects of neurotoxic doses of methamphetamine.

PubMed

Cass, Wayne A; Peters, Laura E; Harned, Michael E; Seroogy, Kim B

2006-08-01

Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) content. It has previously been shown that glial cell line-derived neurotrophic factor (GDNF) can reduce the DA-depleting effects of neurotoxic doses of METH. However, there are several other trophic factors that are protective against dopaminergic toxins. Thus, the present experiments further investigated the protective effect of GDNF as well as the protective effects of several other trophic factors. Male Fischer-344 rats were given an intracerebral injection of trophic factor (2-10 microg) 1 day before METH (5 mg/kg, s.c., 4 injections at 2-h intervals). Seven days later DA levels in the striatum were measured using high-performance liquid chromatography (HPLC). Initial experiments indicated that only intrastriatal GDNF, and not intranigral GDNF, was protective. Thereafter, all other trophic factors were administered into the striatum. Members of the GDNF family (GDNF, neurturin, and artemin) all provided significant protection against the DA-depleting effects of METH, with GDNF providing the greatest protection. Brain-derived neurotrophic factor, neurotrophin-3, acidic fibroblast growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, transforming growth factor-alpha (TGF-alpha), heregulin beta1 (HRG-beta1), and amphiregulin (AR) provided no significant protection at the doses examined. These results suggest that the GDNF family of trophic factors can provide significant protection against the DA-depleting effects of neurotoxic doses of METH.

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects

PubMed Central

Kim, Yu Kyong; Choi, Mun Ju; Oh, Tae Young; Yu, Kyung-Sang; Lee, SeungHwan

2017-01-01

A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread®) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration–time curve to the last quantifiable concentration (AUC0–t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration–time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815–0.990) for Cmax and 0.904 (0.836–0.978) for AUC0–t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF. PMID:29158663

20 CFR 625.9 - Determinations of entitlement; notices to individual.

Code of Federal Regulations, 2010 CFR

2010-04-01

... LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.9 Determinations of entitlement; notices to individual. (a... application for a payment of DUA with respect to a week of unemployment, determine whether the individual is... application for DUA with respect to a week of unemployment which denies DUA or reduces the weekly amount...

20 CFR 625.9 - Determinations of entitlement; notices to individual.

Code of Federal Regulations, 2012 CFR

2012-04-01

... LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.9 Determinations of entitlement; notices to individual. (a... application for a payment of DUA with respect to a week of unemployment, determine whether the individual is... application for DUA with respect to a week of unemployment which denies DUA or reduces the weekly amount...

20 CFR 625.9 - Determinations of entitlement; notices to individual.

Code of Federal Regulations, 2014 CFR

2014-04-01

... LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.9 Determinations of entitlement; notices to individual. (a... application for a payment of DUA with respect to a week of unemployment, determine whether the individual is... application for DUA with respect to a week of unemployment which denies DUA or reduces the weekly amount...

20 CFR 625.9 - Determinations of entitlement; notices to individual.

Code of Federal Regulations, 2013 CFR

2013-04-01

... LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.9 Determinations of entitlement; notices to individual. (a... application for a payment of DUA with respect to a week of unemployment, determine whether the individual is... application for DUA with respect to a week of unemployment which denies DUA or reduces the weekly amount...

20 CFR 625.9 - Determinations of entitlement; notices to individual.

Code of Federal Regulations, 2011 CFR

2011-04-01

... LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.9 Determinations of entitlement; notices to individual. (a... application for a payment of DUA with respect to a week of unemployment, determine whether the individual is... application for DUA with respect to a week of unemployment which denies DUA or reduces the weekly amount...

Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence.

PubMed

Cadoni, Cristina; Pisanu, Augusta; Simola, Nicola; Frau, Lucia; Porceddu, Pier Francesca; Corongiu, Silvia; Dessì, Christian; Sil, Annesha; Plumitallo, Antonio; Wardas, Jadwiga; Di Chiara, Gaetano

2017-09-01

Although MDMA (3,4-methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species-specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis-à-vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate-putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory. Caffeine co-administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long-lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Chen, L; Shen, C; Wang, J

Purpose: To reduce cone beam CT (CBCT) imaging dose, we previously proposed a progressive dose control (PDC) scheme to employ temporal correlation between CBCT images at different fractions for image quality enhancement. A temporal non-local means (TNLM) method was developed to enhance quality of a new low-dose CBCT using existing high-quality CBCT. To enhance a voxel value, the TNLM method searches for similar voxels in a window. Due to patient deformation among the two CBCTs, a large searching window was required, reducing image quality and computational efficiency. This abstract proposes a deformation-assisted TNLM (DA-TNLM) method to solve this problem. Methods:more » For a low-dose CBCT to be enhanced using a high-quality CBCT, we first performed deformable image registration between the low-dose CBCT and the high-quality CBCT to approximately establish voxel correspondence between the two. A searching window for a voxel was then set based on the deformation vector field. Specifically, the search window for each voxel was shifted by the deformation vector. A TNLM step was then applied using only voxels within this determined window to correct image intensity at the low-dose CBCT. Results: We have tested the proposed scheme on simulated CIRS phantom data and real patient data. The CITS phantom was scanned on Varian onboard imaging CBCT system with coach shifting and dose reducing for each time. The real patient data was acquired in four fractions with dose reduced from standard CBCT dose to 12.5% of standard dose. It was found that the DA-TNLM method can reduce total dose by over 75% on average in the first four fractions. Conclusion: We have developed a PDC scheme which can enhance the quality of image scanned at low dose using a DA-TNLM method. Tests in phantom and patient studies demonstrated promising results.« less

Influence of PEG coating on the oral bioavailability of gold nanoparticles in rats.

PubMed

Alalaiwe, Ahmed; Roberts, Georgia; Carpinone, Paul; Munson, John; Roberts, Stephen

2017-11-01

Metallic nanoparticles can be produced in a variety of shapes, sizes, and surface chemistries, making them promising potential tools for drug delivery. Most studies to date have evaluated uptake of metallic nanoparticles from the GI tract with methods that are at best semi-quantitative. This study used the classical method of comparing blood concentration area under the curve (AUC) following intravenous and oral doses to determine the oral bioavailability of 1, 2 and 5 kDa PEG-coated 5 nm gold nanoparticles (AuNPs). Male rats were given a single intravenous dose (0.8 mg/kg) or oral (gavage) dose (8 mg/kg) of a PEG-coated AuNP, and the concentration of gold was measured in blood over time and in tissues (liver, spleen and kidney) at sacrifice. Blood concentrations following oral administration were inversely related to PEG size, and the AUC in blood was significantly greater for the 1 kDa PEG-coated AuNPs than particles coated with 2 or 5 kDa PEG. However, bioavailabilities of all of the particles were very low (< 0.1%). Concentrations in liver, spleen and kidney were similar after the intravenous doses, but kidney showed the highest concentrations after an oral dose. In addition to providing information on the bioavailability of AuNPs coated with PEG in the 1-5 kDa range, this study demonstrates the utility of applying the blood AUC approach to assess the quantitative oral bioavailability of metallic nanoparticles.

Dopamine receptors play distinct roles in sexual behavior expression of rats with a different sexual motivational tone.

PubMed

Guadarrama-Bazante, Irma L; Canseco-Alba, Ana; Rodríguez-Manzo, Gabriela

2014-10-01

Dopamine (DA) plays a central role in the expression of male sexual behavior. The effects of DA-enhancing drugs on copulation seem to vary depending on the dose of the agonist used, the type of DA receptor activated, and the sexual condition of the animals. The aim of the present study was to carry out a systematic analysis of the effects of dopaminergic agonists on the expression of male sexual behavior by sexually competent rats in different sexual motivational states, that is when sexually active (sexually experienced) and when temporarily inhibited (sexually exhausted). To this end, the same doses of the nonselective DA receptor agonist apomorphine, the selective D2-like DA receptor agonist quinpirole, and the selective D1-like DA receptor agonist SKF38393 were injected intraperitoneally to sexually experienced or sexually exhausted male rats and their sexual behavior was recorded. Low apomorphine doses induced expression of sexual behavior in sexually satiated rats, but only reduced the intromission latency of sexually experienced rats. SKF38393 facilitated the expression of sexual behavior by sexually exhausted rats, but not that of sexually experienced males and quinpirole did not exert an effect in both types of animal. In line with these results, the apomorphine-induced reversal of sexual exhaustion was blocked by the D1-like receptor antagonist SCH23390. The data suggest that DA receptors play distinct roles in the expression of sexual behavior by male rats depending on their motivational state and that activation of D1-like receptors promotes the expression of sexual behavior in satiated rats.

Projeto educação em ciências com observatórios virtuais: a participação da Escola Moppe no período 2000-2003

NASA Astrophysics Data System (ADS)

Wuensche, C. A.; Gavioli, E.; Oliveira, A. L. P. R. S.; da Silva, C.; Cardoso, H. P.; Estácio, S.

2003-08-01

O projeto Educação em Ciências com Observatórios Virtuais foi concebido pelo Instituto Astronômico e Geofísico da USP, agregando diversas instituições de ensino e pesquisa no país para desenvolver competências diversas na educação fundamental, média e superior utilizando a astronomia como ferramenta multidisciplinar. Este trabalho descreve a participação da MOPPE, escola-piloto do INPE no projeto, no período de 2000-2003. Serão apresentadas 1) a criação de um clube de ciências (1999 a 2001) cujo tema foi a colonização de Marte e 2) a ementa de astronomia trabalhada com as 7a. e 8a. séries do ensino fundamental. A proposta do projeto Colonizando Marte foi estudar diversos aspectos de uma missão interplanetária e construir experiementos que permitissem quantificar esses aspectos. Os resultados obtidos incluiram apresentações nas SBPC Jovem em 2000 e 2001. Discutiremos também as ementas de astronomia trabalhadas desde 2001 e o envolvimento dos alunos com atividades ligadas a astronomia, fora da aula de ciências. A inclusão de astronomia no currículo das últimas séries motivou a participação de mais alunos culminando com a conquista de duas medalhas para alunos da 7a. série na Olimpiada Brasileira de Astronomia em 2002. Houve também um aumento no número de participantes na OBA 2003 e nos projetos de astronomia mais elaborados nas Feira de Ciências de 2001 e 2002. Destacamos em 2003 a inclusão da MOPPE no projeto TIE - Telescopes in Education - da NASA, que utiliza o telescópio do Observatório de Mount Wilson (EUA) para observações remotas em projetos pedagógicos para o ensino de astronomia.

Robotic Transversus Abdominis Release (TAR): is it possible to offer minimally invasive surgery for abdominal wall complex defects?

PubMed

Amaral, Maria Vitória França DO; Guimarães, José Ricardo; Volpe, Paula; Oliveira, Flávio Malcher Martins DE; Domene, Carlos Eduardo; Roll, Sérgio; Cavazzola, Leandro Totti

2017-01-01

We describe the preliminary national experience and the early results of the use of robotic surgery to perform the posterior separation of abdominal wall components by the Transversus Abdominis Release (TAR) technique for the correction of complex defects of the abdominal wall. We performed the procedures between 04/2/2015 and 06/15/2015 and the follow-up time was up to six months, with a minimum of two months. The mean surgical time was five hours and 40 minutes. Two patients required laparoscopic re-intervention, since one developed hernia by peritoneal migration of the mesh and one had mesh extrusion. The procedure proved to be technically feasible, with a still long surgical time. Considering the potential advantages of robotic surgery and those related to TAR and the results obtained when these two techniques are associated, we conclude that they seem to be a good option for the correction of complex abdominal wall defects. RESUMO Descrevemos a experiência preliminar nacional na utilização da cirurgia robótica para realizar a separação posterior de componentes da parede abdominal pela técnica transversus abdominis release (TAR) na correção de defeitos complexos da parede abdominal e seus resultados precoces. As cirurgias foram realizadas entre 02/04/2015 e 15/06/2015 e o tempo de acompanhamento dos resultados foi de até seis meses, com tempo mínimo de dois meses. O tempo cirúrgico médio foi de cinco horas e 40 minutos. Dois pacientes necessitaram reintervenção por laparoscopia, pois um desenvolveu hérnia por migração peritoneal da tela e um teve escape da tela. A cirurgia provou ser factível do ponto de vista técnico, com um tempo cirúrgico ainda elevado. Tendo em vista as vantagens potenciais da cirurgia robótica e aquelas relacionadas ao TAR e os resultados obtidos ao se associar essas duas técnicas, conclui-se que elas parecem ser uma boa opção para a correção de defeitos complexos da parede abdominal.

Contagem de fontes de radio na direção de aglomerados ricos de galaxias

NASA Astrophysics Data System (ADS)

Andreazza, C. M.; Andernach, H.

A contagem de fontes de rádio, na direção de aglomerados ricos de galáxias, deve fornecer uma distribuçãto acima da média do campo devido aos efeitos do meio. No entanto, a distribução de radiofontes de alguns aglomerados, investigada por vários autores no passado, mostrou, em alguns casos, uma deficência de fontes fracas. Neste trabalho, analisamos os levantamentos em 2.7 GHz (Reuter e Andernach 1990, 1990A&AS...82..279R; Loiseau et al. 1988, 1988A&AS...75...67L) e o catálogo 6CII em 151 MHz (Hales et al. 1988, 1988MNRAS.234..919H). Nosso estudio da distribução de radiofontes, na direção de aglomerados ricos de galáxias, nestas duas frequências, mostra um excesso de fontes fortes somente nas regiões centrais dos aglomerados. Este resultado pode ser explicado devido à evidência de confinamento das radiofontes pelo gás, do meio intra-aglomerado, e devido aos processos de colisão, coalescência e canibalismo de galáxias.

The influence of nicotine in healing of small bowel anastomoses in rats: angiogenesis and miofibroblasts.

PubMed

Skinovsky, James; Malafaia, Osvaldo; Chibata, Mauricio; Tsumanuma, Fernanda; Panegalli, Flávio; Martins, Marcus Vinícius Dantas de Campos

2016-01-01

to know the effect of nicotine on angiogenesis and myofibroblast formation in anastomoses of the small bowel of rats. we randomly divided 60 Wistar rats into the groups Nicotine (N) and control (C), according to the proposed treatment. Each group was subdivided into three subgroups according to the time interval used for the evaluation (7, 14 or 28 days). The N group with 30 animals received nicotine subcutaneously at a dose of 2mg/kg body weight, diluted in 0.3ml of 0.9% saline, twice daily for 28 days prior to the operation, and for more 7, 14 or 28 days, depending on the subgroup. The C group (also 30 animals) received only saline on the same conditions and time intervals. After 28 days we carried out an end-to-end anastomosis 10cm distal to the duodenojejunal flexure in each rat. After 7, 14 or 28 days after surgery, we euthanized ten animals of each group, sent specimens of the anastomosis areas, 1cm proximal to 1cm distal, to counting of blood vessels and myofibroblasts through immunohistochemical staining by the application of monoclonal anti-factor VIII antibodies and anti-smooth muscle alpha-actin. the administration of nicotine led to the decrease in the number of blood vessels measured on the 28th postoperative day and the number of myofibroblasts measured on the seventh day following completion of the anastomoses. administration of nicotine was deleterious on angiogenesis and myofibroblast formation in rats' small intestine anastomoses. conhecer o efeito da nicotina sobre a angiogênese e formação de miofibroblastos em anastomoses do intestino delgado de ratos. sessenta ratos Wistar foram divididos de maneira aleatória em grupos Nicotina(N) e Controle (C), conforme o tratamento proposto. Cada grupo foi subdividido em três subgrupos, de acordo com o intervalo de tempo utilizado para a avaliação (7, 14 ou 28 dias). O grupo N, com 30 animais, recebeu nicotina por via subcutânea, na dose de 2mg/Kg de peso, diluída em 0,3ml de solução salina a 0,9%, em duas aplicações diárias, durante 28 dias prévios à operação e por mais 7, 14 ou 28 dias, conforme o subgrupo. O grupo C (igualmente com 30 animais) recebeu somente a solução salina nas mesmas condições e intervalos de tempo. Após 28 dias efetuou-se, em cada rato, anastomose término-terminal a 10cm da flexura duodenojejunal. Após 7, 14 ou 28 dias da cirurgia, os dez animais de cada subgrupo foram eutanasiados, sendo que as áreas anastomosadas, 1cm proximal a 1cm distal, foram encaminhadas para contagem de vasos sanguíneos e miofibroblastos, através de coloração imuno-histoquímica por aplicação dos anticorpos monoclonais antifator VIII e anti-alfa-actina muscular lisa. a administração de nicotina levou à diminuição do número de vasos sanguíneos aferidos no 28o dia pós-operatório e do número de miofibroblastos aferidos no sétimo dia após a realização das anastomoses. a administração de nicotina foi deletéria sobre a angiogênese e formação de miofibroblastos em anastomoses do intestino delgado de ratos.

Intranasal administration of dopamine attenuates unconditioned fear in that it reduces restraint-induced ultrasound vocalizations and escape from bright light.

PubMed

Talbot, Teddy; Mattern, Claudia; de Souza Silva, Maria Angelica; Brandão, Marcus Lira

2017-06-01

Although substantial evidence suggests that dopamine (DA) enhances conditioned fear responses, few studies have examined the role of DA in unconditioned fear states. Whereas DA does not cross the blood-brain barrier, intranasally-applied dopamine reaches the brain directly via the nose-brain pathways in rodents, providing an alternative means of targeting DA receptors. Intranasal dopamine (IN-DA) has been demonstrated to bind to DA transporters and to increase extracellular DA in the striatum as well as having memory-promoting effects in rats. The purpose of this study was to examine the influence of IN-DA in three tests of fear/anxiety. The three doses of DA hydrochloride (0.03, 0.3, or 1 mg/kg) were applied in a viscous castor oil gel in a volume of 5 µl to each of both nostrils of adult Wistar rats prior to testing of (a) escape from a bright light, using a two-chamber procedure, (b) restraint-induced 22 kHz ultrasound vocalizations (USVs), and (c) exploratory behavior in the elevated plus-maze (EPM). IN-DA dose-dependently reduced escape from bright light and the number of USV responses to restraint. It had no influence on the exploratory behavior in the EPM. IN-DA application reduced escape behavior in two tests of unconditioned fear (escape from bright light and USV response to immobilization). These findings may be interpreted in light of the known antidepressant action of IN-DA and DA reuptake blockers. The results also confirm the promise of the nasal route as an alternative means for targeting the brain's dopaminergic receptors with DA.

Effects of acute amphetamine (AMPH) treatment on rat striatal dopamine (DA) receptor activity

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

Roseboom, P.H.; Iwaniec, L.M.; Ackerman, J.M.

1986-03-05

Upon administration of AMPH rats display a complex series of dose and time dependent behaviors and changes in dopaminergic activity. They found a decrease in D1 DA receptor-stimulated adenylate cyclase (DA-AC) activity in rat striatal membranes after acute in vivo AMPH at a dose and time of intense stereotyped behavior. The Ka for D1-AC activity increased and the Vmax decreased in striatal membranes from rats given 7.5 mg/kg AMPH i.p. and killed 1 hr later as compared to saline (SAL) controls. They examined whether the decrease of DA-AC was due to a change in receptor number or activation of GTP-bindingmore » protein, Ns. Female Holtzman rats were injected with SAL or 7.5 mg/kg AMPH and killed 1 hr later. A 27,000 x g striatal particulate fraction was prepared for AC assay or (/sup 3/H)DA binding with 10 nM spiroperidol. They found no difference in stimulation of AC by NaF, GTP or GppNHp at any dose tested in membranes from SAL- and AMPH-treated rats. Calmodulin-stimulated AC was also unchanged after AMPH. Specific binding at a saturating concentration of (/sup 3/H)DA was 191 +/- 31 and 117 +/- 14 fmol/mg prot in membranes from SAL- and AMPH-treated rats, respectively. This suggests an alteration is occurring at the level of the D1 receptor rather than at coupling of Ns with the AC catalytic subunit.« less

A phase IIa study of rhLTα-Da in combination with cisplatin and fluorouracil for patients with metastatic esophageal squamous cell carcinoma or gastric adenocarcinoma.

PubMed

Wang, Feng-Hua; Wang, Yun; Chen, Zhen-Dong; Chen, Jian-Hua; Qin, Feng-Zhan; Jiang, Wen-Qi; Li, Yu-Hong

2016-11-01

Recombinant human lymphotoxin-α derivative (rhLTα-Da) is a lymphotoxin-α derivative missing 27 N-terminal amino acid residues. This multicenter phase IIa trial was conducted to evaluate the safety, efficacy and pharmacokinetics of rhLTα-Da with cisplatin (DDP) and 5-fluorouracil (5-Fu) for metastatic esophageal squamous cell cancer (ESCC) and gastric adenocarcinoma (GC). Two different rhLTα-Da doses (10 µg/m 2 /d and 20 µg/m 2 /d) in combination with DDP and 5-Fu were evaluated in this study. The first 6 ESCC and 6 GC patients were given 10 µg/m 2 /d rhLTα-Da followed by DDP (15 mg/m 2 /d) and 5-Fu (750 mg/m 2 /d) on days 1-5. The next 6 ESCC and 6 GC patients were given 20 µg/m 2 /d rhLTα-Da after fewer than 2 of the 6 patients who received the 10 µg/m 2 /d dose exhibited dose-limiting rhLTα-Da-related toxicities. The treatment was 21 days a cycle until a maximum of 6. The rhLTα-Da pharmacokinetic analyses were performed. Twelve ESCC and 12 GC patients were enrolled. The toxicities were controllable and reversible. The most common adverse events related to rhLTα-Da were chills (37.5 %, 9/24) and fever (16.7 %, 4/24) (all grades 1-2). The overall response rates in the 10- and 20-µg/m 2 /d groups were 50 % (6/12) and 33.3 % (4/12), respectively, and the overall response rates of the ESCC and GC patients were 66.7 % (8/12) and 16.7 % (2/12), respectively. rhLTα-Da in combination with DDP and 5-Fu exhibited a tolerable toxicity profile. The addition of rhLTα-Da may enhance the anti-tumor efficacy of platinum-based chemotherapy in metastatic ESCC.

Extracellular polymers of ozonized waste activated sludge.

PubMed

Liu, J C; Lee, C H; Lai, J Y; Wang, K C; Hsu, Y C; Chang, B V

2001-01-01

Effect of ozonation on characteristics of waste activated sludge was investigated in the current study. Concentrations of cell-bound extracellular polymers (washed ECPs) did not change much upon ozonation, whereas the sum of cell-bound and soluble extracellular polymers (unwashed ECPs) increased with increasing ozone dose. Washed ECPs in original sludge as divided by molecular weight distribution was 39% < 1,000 Da (low MW), 30% from 1,000 to 10,000 Da (medium MW), and 31% > 10,000 Da (high MW). It was observed that the low-MW fraction decreased, and the high-MW fraction increased in ozonized sludge. The unwashed ECPs were characterized as 44% in low MW, 30% in medium MW, and 26% in high MW. Both low-MW and medium-MW fractions of unwashed ECPs decreased while high-MW fraction increased in ozonized sludge. The dewaterability of ozonized sludge, assessed by capillary suction time (CST) and specific resistance to filtration (SRF), deteriorated with ozone dose. The optimal dose of cationic polyelectrolyte increased with increasing ozone dose. The production rate and the accumulated amount of methane gas of ozonized sludge were also higher.

Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice.

PubMed

Hirata, H; Ladenheim, B; Carlson, E; Epstein, C; Cadet, J L

1996-04-01

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the issue of loss of DA terminals. In the present study, we have used receptor autoradiographic studies of [(125)I]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent in the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.

Nursing appointment and cardiometabolic control of diabetics: a randomized clinical trial.

PubMed

Teston, Elen Ferraz; Arruda, Guilherme Oliveira de; Sales, Catarina Aparecida; Serafim, Deise; Marcon, Sonia Silva

2017-01-01

to verify the effect of nursing appointment on cardiometabolic profile of people with Diabetes Mellitus type 2. randomized controlled trial, developed with 134 individuals chosen for two groups: intervention and control. The intervention consisted of three nursing appointments alternated bimonthly, with two phone calls, over five months. The control group received usual care offered by the Health Unit. Data were collected through semi-structured interviews before and after the intervention, in addition to conducting laboratory tests. after the intervention, a significant difference was shown in the amount of glycated hemoglobin (p = 0.006) and in the systolic blood pressure (p = 0.031), which were higher in the control group. besides being low-cost and easy to develop on the monitoring routine of people with diabetes, the intervention performed influenced positively the biochemical profile. verificar o efeito da consulta de enfermagem sobre o perfil cardiometabólico de pessoas com Diabetes Mellitus tipo 2. ensaio clínico controlado e randomizado, desenvolvido com 134 indivíduos sorteados para dois grupos: intervenção e controle. A intervenção consistiu em três consultas de enfermagem bimensais alternadas, com duas ligações telefônicas, ao longo de cinco meses. O grupo-controle recebeu os cuidados habituais oferecidos pela Unidade de Saúde. Os dados foram coletados mediante entrevistas semiestruturadas antes e após a intervenção, além da realização de exames laboratoriais. após a intervenção, foi evidenciada diferença significativa no valor da hemoglobina glicada (p=0,006) e da pressão arterial sistólica (p=0,031), que se mostraram mais elevadas no grupo-controle. a intervenção realizada, além de ser de baixo custo e de fácil desenvolvimento na rotina de acompanhamento da pessoa com diabetes, influenciou positivamente a melhora do perfil bioquímico.

Determinação da massa de júpiter a partir das órbitas de seus satélites: um experimento didático

NASA Astrophysics Data System (ADS)

Schlickmann, M. S.; Saito, R. K.; Becker, D. A.; Rezende, M. F., Jr.; Cid Fernandes, R.

2003-08-01

Este trabalho apresenta o roteiro piloto de uma prática observacional em astronomia, junto com os primeiros resultados obtidos nesta fase de implementacão. O projeto, que será executado em duas etapas, visa introduzir noções de Astronomia a alunos do Ensino Médio e iniciantes nos cursos de Física. O experimento consiste em medir as órbitas dos satélites Galileanos e, a partir da análise dos dados coletados, verificar a validade da Lei das órbitas de Kepler, determinando a massa do planeta Júpiter. Em uma primeira etapa, as observações serão feitas utilizando um telescópio Meade LX200 10" e câmera CCD para obter uma seqüência de imagens do planeta, que possibilitará medir o movimento de seus satélites. A segunda etapa terá início a partir do funcionamento do telescópio em modo robótico, com a possibilidade de observações via internet por instituições de ensino. Para o desenvolvimento deste experimento foram inicialmente coletadas várias imagens de Júpiter obtidas com os instrumentos citados acima. Estas imagens serviram como base para confecção dos roteiros para a experiência no nível médio e superior. Os roteiros serão inicialmente apresentados em uma home-page. Nela também se buscará uma contextualização histórica da experiência bem como o estabelecimento de relações com professores e alunos, propostas metodológicas e a disponibilização dos programas computacionais necessários para a utilização "on-line" pelos usuários. O projeto conta com apoio da Fundação VITAE.

Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects.

PubMed

Yokota, Tomohiro; Aida, Takashi; Ichikawa, Yasuhiro; Fujita, Takayuki; Yokoyama, Utako; Minamisawa, Susumu

2012-08-01

Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure. To measure the inner diameter of the vessels, a rapid whole-body freezing method was used. Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries. Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.

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.

[Continued Use of Rotigotine Transdermal Patches for Parkinson Disease].

PubMed

Yasutaka, Yuki; Fujioka, Shinsuke; Shibaguchi, Hirotomo; Imakyure, Osamu; Washiyama, Atsushi; Tsuboi, Yoshio; Futagami, Koujiro

2016-06-01

Transdermal patches containing rotigotine, a dopamine agonist (DA) for treatment of Parkinson disease, continuously exert stable effects when applied once daily. Therefore, they are expected to reduce the patient burdens due to complications such as wearing-off and dysphagia. However, dosing is occasionally reduced or discontinued after application because of several reasons such as skin reactions or unsatisfactory efficacy. To identify the risk factors involved in the reduced or discontinued use of rotigotine patches, a retrospective study was conducted with reference to the medical records of patients with Parkinson disease who received rotigotine patches in our hospital. 85 patients were involved in this study. Dosing of rotigotine was reduced or discontinued in 53 patients during the study period. The factors associated with charges in treatment included combination therapy with clonazepam and oral administration of another DA before the application of rotigotine. The reduction or discontinuation rate of rotigotine patches in patients who reduced the equivalent dose of DA on the introduction of rotigotine patches was 94.7%, showing a significantly higher rate compared with 61.3% in the increased dose group. To improve adherence to rotigotine patch therapy, physicians need to carefully consider concomitant drugs and total dose of DAs. (Received December 7, 2015; Accepted February 22, 2016; Published June 1, 2016).

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates.

PubMed

Bruno, J P; Byrnes, E M; Johnson, B J

1995-11-01

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 microliter) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 micrograms, intraventricular) on postnatal day 3. Administration of the D1-like antagonist SCH 23390 (0.5-2.0 micrograms) or the D2-like antagonist clebopride (1.0-4.0 micrograms) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However, combined administration of SCH 23390 + clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D1 + D2 antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D1- and D2-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D1 or D2 receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.

Safety and usage of darbepoetin alfa in children with chronic kidney disease: prospective registry study.

PubMed

Schaefer, Franz; Hoppe, Bernd; Jungraithmayr, Therese; Klaus, Günter; Pape, Lars; Farouk, Mourad; Addison, Janet; Manamley, Nick; Vondrak, Karel

2016-03-01

Limited prospective data are available on the long-term safety of darbepoetin alfa (DA) for treating anemia in children with chronic kidney disease (CKD). In this prospective, phase IV, observational registry study, children ≤16 years of age with CKD anemia and receiving DA were observed for ≤2 years. Adverse events (AEs), DA dosing, hemoglobin (Hb) concentrations, and transfusions were recorded. A total of 319 patients were included in the analysis (mean age, 9.1 years), 158 (49.5%) of whom were on dialysis at study entry. Of 434 serious AEs reported in 162 children, the most common were peritonitis (10.0%), gastroenteritis (6.0%), and hypertension (4.1%). Six patients (1.9%) died (unrelated to DA). Four patients (1.3%) experienced six serious adverse drug reactions. The geometric mean DA dose range was 1.4-2.0 μg/kg/month. Mean baseline Hb concentration was 11.1 g/dl; mean values for children receiving and not receiving dialysis at baseline ranged between 10.9 and 11.5 g/dl and 11.2-11.7 g/dl, respectively. Overall, 48 patients (15.0%) received ≥1 transfusion. No new safety signals for DA were identified in children receiving DA for CKD anemia for ≤2 years. Based on Hb concentrations and transfusion requirements, DA was effective at managing anemia in these patients.

Cocaine. Selective regional effects on central monoamines.

PubMed

Hadfield, M G

1995-01-01

Cocaine HCl (0, 10, or 50 mg/kg) was injected into adult male ICR mice ip. Thirty minutes later, the brains were removed, and nine regions were isolated: olfactory bulbs, olfactory tubercles, prefrontal cortex, septum, striatum, amygdala, hypothalamus, hippocampus, and thalamus. Using high-performance liquid chromatography, concentrations of norepinephrine, dopamine, serotonin, and their major metabolites and the metabolite/neurotransmitter ratios were determined as an indicator of utilization. Serotonergic systems responded most dramatically. 5HIAA/5-HT decreases were seen in all the brain regions, except the septum, hippocampus, and olfactory bulbs. In most instances, the alterations were dose-dependent. The most profound changes were seen in the amygdala, prefrontal cortex, hypothalamus, and thalamus. For noradrenergic systems, significant responses were seen only in the amygdala, prefrontal cortex, and hypothalamus, but then only at the lower dose. The dopaminergic responses were more complex and not always dose-dependent. The DOPAC/DA ratio was decreased only in the amygdala and striatum at the lower dose, and the olfactory tubercles at the higher dose. It was increased in the septum. The HVA/DA ratios were decreased in the amygdala, prefrontal cortex, and hypothalamus, but only at the lower dose (like MHPG/NE). The 3MT/DA ratio was decreased in the thalamus at the lower dose and in the olfactory tubercles at the higher dose, whereas it was increased in the prefrontal cortex at the lower dose. The HVA and DOPAC routes of degradation were both utilized only by the amygdala. Thus, cocaine produced its most comprehensive effects in this nucleus, as well as the greatest absolute percentage changes for all three of the monoamine systems studied.

Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice.

PubMed

Viñals, Xavier; Maldonado, Rafael; Robledo, Patricia

2013-03-01

Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces dopaminergic neurotoxicity in mice. However, it is still not clear whether this exposure induces deficits in cognitive processing related to specific subsets of executive functioning. We evaluated the effects of neurotoxic and non-neurotoxic doses of MDMA (0, 3 and 30 mg/kg, twice daily for 4 days) on working memory and attentional set-shifting in mice, and changes in extracellular levels of dopamine (DA) in the striatum. Treatment with MDMA (30 mg/kg) disrupted performance of acquired operant alternation, and this impairment was still apparent 5 days after the last drug administration. Decreased alternation was not related to anhedonia because no differences were observed between groups in the saccharin preference test under similar experimental conditions. Correct responding on delayed alternation was increased 1 day after repeated treatment with MDMA (30 mg/kg), probably because of general behavioural quiescence. Notably, the high dose regimen of MDMA impaired attentional set-shifting related to an increase in total perseveration errors. Finally, basal extracellular levels of DA in the striatum were not modified in mice repeatedly treated with MDMA with respect to controls. However, an acute challenge with MDMA (10 mg/kg) failed to increase DA outflow in mice receiving the highest MDMA dose (30 mg/kg), corroborating a decrease in the functionality of DA transporters. Seven days after this treatment, the effects of MDMA on DA outflow were recovered. These results suggest that repeated neurotoxic doses of MDMA produce lasting impairments in recall of alternation behaviour and reduce cognitive flexibility in mice. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin? Implication for Anti-Addiction Medications

PubMed Central

Peng, Xiao-Qing; Xi, Zheng-Xiong; Li, Xia; Spiller, Krista; Li, Jie; Chun, Lauren; Wu, Kuo-Ming; Froimowitz, Mark; Gardner, Eliot L

2010-01-01

The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48 h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA. PMID:20827272

Acanthocheilonema viteae: Vaccination of jirds with irradiation-attenuated stage-3 larvae and with exported larval antigens

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

Lucius, R.; Textor, G.; Kern, A.

1991-08-01

Jirds (Meriones unguiculatus) were immunized with irradiated (35 krad) stage-3 larvae (L3) of Acanthocheilonema viteae. The induced resistance against homologous challenge infection and the antibody response of the animals were studied. Immunization with 3, 2, or 1 dose of 50 irradiated L3 induced approximately 90% resistance. Immunization with a single dose of only 5 irradiated L3 resulted in 60.8% protection while immunization with a single dose of 25 L3 induced 94.1% protection. The protection induced with 3 doses of 50 irradiated L3 did not decrease significantly during a period of 6 months. Sera of a proportion, but not all resistantmore » jirds, contained antibodies against the surface of vector derived L3 as defined by IFAT. No surface antigens of microfilariae or adult worms were recognized by the sera. Vaccinated animals had antibody responses against antigens in the inner organs of L3 and in the cuticle and reproductive organs of adult worms as shown by IFAT. Immunoblotting with SDS-PAGE-separated L3 antigens and L3-CSN revealed that all sera contained antibodies against two exported antigens of 205 and 68 kDa, and against a nonexported antigen of 18 kDa. The 205-kDa antigen easily degraded into fragments of 165, 140, 125, and 105 kDa which were recognized by resistant jird sera. Various antigens of adult worms, but relatively few antigens of microfilariae, were also recognized. To test the relevance of exported antigens of L3 to resistance, jirds were immunized with L3-CSN together with a mild adjuvant. This immunization induced 67.7% resistance against challenge infection and sera of the immunized animals recognized the 205- and 68-kDa antigens of L3.« less

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory.

PubMed

Naef, M; Müller, U; Linssen, A; Clark, L; Robbins, T W; Eisenegger, C

2017-04-25

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

DA1 receptors modulation in rat isolated trachea.

PubMed

Cabezas, Gloria A; Velasco, Manuel

2010-01-01

We have previously demonstrated that low dose of inhaled dopamine (0.5-2 microg kg(-1) min(-1)) induces broncodilatacion in patients with acute asthma attack, suggesting that this dopamine effect is mediated by dopaminergic rather than by adrenergic receptors. To understand better these dopamine effect, rat tracheal smooth muscle was used as a model to evaluate the responses of beta2-, alpha1-, alpha2-adrenergic and DA1 and DA2 dopaminergic antagonists. Tracheal rings from male Sprague-Dawley rats (n = 90) were excised and placed in an organ bath containing modified Krebs-Ringer bicarbonate buffer at 37 degrees C, and gassed with O2 (95%) and CO2 (5%). Contractile responses were recorded with an isometric transducer in a polygraph (Letica, Spain). Contraction was induced by accumulative doses of acetylcholine (0.1, 0.3, 1, 3, 10 mM) or by electric field stimulation (10 Hz at 2 milliseconds), and accumulative doses of dopamine were added to the bath. Low concentration (0.1-0.3 mM) elicited a small initial contraction, followed by a marked relaxation. Cholinergic contraction was completely reversed at 6 mM of dopamine. This biphasic dopaminergic response was not blocked by incubation with beta2-adrenergic antagonist propranolol (0.1 microM), alpha1-antagonist, terazosin (0.1 mM), alpha2-antagonist, yohimbine (0.1 mM), or by DA2 antagonist metoclopramide (1-8 mM); DA1 antagonist SCH23390 (0.1 microM) produced a sustained increase of basal tone but did not block initial dopaminergic contraction and partially inhibited bronchodilator effect of dopamine. Dopaminergic relaxation in rat trachea is mediated by DA1 rather than by DA2 receptors; and adrenergic receptors are not involved in such dopamine-induced response. Finally, DA1 antagonist SCH23390 exerts intrinsic contractile activity on airway smooth muscle that deserves further research.

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

PubMed Central

Robinson, Bonnie L.; Dumas, Melanie; Cuevas, Elvis; Gu, Qiang; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna

2016-01-01

Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. PMID:26898327

A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise.

PubMed

Jung, Chang Hee; Park, Cheol-Young; Ahn, Kyu-Joeng; Kim, Nan-Hee; Jang, Hak-Chul; Lee, Moon-Kyu; Park, Joong-Yeol; Chung, Choon-Hee; Min, Kyung-Wan; Sung, Yeon-Ah; Park, Jeong-Hyun; Kim, Sung Jin; Lee, Hyo Jung; Park, Sung-Woo

2015-03-01

DA-1229 is a novel, potent and selective dipeptidyl peptidase-4 (DPP-IV) inhibitor that is orally bioavailable. We aimed to evaluate the optimal dose, efficacy and safety of DA-1229, in Korean subjects with type 2 diabetes mellitus suboptimally controlled with diet and exercise. We enrolled 158 patients (mean age, 53 years and a mean BMI, 25.6 kg/m(2) ). The mean baseline fasting plasma glucose level, HbA1c and duration of diabetes were 8.28 mmol/L, 7.6% (60 mmol/mol) and 3.9 years, respectively. After 2 or 6 weeks of an exercise and diet program followed by 2 weeks of a placebo period, the subjects were randomized into one of four groups for a 12-week active treatment period: placebo, 2.5, 5 or 10 mg of DA-1229. All three doses of DA-1229 significantly reduced HbA1c from baseline compared to the placebo group (-0.09 in the placebo group vs. -0.56, -0.66 and -0.61% in 2.5, 5 and 10-mg groups, respectively) but without any significant differences between the doses. Insulin secretory function, as assessed by homeostasis model assessment β-cell, the insulinogenic index, 2-h oral glucose tolerance test (OGTT) C-peptide and post-OGTT C-peptide area under the curve (AUC)0-2h, significantly improved with DA-1229 treatment. The incidence of adverse events was similar between the treatment groups and DA-1229 did not affect body weight or induce hypoglycaemic events. DA-1229 monotherapy (5 mg for 12 weeks) improved HbA1c, fasting plasma glucose level, OGTT results and β-cell function. This drug was well tolerated in Korean subjects with type 2 diabetes mellitus. © 2014 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons, Ltd.

Conceptus radiation dose and risk from chest screen-film radiography.

PubMed

Damilakis, John; Perisinakis, Kostas; Prassopoulos, Panos; Dimovasili, Evangelia; Varveris, Haralambos; Gourtsoyiannis, Nicholas

2003-02-01

The objectives of the present study were to (a) estimate the conceptus radiation dose and risks for pregnant women undergoing posteroanterior and anteroposterior (AP) chest radiographs, (b) study the conceptus dose as a function of chest thickness of the patient undergoing chest radiograph, and (c) investigate the possibility of a conceptus to receive a dose of more than 10 mGy, the level above which specific measurements of conceptus doses may be necessary. Thermoluminescent dosimeters were used for dose measurements in anthropomorphic phantoms simulating pregnancy at the three trimesters of gestation. The effect of chest thickness on conceptus dose and risk was studied by adding slabs of lucite on the anterior and posterior surface of the phantom chest. The conceptus risk for radiation-induced childhood fatal cancer and hereditary effects was calculated based on appropriate risk factors. The average AP chest dimension (d(a)) was estimated for 51 women of childbearing age from chest CT examinations. The value of d(a) was estimated to be 22.3 cm (17.4-27.2 cm). The calculated maximum conceptus dose was 107 x 10(-3) mGy for AP chest radiographs performed during the third trimester of pregnancy with maternal chest thickness of 27.2 cm. This calculation was based on dose data obtained from measurements in the phantoms and d(a) estimated from the patient group. The corresponding average excess of childhood cancer was 10.7 per million patients. The risk for hereditary effects was 1.1 per million births. Radiation dose for a conceptus increases exponentially as chest thickness increases. The conceptus dose at the third trimester is higher than that of the second and first trimesters. The results of the current study suggest that chest radiographs carried out in women at any time during gestation will result in a negligible increase in risk of radiation-induced harmful effects to the unborn child. After a properly performed maternal chest X-ray, there is no need for individual conceptus dose estimations.

S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: A microdialysis study

PubMed Central

Faiman, Morris D.; Kaul, Swetha; Latif, Shaheen A.; Williams, Todd D.; Lunte, Craig E.

2015-01-01

Disulfiram (DSF), used for the treatment of alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating cocaine dependence. Although DSF’s mechanism of action in alcohol abuse is due to the inhibition of liver mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of cocaine dependence is unknown. DSF is a pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl) glutathione (carbamathione) (carb). We previously showed that carb affects glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on dopamine (DA), GABA, and glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in substance abuse dependence. The effect of DSF on DA, GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA, GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the cytochrome P450 inhibitor N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA, GABA, and GLu occurred. Changes in these neurotransmitters occurred only if carb was formed from DSF. When NBI was administered prior to dosing with carb, the increase in DA, decrease in GABA, and biphasic effect on GLu was similar to that seen after dosing with carb only. The i p or i v administration of carb showed similar changes in DA, GABA, and GLu, except the time to reach Cmax for DA as well as the changes in GABA, and GLu after i p administration occurred later. The elimination half-life of carb and the area under the curve (AUC) were similar after both routes of administration. It is concluded that carb must be formed from DSF before any changes in DA, GABA, and GLu in the NAc and mPFC are observed. DSF and carb, when administered to rats, co-release DA, GABA, and GLu. Carb, once formed can cross the blood brain barrier and enter the brain. Although inhibition of liver ALDH2 is the accepted mechanism for DSF’s action in treating AUDs, the concurrent changes in DA, GABA, and GLu in the NAc and mPFC after DSF administration suggest that changes in these neurotransmitters as a potential mechanism of action not only for AUDs, but also for cocaine dependence cannot be excluded. PMID:23891816

Cytochrome P450 isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

PubMed Central

ZHANG, Jinhui; LI, Li; TANG, Suni; HALE, Thomas W.; XING, Chengguo; JIANG, Cheng; LÜ, Junxuan

2016-01-01

We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 enzymes (CYP) whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal preparation, general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol and ketoconazole, substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0–48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0–48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D. PMID:26394652

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica.

PubMed

Zhang, Jinhui; Li, Li; Tang, Suni; Hale, Thomas W; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2015-01-01

We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 (CYP) enzymes, whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal (HLM) preparation, the general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol (NBN) and ketoconazole substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic (PK) study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0-48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.

Multiple toxic doses of methamphetamine alter neurotensin concentrations in various region of the rat brain

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

Hanson, G.R.; Merchant, K.; Gibb, J.W.

1986-03-05

The authors have previously reported that multiple high doses of methamphetamine (METH) alter neuronal monoamine metabolism and release. Recently, Hokfelt et al. showed that neurotensin, a tridecapeptide, has neurotransmitter properties which may be involved with DA neuronal activity. In the present study they investigated the possible effects of METH on the CNS neurotensin system. Five doses of METH (15 mg/kg) were administered every 6 h; control and treated rats were sacrificed 18 h after the last dose and concentrations of neurotensin-like immuno-reactivity (NTLI) were measured by radioimmunoassay. NTLI was elevated 200-300% in the nucleus accumbens, neostriatum, and substantia nigra; 30-40%more » increases in NTLI were measured in the hippocampus and hypothalamus. No change was observed in amygdala, A-10 or periaqueductal gray. In contrast to the above measured areas, the frontal lobe and olfactory bulb showed decreases of 25-35%. These findings demonstrate that METH treatment alters the activities of several CNS neurotensin systems, possibly due to the influence of this drug on DA pathways. The variability in the type and magnitude of these responses suggests that DA and neurotensin systems interact by more than one mechanism.« less

Neurochemical changes following a single dose of polybrominated diphenyl ether 47 in mice.

PubMed

Gee, Jillian R; Moser, Virginia C; McDanie, Katherine L; Herr, David W

2011-04-01

Polybrominated diphenyl ethers (PBDEs) are commonly used as commercial flame retardants in a variety of products, including plastics and textiles. Previous studies in our laboratory, and in the literature, showed that exposure to a specific PBDE congener (PBDE 47) during a critical period of brain development may lead to developmental delays and hyperactivity in adulthood. To date, the underlying causes of these behavioral alterations are unknown, although in vitro studies linked PBDEs with potential alterations in neurotransmitter levels, particularly acetylcholine (ACh) and dopamine (DA). Alterations in DA function have also been noted in cases of hyperactivity in rodents and humans. The current study examined monoamine levels in male mice acutely exposed to corn oil vehicle or PBDE 47 (1, 10, or 30 mg/kg) on postnatal day (PND) 10. Animals were sacrificed on PND 15, PND 20, and in adulthood (131-159 days old). The cortex, striatum, and cerebellum were isolated and analyzed by high-performance liquid chromatography to determine the concentration of monoamines within each brain region. A statistically significant increase in DA levels was seen within the cortex, regardless of age, but only in the 10-mg/kg PBDE treatment group. While these effects did not show a monotonic dose response, we previously reported hyperactivity in littermates in the same dose group, but not at the lower or higher dose. Thus, early developmental exposure to PBDE 47 alters the levels of cortical DA in male mice, which may correlate with behavioral observations in littermates.

Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

PubMed

Clark, Robert E; Kuczenski, Ronald; Segal, David S

2007-07-01

Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

A calibration method for realistic neutron dosimetry in radiobiological experiments assisted by MCNP simulation

PubMed Central

Shahmohammadi Beni, Mehrdad; Krstic, Dragana; Nikezic, Dragoslav; Yu, Kwan Ngok

2016-01-01

Many studies on biological effects of neutrons involve dose responses of neutrons, which rely on accurately determined absorbed doses in the irradiated cells or living organisms. Absorbed doses are difficult to measure, and are commonly surrogated with doses measured using separate detectors. The present work describes the determination of doses absorbed in the cell layer underneath a medium column (DA) and the doses absorbed in an ionization chamber (DE) from neutrons through computer simulations using the MCNP-5 code, and the subsequent determination of the conversion coefficients R (= DA/DE). It was found that R in general decreased with increase in the medium thickness, which was due to elastic and inelastic scattering. For 2-MeV neutrons, conspicuous bulges in R values were observed at medium thicknesses of about 500, 1500, 2500 and 4000 μm, and these were attributed to carbon, oxygen and nitrogen nuclei, and were reflections of spikes in neutron interaction cross sections with these nuclei. For 0.1-MeV neutrons, no conspicuous bulges in R were observed (except one at ~2000 μm that was due to photon interactions), which was explained by the absence of prominent spikes in the interaction cross-sections with these nuclei for neutron energies <0.1 MeV. The ratio R could be increased by ~50% for small medium thickness if the incident neutron energy was reduced from 2 MeV to 0.1 MeV. As such, the absorbed doses in cells (DA) would vary with the incident neutron energies, even when the absorbed doses shown on the detector were the same. PMID:27380801

Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

PubMed

Collins, Lyndsey E; Galtieri, Daniel J; Brennum, Lise T; Sager, Thomas N; Hockemeyer, Jörg; Müller, Christa E; Hinman, James R; Chrobak, James J; Salamone, John D

2010-02-01

Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine. While the adenosine A(2A) antagonist MSX-3 was incapable of reversing the tremulous jaw movements induced by the 4.0mg/kg dose of pilocarpine, both MSX-3 and the adenosine A(2A) antagonist SCH58261 reversed the tremulous jaw movements elicited by 0.5mg/kg pilocarpine. Systemic administration of the adenosine A(1) antagonist DPCPX failed to reverse the tremulous jaw movements induced by either an acute 0.5mg/kg dose of the cholinomimetic pilocarpine or the DA D2 antagonist pimozide, indicating that the tremorolytic effects of adenosine antagonists may be receptor subtype specific. Behaviorally active doses of MSX-3 and SCH 58261 showed substantial in vivo occupancy of A(2A) receptors, but DPCPX did not. The results of these studies support the use of adenosine A(2A) antagonists for the treatment of tremor. Copyright 2009 Elsevier Inc. All rights reserved.

Nicotine and cigarette smoke modulate Nrf2-BDNF-dopaminergic signal and neurobehavioral disorders in adult rat cerebral cortex.

PubMed

Naha, Nibedita; Gandhi, D N; Gautam, A K; Prakash, J Ravi

2018-05-01

Nicotine and cigarette smoking (CS) are associated with addiction behavior, drug-seeking, and abuse. However, the mechanisms that mediate this association especially, the role of brain-derived neurotrophic factor (BDNF), dopamine (DA), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the cerebral cortex, are not fully known. Therefore, we hypothesized that overexpression of BDNF and DA, and suppression of Nrf2 contribute to several pathological and behavioral alterations in adult cerebral cortex. Methodology/Principal Observations: We treated Wistar rats with different doses of oral nicotine and passive CS for 4-week (short-term) and 12-week (long-term) duration, where doses closely mimic the human smoking scenario. Our result showed dose-dependent association of anxiogenic and depressive behavior, and cognitive interference with neurodegeneration and DNA damage in the cerebral cortex upon exposure to nicotine/CS as compared to the control. Further, the results are linked to upregulation of oxidative stress, overexpression of BDNF, DA, and DA marker, tyrosine hydroxylase (TH), with concomitant downregulation of ascorbate and Nrf2 expression in the exposed cerebral cortex when compared with the control. Overall, our data strongly suggest that the intervention of DA and BDNF, and depletion of antioxidants are important factors during nicotine/CS-induced cerebral cortex pathological changes leading to neurobehavioral impairments, which could underpin the novel therapeutic approaches targeted at tobacco smoking/nicotine's neuropsychological disorders including cognition and drug addiction.

Low completion rate of hepatitis B vaccination in female sex workers.

PubMed

Magalhães, Rosilane de Lima Brito; Teles, Sheila Araújo; Reis, Renata Karina; Galvão, Marli Teresinha Gimeniz; Gir, Elucir

2017-01-01

to assess predictive factors for noncompletion of the hepatitis B vaccination schedule in female sex workers in the city of Teresina, Northeastern Brazil. 402 women were interviewed and, for those who did not wish to visit specialized sites, or did not know their hepatitis B vaccination status, the vaccine was offered at their workplaces. Bi- and multivariate analyses were performed to identify potential predictors for noncompletion of the vaccination schedule. of the 284 women eligible for vaccination, 258 (90.8%) received the second dose, 157/258 (60.8%) and 68/258 (26.3%) received the second and third doses, respectively. Working at clubs and consuming illicit drugs were predictors for noncompletion of the vaccination schedule. the high acceptability of the vaccine's first dose, associated with low completion rates of the vaccination schedule in sex workers, shows the need for more persuasive strategies that go beyond offering the vaccine at their workplaces. avaliar fatores preditores de não completude do esquema vacinal contra hepatite B em mulheres que se prostituem em Teresina, Nordeste do Brasil. Um total de 402 mulheres foi entrevistado e, para as que se negaram a irem a lugares especializados, ou desconheciam sua situação vacinal contra hepatite B, a vacina foi oferecida no local do trabalho. Análises bi e multivariadas foram realizadas para identificar potenciais preditores de não completude do esquema vacinal. Das 284 mulheres elegíveis para vacinação, 258 (90,8%) receberam a primeira dose, 157/258 (60,8%) e 68/258 (26,3%) receberam a segunda e terceira doses. Trabalhar em boates e consumir drogas ilícitas foram preditores de não completude do esquema vacinal (p<0,05). A elevada aceitabilidade da primeira dose da vacina, associada à baixa completude do esquema vacinal em profissionais do sexo, evidencia a necessidade de estratégia mais persuasiva que vá além da oferta da vacina no local de trabalho.

Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

PubMed Central

Darvish-Ghane, Soroush; Yamanaka, Manabu

2016-01-01

Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

Conhecimento Científico e Cotidiano em Astronomia: Uma Investigação com Alunos da Educação Básica

NASA Astrophysics Data System (ADS)

Vieira, J. B.; Longhini, M. D.

2011-12-01

Este texto apresenta resultados de uma investigação que teve como objetivo, investigar como os conhecimentos científicos e do cotidiano relacionados a essa área de conhecimento apresentam na escola de Educação Básica, especialmente, em alunos do Ensino Médio prestes a deixar Educação Básica. Para realização da pesquisa, utilizamos como recurso metodológico a aplicação de um questionário estruturado contendo 47 questões, organizadas em duas categorias: Conhecimento Cotidiano e Conhecimento Científico. As questões da categoria “Conhecimento Cotidiano” possuíam afirmações relacionadas a crendices, contos populares, especulações e temáticas do gênero, as quais, geralmente, estão fora do círculo de discussão da comunidade científica, talvez por não serem consideradas como objeto de estudo da ciência. As questões da categoria “Conhecimento Científico” são relacionadas a conteúdos específicos de Astronomia, as quais são compartilhadas pela comunidade científica e aceitas, pelo menos provisoriamente, como possuindo fundamentação científica. Concluímos que, possuem ainda concepções de temas Astronômicos persistentes à mudança, por exemplo, fases da Lua relacionadas à melhor período para corte de cabelo e também para plantio; estrela cadente e ocasião perfeita para se fazer um pedido. Entretanto, podemos observar no que diz respeito a mitos e superstições, que quase não existe influência destes entre os alunos. Portanto, ao trabalharmos com os alunos determinados conceitos científicos, é importante lembrarmos que o professor não opera no vazio; os alunos são sujeitos de saberes, práticas e, dessa forma constroem e reconstroem saberes. Cabe ao professor ouvir os estudantes reconstruindo junto deles conceitos científicos. Acreditamos que o ensino de Ciências na Educação Básica deve lidar criticamente com o conhecimento cotidiano e científico e, assim, efetivar a Ciência como disciplina educativa, formativa e libertadora.

Spin-Transfer-Torque Nano-Oscillators: Fabrication, Characterization and Dynamics

NASA Astrophysics Data System (ADS)

Costa, Jose Diogo Teixeira Barbosa

Este trabalho aborda algumas propriedades magneticas e estruturais de nanoparticulas de oxidos e oxidos-hidroxidos de ferro crescidos em matrizes hibridas orgânicas-inorgânicas. As matrizes hibridas, denominadas di-ureasils e obtidas pelo processo sol-gel, sao compostas por uma rede siliciosa ligada covalentemente por pontes ureia a cadeias orgânicas de diferente peso molecular. A estrutura local dos di-ureasils nao dopados esta modelada como grupos de dominios siliciosos com dimensoes nanometricas, estruturalmente correlacionados no seio de uma matriz rica em polimero. Neste trabalho mostra-se que os di-ureasils permitem o crescimento controlado de oxidos e oxidos-hidroxidos de ferro, incluindo a magnetite, maguemite, oxihidroxinitrato de ferro e ferrihidrite. O crescimento das nanoparticulas de ferrihidrite da-se em condicoes acidas a superficie dos dominios siliciosos, junto aos grupos carbonilo, que funcionam como pontos de nucleacao. Desse modo da-se uma nucleacao heterogenea, onde o tamanho das nanoparticulas depende da concentracao de ferro (entre 1 e 6% em massa), sendo a concentracao de particulas constante. As propriedades magneticas das nanoparticulas de ferrihidrite revelam a existencia de interaccoes antiferromagneticas e de momentos descompensados. A contribuicao destas duas componentes nas curvas de magnetizacao em funcao do campo magnetico pode ser separada usando um metodo aqui proposto, o que permite um adequado estudo da evolucao do momento magnetico com a temperatura. O estudo das propriedades magneticas dinâmicas das particulas de ferrihidrite, atraves de susceptibilidade ac, medidas de relaxacao e medidas de efeito Mossbauer, permitiu estudar a evolucao das interaccoes dipolares em funcao da concentracao de ferro, bem como determinar a distribuicao de barreiras de energia de anisotropia no caso em que essas interaccoes sao desprezaveis. E apresentado um novo metodo para comparacao desta distribuicao com a distribuicao de tamanhos, que permitiu concluir que os momentos magneticos descompensados estao aleatoriamente distribuidos em volume. Usando baixas concentracoes de agua, foi possivel crescer fases de oxihidroxinitrato de ferro com diferentes graus de cristalinidade, sendo algumas precursoras da ferrihidrite (como observado noutros trabalhos) e sendo outras novas fases. O crescimento de nanoparticulas de maguemite e magnetite acontece apos incorporacao de ioes de Fe2+ e Fe3+ seguidos de tratamento basico e termico. Estes sistemas apresentam propriedades magneticas tipicas de nanoparticulas superparamagneticas sem interaccoes dipolares. As propriedades magneticas dependem criticamente da existencia de grupos isocianato livres, que actuarao como pontos de nucleacao. None

Structural and Magnetic Studies on Iron Oxide Nanoparticles in Hybrid Matrices =

NASA Astrophysics Data System (ADS)

Silva, Nuno Joao de Oliveira

Este trabalho aborda algumas propriedades magneticas e estruturais de nanoparticulas de oxidos e oxidos-hidroxidos de ferro crescidos em matrizes hibridas orgânicas-inorgânicas. As matrizes hibridas, denominadas di-ureasils e obtidas pelo processo sol-gel, sao compostas por uma rede siliciosa ligada covalentemente por pontes ureia a cadeias orgânicas de diferente peso molecular. A estrutura local dos di-ureasils nao dopados esta modelada como grupos de dominios siliciosos com dimensoes nanometricas, estruturalmente correlacionados no seio de uma matriz rica em polimero. Neste trabalho mostra-se que os di-ureasils permitem o crescimento controlado de oxidos e oxidos-hidroxidos de ferro, incluindo a magnetite, maguemite, oxihidroxinitrato de ferro e ferrihidrite. O crescimento das nanoparticulas de ferrihidrite da-se em condicoes acidas a superficie dos dominios siliciosos, junto aos grupos carbonilo, que funcionam como pontos de nucleacao. Desse modo da-se uma nucleacao heterogenea, onde o tamanho das nanoparticulas depende da concentracao de ferro (entre 1 e 6% em massa), sendo a concentracao de particulas constante. As propriedades magneticas das nanoparticulas de ferrihidrite revelam a existencia de interaccoes antiferromagneticas e de momentos descompensados. A contribuicao destas duas componentes nas curvas de magnetizacao em funcao do campo magnetico pode ser separada usando um metodo aqui proposto, o que permite um adequado estudo da evolucao do momento magnetico com a temperatura. O estudo das propriedades magneticas dinâmicas das particulas de ferrihidrite, atraves de susceptibilidade ac, medidas de relaxacao e medidas de efeito Mossbauer, permitiu estudar a evolucao das interaccoes dipolares em funcao da concentracao de ferro, bem como determinar a distribuicao de barreiras de energia de anisotropia no caso em que essas interaccoes sao desprezaveis. E apresentado um novo metodo para comparacao desta distribuicao com a distribuicao de tamanhos, que permitiu concluir que os momentos magneticos descompensados estao aleatoriamente distribuidos em volume. Usando baixas concentracoes de agua, foi possivel crescer fases de oxihidroxinitrato de ferro com diferentes graus de cristalinidade, sendo algumas precursoras da ferrihidrite (como observado noutros trabalhos) e sendo outras novas fases. O crescimento de nanoparticulas de maguemite e magnetite acontece apos incorporacao de ioes de Fe2+ e Fe3+ seguidos de tratamento basico e termico. Estes sistemas apresentam propriedades magneticas tipicas de nanoparticulas superparamagneticas sem interaccoes dipolares. As propriedades magneticas dependem criticamente da existencia de grupos isocianato livres, que actuarao como pontos de nucleacao. None

Health Policy on the pages of Revista de Saúde Pública.

PubMed

Bousquat, Aylene; Tanaka, Oswaldo Yoshimi

2016-11-10

We carried out a narrative review of the scientific production in the area of Policy, Planning and Management in Revista de Saúde Pública (RSP), between 1967 and 2015. All the fascicles of RSP, in the period, were accessed via SciELO platform, which provides all articles online. We selected and classified the articles according to the main topics of scientific production in the area of Policy, Planning and Management. Revista de Saúde Pública has published 343 articles on this subject, with significant growth in the last two decades. The most discussed topics were Health Economics, Primary Health-care, Access and Use of Health Services, and Evaluation of Services and Programs. In the last decade, the topics of Policy and Access to Medicines and Public-Private Relationship, including judicialization, gained importance. The pages of RSP embraced the vast and diverse production of Policy, Planning and Management in its first 50 years, contributing to the consolidation of the area in Brazil. RESUMO Foi realizada revisão narrativa da produção científica do campo de Política, Planejamento e Gestão veiculada na Revista de Saúde Pública (RSP), entre 1967 e 2015. Todos os fascículos da RSP, no período, foram acessados via plataforma SciELO, que disponibiliza todos os artigos online. Foram selecionados e classificados os artigos segundo os principais temas da produção científica da área de Política, Planejamento e Gestão. Foram publicados 343 artigos, com crescimento expressivo nas últimas duas décadas. Economia da Saúde, Atenção Primária à Saúde, Acesso e Utilização de Serviços de Saúde e Avaliação de Serviços e Programas foram os temas mais abordados. Na última década, os temas Política e Acesso a Medicamentos e Relação Público-Privado, incluindo a judicialização, ganharam importância. As páginas da RSP abrigaram vasta e diversa produção de Política, Planejamento e Gestão nos seus primeiros 50 anos, contribuindo para consolidação da área no Brasil.

Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo.

PubMed

Song, Im-Sook; Kong, Tae Yeon; Jeong, Hyeon-Uk; Kim, Eun Nam; Kwon, Soon-Sang; Kang, Hee Eun; Choi, Sang-Zin; Son, Miwon; Lee, Hye Suk

2014-07-17

Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC50 values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the Cmax of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose.

DA-9701 on gastric motility in patients with Parkinson's disease: A randomized controlled trial.

PubMed

Shin, Cheol Min; Lee, Yoon Jin; Kim, Jong-Min; Lee, Jee Young; Kim, Kyung-Joon; Choi, Yoon Jin; Kim, Nayoung; Lee, Dong Ho

2018-04-21

To evaluate the effect of DA-9701, a novel prokinetic drug, on gastric motility evaluated by magnetic resonance imaging in patients with Parkinson's disease (PD). Forty PD patients were randomly allocated to receive either domperidone or DA-9701. Their gastric functions were evaluated using magnetic resonance imaging before and after 4-week treatment period. Information on levodopa daily dose, disease duration, and Unified PD Rating Scale scores was collected. In 18 patients (domperidone: 9, DA-9701: 9), plasma levodopa concentrations were determined. Primary outcome was assessed by a one-sided 95% confidence interval to show non-inferiority of DA-9701 vs. domperidone with a pre-determined non-inferiority margin of -10%. Thirty-eight participants (19 men and 19 women; mean age, 67.1 years) completed the study protocol (domperidone: DA-9701 = 19:19). Gastric emptying rate at 120 min (2-hr GER) was comparable between the 2 groups; it was not correlated with levodopa daily dose or disease duration or Unified PD Rating Scale scores (all p > 0.05). DA-9701 was not inferior to domperidone in changes of 2-hr GERs before and after the treatment (absolute difference, 4.0 %; one-sided 95% confidence interval, - 3.7 to infinity). However, a significant increase in 2-hr GER was observed only in DA-9701 group (54.5% and 61.8%, before and after treatment, respectively, p < 0.05). Plasma levodopa concentration showed an insignificant but increasing trend in DA-9701 group. There were neither adverse reactions nor deteriorations of parkinsonian symptoms observed in the study participants. DA-9701 can be used for the patients with PD to enhance gastric motility without aggravating PD symptoms (ClinicalTrials.gov number: NCT03022201). Copyright © 2018 Elsevier Ltd. All rights reserved.

20 CFR 625.15 - Inviolate rights to DUA.

Code of Federal Regulations, 2010 CFR

2010-04-01

... UNEMPLOYMENT ASSISTANCE § 625.15 Inviolate rights to DUA. Except as specifically provided in this part, the... of persons to regular unemployment compensation are protected under the applicable State law. Such...

20 CFR 625.15 - Inviolate rights to DUA.

Code of Federal Regulations, 2012 CFR

2012-04-01

... UNEMPLOYMENT ASSISTANCE § 625.15 Inviolate rights to DUA. Except as specifically provided in this part, the... of persons to regular unemployment compensation are protected under the applicable State law. Such...

20 CFR 625.15 - Inviolate rights to DUA.

Code of Federal Regulations, 2011 CFR

2011-04-01

... UNEMPLOYMENT ASSISTANCE § 625.15 Inviolate rights to DUA. Except as specifically provided in this part, the... of persons to regular unemployment compensation are protected under the applicable State law. Such...

20 CFR 625.15 - Inviolate rights to DUA.

Code of Federal Regulations, 2013 CFR

2013-04-01

... UNEMPLOYMENT ASSISTANCE § 625.15 Inviolate rights to DUA. Except as specifically provided in this part, the... of persons to regular unemployment compensation are protected under the applicable State law. Such...

20 CFR 625.15 - Inviolate rights to DUA.

Code of Federal Regulations, 2014 CFR

2014-04-01

... UNEMPLOYMENT ASSISTANCE § 625.15 Inviolate rights to DUA. Except as specifically provided in this part, the... of persons to regular unemployment compensation are protected under the applicable State law. Such...

Angiotensin I converting enzyme inhibitory activity and antihypertensive effect in spontaneously hypertensive rats of cobia (Rachycentron canadum) head papain hydrolysate.

PubMed

Yang, Ping; Jiang, Yuchuan; Hong, Pengzhi; Cao, Wenhong

2013-06-01

Cobia head protein hydrolysate (CHPH) with angiotensin I converting enzyme (ACE) inhibitory activity was prepared with papain. The 3 kDa ultrafiltration filtrate CHPH-IV of the hydrolysate exerted a potent ACE inhibitory activity with IC50 being 0.24 mg/mL. The fractions with molecular weight located between 1749 Da and 173 Da represented up 66.96% of CHPH-IV, and those between 494 Da and 173 Da represented up 31.37% of CHPH-IV. It was found that the ACE inhibitory activity of CHPH-IV was intensified from IC50 0.24 mg/mL to 0.17 mg/mL after incubation with gastrointestinal proteases. The CHPH-IV significantly decreased the systolic blood pressure in a dose-dependent manner after oral administration to spontaneously hypertensive rats (SHR) at dose of 150 mg/kg, 600 mg/kg and 1200 mg/kg body weight. These results suggested that CHPH-IV from cobia head protein hydrolysate by papain could serve as a source of peptides with antihypertensive activity in functional food industry.

Advanced Development of Leishmania Topical Skin Test Antigen

DTIC Science & Technology

2012-09-28

can cause sensitization manifest by the conversion of a negative to positive delayed-type hypersensitivity (DTH) skin test. This was observed on the...third skin test with 30 ug and 50 ug doses of the crude lysate administered intradermally at monthly intervals. Fractionation of the lysate...identified dominant proteins at 8 kDa, 20 kDa, and 56-58 kDa. Skin tests in L. tropica sensitized guinea pigs with each of these fractions revealed

Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry.

PubMed

Liu, Qing; Xu, Tian-Yong; Zhang, Zhi-Bi; Leung, Chi-Kwan; You, Ding-Yun; Wang, Shang-Wen; Yi, Shuai; Jing, Qiang; Xie, Run-Fang; Li, Huifang-Jie; Zeng, Xiao-Feng

2017-06-15

Ketamine and ethanol are increasingly being used together as recreational drugs in rave parties. Their effects on the dopamine (DA) system remain largely unknown. This study aimed to investigate the effects of consuming two different concentrations of ketamine with and without alcohol on the DA system. We employed the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of the combined administration of two different doses of ketamine (30mg/kg and 60mg/kg) with ethanol (0.3156g/kg). We evaluated the effects of the combined drug treatment on the transcriptional output of tyrosine hydroxylase (TH), dopa decarboxylase (DDC), synaptosomal-associated protein 25 (SNAP25), and vesicular monoamine transporter 2 (VMAT2) as well as protein expression level of brain-derived neurotrophic factor (BDNF) in rat prefrontal cortex (PFC) and striatum. We found that rats exhibited a dose-dependent, drug-paired, place preference to ketamine and ethanol associated with an elevated DA level in the striatum but not in the PFC. Moreover, treatment involving low- or high-dose ketamine with or without ethanol caused a differential regulatory response in the mRNA levels of the four DA metabolism genes and the cellular protein abundance of BDNF via the cortex-striatum circuitry. This study investigated the molecular mechanisms that occur following the combined administration of ketamine and ethanol in the DA system, which could potentially lead to alterations in the mental status and behavior of ketamine/ethanol users. Our findings may aid the development of therapeutic strategies for substance abuse patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of CDP-choline on striatal dopamine level and behavior in rats.

PubMed

Shibuya, M; Kageyama, N; Taniguchi, T; Hidaka, H; Fujiwara, M

1981-02-01

To further assess the effects of CDP (cytidine diphosphate)-choline on Parkinsonian symptoms, striatal dopamine (DA) was measured fluorometrically in rats after injection of CDP-choline. CDP-choline (300 mg/kg, i.p.) increased the DA content in the striatum (p less than 0.05) one hour after injection. The behavioral effect of CDP-choline was then tested in rats in which the unilateral nigro-striatal DA neurons had degenerated following an intranigral injection of 6-hydroxydopamine (6-OHDA). CDP-choline alone did not produce behavioral changes in these rats. However, pretreatment with a single dose of CDP-choline (900 mg/kg, i.p.) suppressed both the apomorphine-induced contralateral and the d-amphetamine-induced ipsilateral circling. The same dose of CDP-choline suppressed the number of treadmill revolutions in mice. On the other hand, a 7-day consecutive treatment with 300 mg/kg of CDP-choline enhanced the apomorphine-induced contralateral circling (by 42%, p less than 0.05). The same treatment with CDP-choline raised the striatal DA content by 29% (p less than 0.05) on the intact side, but not on the 6-OHDA injected side. These results indicate that CDP-choline has either a direct nor an indirect DA agonistic effect. The increase in DA content, decrease in locomotion and enhancement of the effect of apomorphine can be explained on the hypothesis that CDP-choline may act as an antagonist on the DA neurons and receptors. The validity of this apparently paradoxical use of CDP-choline with antagonistic effect on DA neurons in the treatment of Parkinson's disease is discussed.

MK-801-induced behavioural sensitisation alters dopamine release and turnover in rat prefrontal cortex.

PubMed

Cui, Xiaoying; Lefevre, Emilia; Turner, Karly M; Coelho, Carlos M; Alexander, Suzy; Burne, Thomas H J; Eyles, Darryl W

2015-02-01

Repeated exposure to psychostimulants that either increase dopamine (DA) release or target N-methyl-D-aspartate (NMDA) receptors can induce behavioural sensitisation, a phenomenon that may be important for the processes of addiction and even psychosis. A critical component of behavioural sensitisation is an increase in DA release within mesocorticolimbic circuits. In particular, sensitisation to amphetamine leads to increased DA release within well-known sub-cortical brain regions and also regulatory regions such as prefrontal cortex (PFC). However, it is unknown how DA release within the PFC of animals is altered by sensitisation to NMDA receptor antagonists. The aims of the present study were twofold, firstly to examine whether a single dose of dizocilpine maleate (MK-801) could induce long-term behavioural sensitisation and secondly to examine DA release in the PFC of sensitised rats. Behavioural sensitisation was assessed by measuring locomotion after drug exposure. DA release in the PFC was measured using freely moving microdialysis. We show that a single dose of MK-801 can induce sensitisation to subsequent MK-801 exposure in a high percentage of rats (66 %). Furthermore, rats sensitised to MK-801 have altered DA release and turnover in the PFC compared with non-sensitised rats. Schizophrenia patients have been postulated to have 'endogenous sensitisation' to psychostimulants. MK-801-induced sensitised rats, in particular when compared with non-sensitised rats, provide a useful model for studying PFC dysfunction in schizophrenia.

Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and women.

PubMed

Zhang, Jinhui; Li, Li; Hale, Thomas W; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2015-01-01

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. ClinicalTrials.gov NCT02114957.

Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

PubMed Central

Zhang, Jinhui; Li, Li; Hale, Thomas W.; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2015-01-01

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. Trial Registration ClinicalTrials.gov NCT02114957 PMID:25695490

Physical Biologycal Interactions Controlling Larvae Dispersion: Application to Regions in the Neighbourhood of the Estuaries of North Portugal

NASA Astrophysics Data System (ADS)

Almeida, Martinho Marta

Um modelo numerico tridimensional oceânico foi usado para estudar a influencia das condicoes fisicas na dispersao e recrutamento de larvas com migracao vertical diaria (MVD) activa na plataforma continental noroeste de Portugal. As primeiras simulacoes foram forcadas por mares e verificou-se que a interaccao entre MVD e correntes de mare nao e importante para o transporte de larvas na plataforma continental oeste portuguesa. O trabalho realizado com forcamento de mares incrementou o presente conhecimento da dinâmica da mare na regiao. A analise da variacao vertical dos parâmetros das elipses de mare mostra uma separacao clara entre os harmonicos diurnos e semi-diurnos, e entre a circulacao oceânica quase barotropica e as correntes com dependencia vertical na plataforma. Desprezando a interaccao entre MVD e as mares o proximo passo foi a construcao e validacao dum modelo realistico forcado por fluxos atmosfera-oceano, capaz de reproduzir as correntes dominantes, geradas pelo vento, na plataforma continental. Na configuracao criada a MVD das larvas foi simulada com quatro cenarios de distribuicao e migracao vertical. Foram feitas duas simulacoes, uma para o final do Inverno e outra para a Primavera, abrangendo os meses de Fevereiro a Abril e Abril a Junho de 2002. Estes periodos foram escolhidos pois exibem diferentes regimes de vento, nao favoravel e favoravel ao afloramento costeiro. Os resultados mostram que as particulas com MVD sofreram maior retencao na plataforma continental interna durante condicoes de afloramento do que em qualquer outra combinacao de cenario de migracao e regime de vento. Na costa noroeste da Peninsula Iberica, que nao exibe irregularidades topograficas que poderiam criar areas de concentracao e retencao, a MVD pode constituir um mecanismo importante para evitar a dispersao de larvas em direccao ao mar aberto. None

Differential effects of dopamine antagonists infused to the medial preoptic area on the sexual behavior of female rats primed with estrogen and progesterone.

PubMed

Graham, M Dean; Pfaus, James G

2012-10-01

Dopamine (DA) in the medial preoptic area (mPOA) is important for the control of appetitive aspects of sexual behavior in the female rat. Recently, following infusions of DA agonists to the mPOA of females primed with estradiol benzoate (EB) alone, we found that the ratio of D1R/D2R activity within the mPOA determines the expression of appetitive behaviors (Graham and Pfaus, 2010). To further the knowledge of this mechanism, the present experiments examined the effects of intra-mPOA infusions of selective DA receptor antagonists. Ovariectomized, sexually-experienced rats primed with EB and progesterone (P) were implanted bilaterally with cannulae aimed at the mPOA and infused with 4 doses (0, 0.25, 1.0 and 4.0 μg) of the nonselective D1R/D2R antagonist flupenthixol (FLU), and selective D1R or D2R antagonists, SCH 23390 (SCH) or raclopride (RAC), respectively, in a randomized order prior to tests of sexual behavior in bilevel chambers. The high dose of FLU significantly decreased solicitations, hops and darts, and pacing behavior. The high dose of SCH also significantly decreased solicitations. In contrast, the high dose of RAC produced an increase in pacing, and a trend toward an increase in solicitations but no other effect on sexual behavior. These results reinforce the idea that the ratio of D1R/D2R activity within the mPOA of female rats is critical for the expression of appetitive behaviors, and further that this ratio is altered by P which shifts the DA effect to a predominantly facilitative D1R activation. Copyright © 2012 Elsevier Inc. All rights reserved.

Epothilone D Prevents Binge Methamphetamine-Mediated Loss of Striatal Dopaminergic Markers

PubMed Central

Killinger, Bryan A.; Moszczynska, Anna

2016-01-01

Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter (DAT), and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed for the levels of several DAergic markers as well as for the levels of tubulins and their posttranslational modifications (PMTs) at 3 days after the treatments. Binge METH induced a loss of stable long-lived MTs within the striatum but not within the SNpc. Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. By contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs, such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. PMID:26465779

Profilaxia da trombose venosa profunda em cirurgia bariátrica: estudo comparativo com doses diferentes de heparina de baixo peso molecular

PubMed Central

Goslan, Carlos José; Baretta, Giórgio Alfredo Pedroso; de Souza, Hemuara Grasiela Pestana; Orsi, Bruna Zanin; Zanoni, Esdras Camargo A.; Lopes, Marco Antonio Gimenez; Engelhorn, Carlos Alberto

2018-01-01

Resumo Contexto A cirurgia bariátrica é considerada a melhor opção para o tratamento da obesidade, cujos pacientes são considerados de alto risco para fenômenos tromboembólicos. Objetivos Comparar o uso de doses diferentes de heparina de baixo peso molecular (HBPM) na profilaxia da trombose venosa profunda (TVP) em pacientes candidatos à cirurgia bariátrica em relação ao risco de TVP, alteração na dosagem do fator anti-Xa e sangramento pré ou pós-operatório. Métodos Estudo comparativo transversal em pacientes submetidos à cirurgia bariátrica distribuídos em dois grupos, que receberam doses de HBPM de 40 mg (grupo controle, GC) e 80 mg (grupo de estudo, GE). Foram avaliados por ultrassonografia vascular e dosagem de KPTT, TAP, plaquetas e fator anti-Xa. Resultados Foram avaliados 60 pacientes, sendo 34 no GC e 26 no GE. Foi observada diferença significativa somente no peso (p = 0,003) e índice de massa corporal (p = 0,018) no GE em relação ao GC. Não houve diferença na dosagem de KPTT, TAP, plaquetas e fator anti-Xa entre os grupos. Não foram detectados TVP ou sangramentos significativos em ambos os grupos. Conclusões Não houve diferença estatisticamente significativa na utilização de doses maiores de HBPM na profilaxia da TVP em pacientes candidatos à cirurgia bariátrica em relação ao risco de TVP, dosagem do fator anti-Xa e sangramento pré ou pós-operatório.

Visceral leishmaniasis in the state of Sao Paulo, Brazil: spatial and space-time analysis.

PubMed

Cardim, Marisa Furtado Mozini; Guirado, Marluci Monteiro; Dibo, Margareth Regina; Chiaravalloti, Francisco

2016-08-11

To perform both space and space-time evaluations of visceral leishmaniasis in humans in the state of Sao Paulo, Brazil. The population considered in the study comprised autochthonous cases of visceral leishmaniasis and deaths resulting from it in Sao Paulo, between 1999 and 2013. The analysis considered the western region of the state as its studied area. Thematic maps were created to show visceral leishmaniasis dissemination in humans in the municipality. Spatial analysis tools Kernel and Kernel ratio were used to respectively obtain the distribution of cases and deaths and the distribution of incidence and mortality. Scan statistics were used in order to identify spatial and space-time clusters of cases and deaths. The visceral leishmaniasis cases in humans, during the studied period, were observed to occur in the western portion of Sao Paulo, and their territorial extension mainly followed the eastbound course of the Marechal Rondon highway. The incidences were characterized as two sequences of concentric ellipses of decreasing intensities. The first and more intense one was found to have its epicenter in the municipality of Castilho (where the Marechal Rondon highway crosses the border of the state of Mato Grosso do Sul) and the second one in Bauru. Mortality was found to have a similar behavior to incidence. The spatial and space-time clusters of cases were observed to coincide with the two areas of highest incidence. Both the space-time clusters identified, even without coinciding in time, were started three years after the human cases were detected and had the same duration, that is, six years. The expansion of visceral leishmaniasis in Sao Paulo has been taking place in an eastbound direction, focusing on the role of highways, especially Marechal Rondon, in this process. The space-time analysis detected the disease occurred in cycles, in different spaces and time periods. These meetings, if considered, may contribute to the adoption of actions that aim to prevent the disease from spreading throughout the whole territory of São Paulo or to at least reducing its expansion speed. Avaliar, no espaço e espaço-tempo, a ocorrência da leishmaniose visceral em humanos no estado de São Paulo, Brasil. Considerou-se como população de estudo os casos autóctones e óbitos por leishmaniose visceral em humanos ocorridos em São Paulo entre 1999 e 2013 e, como área de estudo, a região oeste do estado. Construíram-se mapas temáticos que mostraram a disseminação da leishmaniose visceral em humanos nos municípios. Ferramentas de análise espacial Kernel e razão Kernel foram utilizadas para obter, respectivamente, a distribuição dos casos e óbitos e a distribuição da incidência e mortalidade. Utilizaram-se estatísticas de varredura para identificar aglomerados espaciais e espaço-temporais de casos e óbitos. Os casos de leishmaniose visceral em humanos, no período de estudo, ocorreram na parte ocidental de São Paulo e sua expansão territorial seguiu principalmente o curso da rodovia Marechal Rondon, no sentido oeste-leste. As incidências foram caracterizadas como duas sequências de elipses concêntricas com intensidade decrescente. A primeira, com maior intensidade, teve epicentro no município de Castilho (cruzamento da rodovia Marechal Rondon com a divisa com o estado de Mato Grosso do Sul) e a segunda, em Bauru. A mortalidade apresentou comportamento similar ao da incidência. Os aglomerados espaciais e espaço-temporais de casos coincidiram com as duas áreas de maiores incidências. Ambos os aglomerados espaço-temporais identificados, mesmo sem coincidirem temporalmente, tiveram início após três anos da detecção dos casos humanos e tiveram a mesma duração, seis anos. A expansão da leishmaniose visceral em São Paulo vem ocorrendo no sentido oeste-leste, com destaque ao papel das rodovias, especialmente a Marechal Rondon, neste processo. A análise espaço-temporal detectou, em diferentes espaços e períodos de tempo, ciclicidade na ocorrência da doença. Esses encontros, se considerados, podem colaborar para a adoção de ações que visem a evitar que a doença se espalhe por todo o território paulista ou, no mínimo, diminuir sua velocidade de expansão.

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside.

PubMed

Capizzi, R L

1996-01-01

In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.

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

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

PubMed

Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

2015-04-14

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [(11)C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

PubMed Central

Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

2015-01-01

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors. PMID:25871974

Caffeine increases striatal dopamine D 2/D 3 receptor availability in the human brain

DOE PAGES

Volkow, N. D.; Wang, G. -J.; Logan, J.; ...

2015-04-14

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A 2A receptors (A 2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [ 11C]raclopride (DA D 2/D 3 receptor radioligand sensitive to endogenous DA) to assess ifmore » caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300mg p.o.) significantly increased the availability of D 2/D 3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D 2/D 3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D 2/D 3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D 2/D 3 receptor availability. Instead, we interpret our findings to reflect an increase in D 2/D 3 receptor levels in striatum with caffeine (or changes in affinity). Furthermore, the association between increases in D 2/D 3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D 2/D 3 receptors.« less

Toxicity of a dental adhesive compared with ionizing radiation and zoledronic acid.

PubMed

Alcaraz, Miguel; Olivares, Amparo; Achel, Daniel-Giyngiri; García-Cruz, Emilio; Fondevilla-Soler, Adriana; Canteras-Jordana, Manuel

2015-07-01

To determine the toxicity of aqueous dilutions of a universal self-priming dental adhesive (DA) and comparing these with those elicited by exposure to ionizing radiation (IR), Zoledronic acid (Z) treatment and the synergic effects of the combined treatment with IR+Z. The genotoxic effect of DA was determined by the increase in the frequency of micronuclei in cytokinesis-blocked in cultured human lymphocytes before and after exposure to 2Gy of X-rays. The cytotoxic effect was studied by using the MTT cell viability test in normal prostate cell lines (PNT2) after exposure to different X-ray doses (0Gy-20Gy). The cell lines divided into different groups and treated with different test substances: DA in presence of O2, DA in absence of O2, Z-treated and control. An in vitro dose-dependent and time-dependent cytotoxic effect of DA, Z and IR on PNT2 cells (p>0.001) was demonstrated. DA without-O2, following the recommendations of manufacturers, had a more pronounced effect of increasing cell death than DA with-O2 (p<0.001). In the genotoxicity assay, DA at 25% of its original concentration significantly increased chromosome damage (p<0.001). The samples studied were found to be toxic, and the samples photo-polymerized in absence of O2 showed a bigger cytotoxic effect comparable to the additive toxic effect showed by the combined treatment of IR+Z. Additional effort should be carried out to develop adhesives, which would reduce the release of hazardous substances; since toxic effects are similar to that reported by other agents whose clinical use is controlled by the health authorities.

Caffeine increases striatal dopamine D 2/D 3 receptor availability in the human brain

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

Volkow, N. D.; Wang, G. -J.; Logan, J.

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A 2A receptors (A 2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [ 11C]raclopride (DA D 2/D 3 receptor radioligand sensitive to endogenous DA) to assess ifmore » caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300mg p.o.) significantly increased the availability of D 2/D 3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D 2/D 3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D 2/D 3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D 2/D 3 receptor availability. Instead, we interpret our findings to reflect an increase in D 2/D 3 receptor levels in striatum with caffeine (or changes in affinity). Furthermore, the association between increases in D 2/D 3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D 2/D 3 receptors.« less

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

PubMed Central

Suyama, Julie A.; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A.; Lazenka, Matthew F.; Negus, S. Stevens

2016-01-01

Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = −0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID:26645638

A cell wall protein-based vaccine candidate induce protective immune response against Sporothrix schenckii infection.

PubMed

Portuondo, Deivys Leandro; Batista-Duharte, Alexander; Ferreira, Lucas Souza; Martínez, Damiana Téllez; Polesi, Marisa Campos; Duarte, Roberta Aparecida; de Paula E Silva, Ana Carolina Alves; Marcos, Caroline Maria; Almeida, Ana Marisa Fusco de; Carlos, Iracilda Zeppone

2016-02-01

Sporotrichosis is a subcutaneous mycosis caused by several closely related thermo-dimorphic fungi of the Sporothrix schenckii species complex, affecting humans and other mammals. In the last few years, new strategies have been proposed for controlling sporotrichosis owning to concerns about its growing incidence in humans, cats, and dogs in Brazil, as well as the toxicity and limited efficacy of conventional antifungal drugs. In this study, we assessed the immunogenicity and protective properties of two aluminum hydroxide (AH)-adsorbed S. schenckii cell wall protein (ssCWP)-based vaccine formulations in a mouse model of systemic S. schenckii infection. Fractioning by SDS-PAGE revealed nine protein bands, two of which were functionally characterized: a 44kDa peptide hydrolase and a 47kDa enolase, which was predicted to be an adhesin. Sera from immunized mice recognized the 47kDa enolase and another unidentified 71kDa protein, whereas serum from S. schenckii-infected mice recognized both these proteins plus another unidentified 9.4kDa protein. Furthermore, opsonization with the anti-ssCWP sera led to markedly increased phagocytosis and was able to strongly inhibit the fungus' adhesion to fibroblasts. Immunization with the higher-dose AH-adjuvanted formulation led to increased ex vivo release of IL-12, IFN-γ, IL-4, and IL-17, whereas only IL-12 and IFN-γ were induced by the higher-dose non-adjuvanted formulation. Lastly, passive transference of the higher-dose AH-adjuvanted formulation's anti-ssCWP serum was able to afford in vivo protection in a subsequent challenge with S. schenckii, becoming a viable vaccine candidate for further testing. Copyright © 2015 Elsevier GmbH. All rights reserved.

Effect of 3 Different Doses of Intrathecal Dexmedetomidine (2.5µg, 5µg, and 10 µg) on Subarachnoid Block Characteristics: A Prospective Randomized Double Blind Dose-Response Trial.

PubMed

Gupta, Mayank; Gupta, Priyanka; Singh, Dhananjay Kumar

2016-03-01

The extended analgesic efficacy of intrathecal dexmedetomidine (ITD) has been investigated in a few clinical trials; however, there is a lack of conclusive evidence upon its ideal dosage. To elucidate the dose-response relationship between ITD and subarachnoid block characteristics, particularly the duration of analgesia and differential analgesia (DA: defined as time difference from the offset of motor blockade to the first analgesic requirement on numerical rating scale = 4.0). Prospective, randomized double blind active control trial. Medical college teaching hospital. Ninety adult (18 - 60 years) patients undergoing elective lower abdominal and lower limb surgeries were randomized into 3 groups to receive intrathecal 0.5% bupivacaine 3 mL with 2.5 µg (group BD2.5), 5µg (group BD5), or 10 µg (group BD10) dexmedetomidine in 0.5 mL normal saline. The 2 segment sensory regression times (TSSRT), duration of motor blockade analgesia, DA, and perioperative adverse effects were assessed. The primary outcome was duration of analgesia and DA. ANOVA, Kruskal Wallis test, Chi-square (x2), and Fisher's exact test, significance: P < 0.05. The onset of sensory block was significantly earlier in group BD10 compared with group BD5 (P = 0.035) and BD2.5 (P = 0.010) while the onset of motor block was significantly earlier in group BD10 compared with BD2.5 (P = 0.020). There was a significant and dose-dependent prolongation of the duration of sensory block (127.50, 149.17, and 187.50 minutes; P < 0.001), motor block (258.50, 331, and 365 minutes; P < 0.001), analgesia (306.17, 396.50, and 512 minutes; P < 0.001), and DA (47.67, 65.50, and147 minutes; P < 0.001) with escalating doses of ITD, respectively. Group BD10 required significantly fewer rescue analgesics compared with other 2 groups (P = 0.001). Except for mild sedation which was significantly higher in group BD10; all the groups were comparable with respect to hemodynamic and other adverse effects. Lack of placebo group, exclusion of higher doses (15µg) of ITD, and short duration of postoperative follow-up. The addition of 10 µg compared with 2.5 µg or 5µg ITD to 0.5% hyperbaric bupivacaine is associated with significantly earlier onset of sensory and motor block as well as prolonged duration of sensory block, motor block, analgesia, and DA with a comparable adverse effect profile.

Differences in the time course of dopaminergic supersensitivity following chronic administration of haloperidol, molindone, or sulpiride.

PubMed

Prosser, E S; Pruthi, R; Csernansky, J G

1989-01-01

The onset and persistence of changes in 3H-spiroperidol binding to dopamine (DA) D2 receptors were examined in rat mesolimbic and striatal brain regions following daily administration of haloperidol, molindone, or sulpiride for 3, 7, 14, or 28 days. Neuroleptic dose equivalencies were determined by inhibition of 3H-spiroperidol in vivo binding in several rat brain regions. Changes in locomotor and stereotyped responses to the specific DA D2 agonist quinpirole were examined 3 days after the last treatment dose. Haloperidol or molindone administration increased mean stereotypy scores and striatal DA D2 receptor densities throughout the 28-day treatment period. In contrast, mesolimbic DA D2 receptor densities were transiently increased and returned to control values, after 28 days of haloperidol or molindone treatment. Sulpiride treatment increased mean stereotypy scores and striatal Bmax values, but had no effect on locomotion or mesolimbic dopamine receptor density. Additionally, the magnitude of change in the various measures of brain DA function varied among the three neuroleptic treatment groups. Results from this study suggest that mesolimbic and striatal brain regions differ in their response to long-term neuroleptic administration and that drug choice may influence the magnitude of neuroleptic-induced dopaminergic supersensitivity.

Fotometria superficial BVRI de 18 galáxias fracas

NASA Astrophysics Data System (ADS)

Saraiva, M. F. O.; Silva, P. R.

2003-08-01

Conhecer as propriedades de galáxias a diferentes redshifts é uma questão fundamental para entender o problema da formação e evolução das galáxias, e desde a década passada tem se intensificado fortemente o estudo de galáxias muito distantes. No entanto parece haver um interesse menor em galáxias a distâncias intermediárias, que aparecem como objetos de fundo em imagens de objetos próximos, e que são igualmente importantes. Examinando imagens BVRI de longa exposição, ótimo sinal/ruído, grande campo (46'x46'), das vizinhanças de NGC 7479, detectamos 18 galáxias fracas (18 < B < 21) nessas imagens. Neste trabalho, apresentamos a fotometria superficial desses objetos. Determinamos coordenadas equatoriais, magnitudes e cores integradas, perfis de brilho e de cor, e parâmetros isofotais calculados por ajuste de ellipses, dentro do limite permitido pela baixa resolução espacial dos dados (1,35 segarc/pixel). Nosso objetivo é procurar correlações entre as propriedades das galáxias e, tentativamente, comparar esses dados com aqueles de galáxias de redshift conhecido, disponíveis na literatura, para estimar suas distâncias (a partir da relação cor x redshift) e suas morfologias. Uma análise preliminar nesse sentido mostrou que as cores aparentes B-V, V-R e V-I dos objetos da nossa amostra, a menos de duas exceções, ocupam regiões bem definidas nos diagramas cor-cor, e não apresentam diferenças notáveis em relação às cores típicas de galáxias próximas.

Evaluation of the Psychometric Properties of NOC Outcomes "Anxiety Level" and "Anxiety Self-Control" in a Portuguese Outpatient Sample.

PubMed

Sampaio, Francisco Miguel Correia; Araújo, Odete Sofia Silva Lomba; Sequeira, Carlos Alberto da Cruz; Lluch Canut, María Teresa; Martins, Teresa

2017-01-25

To adopt the language and to evaluate the psychometric properties of "Anxiety level" and "Anxiety self-control" NOC outcomes in Portuguese adult patients. Methodological design. The final European Portuguese version of the NOC outcome "Anxiety level," composed by 16 indicators, proved excellent internal consistency. Exploratory factor analysis (EFA) was forced to three factors. The NOC outcome "Anxiety self-control," composed of nine indicators, demonstrated a questionable internal consistency. EFA was forced to two factors. European Portuguese versions of the studied NOC outcomes proved to be tools with acceptable psychometric properties for evaluating anxiety in Portuguese patients. This study contributed to the development of NOC language and to the enrichment of nursing's body of knowledge. Adaptar a linguagem e avaliar as propriedades psicométricas dos resultados NOC "Nível de ansiedade" e "Autocontrolo da ansiedade" em utentes portugueses adultos. MÉTODOS: Estudo metodológico. A versão portuguesa do resultado NOC "Nível de ansiedade", composta por 16 indicadores, apresentou uma excelente consistência interna. A análise fatorial exploratória (AFE) foi forçada a três dimensões. O resultado NOC "Autocontrolo da ansiedade", composto por nove indicadores, apresentou uma consistência interna questionável. A AFE foi forçada a duas dimensões. CONCLUSÕES: As versões portuguesas dos resultados NOC estudados são instrumentos com propriedades psicométricas aceitáveis para avaliar a ansiedade em utentes portugueses. IMPLICAÇÕES PARA A PRÁTICA DE ENFERMAGEM: Este estudo contribuiu para o desenvolvimento da linguagem NOC e para enriquecer o corpo de conhecimento de Enfermagem. © 2017 NANDA International, Inc.

Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens.

PubMed

Tzeng, Wen-Yu; Cherng, Chian-Fang G; Wang, Shyi-Wu; Yu, Lung

2016-06-01

This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens. Copyright © 2016 Elsevier B.V. All rights reserved.

3,4-Methylenedioxy-N-methamphetamine (Ecstasy) Promotes the Survival of Fetal Dopamine Neurons in Culture

PubMed Central

Lipton, Jack W.; Tolod, Emeline G.; Thompson, Valerie B.; Pei, Lin; Paumier, Katrina L.; Terpstra, Brian T.; Lynch, Kaari A.; Collier, Timothy J.; Sortwell, Caryl E.

2008-01-01

Summary The current study examined whether modest concentrations of MDMA could increase the survival and/or neurite outgrowth of fetal midbrain dopamine (DA) neurons in vitro since increased DA neurite outgrowth has been previously observed in vivo from prenatal exposure. MDMA concentrations in fetal brain were quantified to determine relevant in vivo concentrations to employ in vitro. A dose-response study in vitro demonstrated that MDMA, at concentrations observed in vivo, resulted in increased, DA-specific, neuron survival. Higher doses resulted in nonspecific neurotoxicity. MDMA application immediately after culture establishment resulted in greater survival than delayed application, however both were superior to control. MDMA significantly increased the expression of the slc6a3 gene (dopamine transporter; DAT) in culture. Co-application of the DAT reuptake inhibitor methylphenidate (MPH) with MDMA attenuated this effect. Progressive reductions in MPH concentrations restored the MDMA-induced survival effect. This suggests that MDMA’s action at DAT mediates the survival effect. Neurite density per neuron was unaffected by MDMA in vitro suggesting that MDMA promotes DA neuron survival but not neurite outgrowth in culture. Finally, animals prenatally exposed to MDMA and examined on postnatal day 35 showed an increase in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra but not in the ventral tegmental area. These data suggest that during development, MDMA can increase the survival of DA neurons through its action at its transporter. Understanding how MDMA increases DA neuron survival may provide insight into normal DA neuron loss during development. PMID:18655796

Mephedrone Does not Damage Dopamine Nerve Endings of the Striatum but Enhances the Neurotoxicity of Methamphetamine, Amphetamine and MDMA

PubMed Central

Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Francescutti, Dina M.; Sykes, Catherine E.; Shah, Mrudang M.; Thomas, David M.; Kuhn, Donald M.

2012-01-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its reuptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20 or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (4 injections of 2.5 or 5.0 mg/kg at 2 hr intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and MDMA on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. Because mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. PMID:23205838

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

PubMed

Killinger, Bryan A; Moszczynska, Anna

2016-02-01

Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter, and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to a destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague-Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed 3 days after the treatments for the levels of several DAergic markers as well as for the levels of tubulins and their post-translational modifications (PMTs). Binge METH induced a loss of stable long-lived MTs within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include decreasing the levels of DAergic markers in the striatum. We have determined that high-dose METH destabilizes microtubules in this pathway, which is manifested by decreased levels of acetylated (Acetyl) and detyrosinated (Detyr) α-tubulin (I). A microtubule stabilizing agent epothilone D protects striatal microtubules form the METH-induced loss of DAergic markers (II). These findings provide a new strategy for protection form METH - restoration of proper axonal transport. © 2015 International Society for Neurochemistry.

Resposta do detector de ondas gravitacionais Mario Schenberg ao "ringdown" de buraco negros

NASA Astrophysics Data System (ADS)

Costa, C. A.; Aguiar, O. D.; Magalhães, N. S.

2003-08-01

Acredita-se que quando duas estrelas de nêutrons coalescem, elas, eventualmente, formam um buraco negro com massa igual a soma das massas dos objetos originais. Durante a formação do buraco negro, o espaço-tempo em torno do sistema sofre perturbações que se propagam na forma de radiação gravitacional. A forma de onda associada a radiação gravitacional, durante este estágio, aproxima-se a uma senóide exponencialmente amortecida. Este tipo de sinal é conhecido como "ringdown", e seu comportamento e parametrização são muito bem conhecidos. Neste trabalho, simulamos computacionalmente sinais provenientes do "ringdown" de buracos negros, com a finalidade de testar o desempenho do detector de ondas gravitacionais Mario Schenberg em observá-los, quando entrar em funcionamento. Este primeiro teste teórico ajudou-nos a criar estratégias de detecção de sinais imersos no ruído instrumental. Calculamos a relação sinal-ruído como uma função da frequência, bem como sua integral dentro da faixa de sensibilidade do detector. Os resultados obtidos mostraram que o detector Schenberg terá sensibilidade suficiente para detectar este tipo de sinal, proveniente de fontes astrofísicas localizadas dentro de um raio de ~100kpc.

Coerência espectroscópica de famílias de asteróides

NASA Astrophysics Data System (ADS)

Mothé Diniz, T.; Roig, F. V.

2003-08-01

As Famílias de asteróides são caracterizadas como agrupamentos de objetos provenientes da quebra por colisão de corpos precursores. Desta forma, seus membros devem preservar relações genéticas que podem ser traduzidas sob a análise de suas características espectrais. Neste trabalho é apresentado o primeiro estudo espectroscópico de todas as famílias de asteróides do cinturão principal. Para tal, a divisão em famílias foi refeita utilizando-se o método HCM com uma base de elementos próprios analíticos (Knezevic e Milani, Jun 2001) e para o estudo espectroscópico foram utilizadas diversas campanhas de observação espectroscópica, tais o S3OS2 e o SMASSII, bem como outros dados disponíveis na literatura. A homogeneidade espectroscópica de cada família foi avaliada através da verificação das classes espectroscópicas presentes, bem como da comparação destes espectros com os de objetos de fundo, localizados na vizinhança da família. Vinte e duas famílias foram analisadas (as que possuíam mais do que 3 membros com espectro) e, dentre as principais conclusões pode-se citar a homogeneidade espectroscópica e, provavelmente mineralógica das famílias de Vesta, Eunomia, Hoffmeister, Dora, Merxia, Agnia, Koronis e Veritas. Esta última em particular, foi tida como uma família não homogênea espectroscopicamente em trabalho anterior (Di Martino et al. 1997). Outro resultado interessante é, por um lado, a aparente falta de homogeneidade dos membros da família de Eos, e por outro sua forte distinção dos objetos de fundo. O oposto ocorre na família de Themis, esta apresentando-se espectroscopicamente compatível com os objetos de fundo, mas com grande homogeneidade taxonômica entre seus membros. Algumas das famílias apresentam asteróides "intrusos" (objetos cujas características físicas não são compatíveis com aquelas dos membros da família) que, de modo geral desaparecem ao se considerarem níveis mais baixos de corte para a divisão da família no HCM, sem prejuízo para o agrupamento dos demais membros.

Estudo em microondas do aprisionamento e precipitação de elétrons em explosões solares

NASA Astrophysics Data System (ADS)

Rosal, A. C.; Costa, J. E. R.

2003-08-01

Uma explosão solar é uma variação rápida e intensa do brilho que ocorre nas chamadas regiões ativas da atmosfera, constituídas por um plasma magnetizado com intensa indução magnética. Os modelos de explosões solares atuais, discutidos na literatura, apresentam características de aprisionamento e precipitação de elétrons em ambientes magnéticos simplificados. Neste trabalho, nos propusemos a separar a emissão dos elétrons aprisionados da emissão dos elétrons em precipitação apenas a partir da emissão em microondas, melhorando portanto o controle sobre o conjunto de parâmetros inferidos. A emissão em microondas da população em precipitação é bastante fraca e portanto da nossa base de dados de 130 explosões observadas pelo Rádio Polarímetro de Nobeyama, em sete freqüências, apenas para 32 foi possível separar as duas componentes de emissão com uma boa razão sinal/ruído. A partir de estudos das escalas de tempo das emissões devidas à variação gradual da emissão no aprisionamento e da variação rápida da emissão dos elétrons em precipitação foi possível obter a separação utilizando um filtro temporal nas emissões resultantes. Em nossa análise destas explosões estudamos os espectros girossincrotrônicos da emissão gradual, a qual associamos provir do topo dos arcos magnéticos e da emissão de variação rápida associada aos elétrons em precipitação. Estes espectros foram calculados e dos quais inferimos que a indução magnética efetiva do topo e dos pés foi em média, Btopo = 236 G e Bpés = 577 G, inferidas das freqüências de pico dos espectros em ntopo = 11,8 GHz e npés = 14,6 GHz com leve anisotropia (pequeno alargamento espectral). O índice espectral da distribuição não-térmica de elétrons d, inferido do índice espectral de fótons da emissão em regime opticamente fino, foi de dtopo = 3,3 e dpés = 3,9. Estes parâmetros são típicos da maioria das análises realizadas em ambiente único de emissão e a relação dos índices espectrais, dpés > dtopo prioriza as interpretações com difusão em ângulo de passo devida a colisões Coulombianas. Nesta difusão o déficit de elétrons energéticos na precipitação seria uma conseqüência natural da dependência em e-3/2 das colisões elétron-próton (onde e é a energia dos elétrons).

População nuclear e extranuclear em rádio-galáxias

NASA Astrophysics Data System (ADS)

Raimann, D. I.; Storchi-Bergmann, T.; Quintana, H.; Alloin, D.; Hunstead, R.; Wisotzki, L.

2003-08-01

A natureza do contínuo UV/ótico em rádio-galáxias é muito importante para o seu entendimento. Em baixos redshifts existem evidências de que muitas delas são dominadas no ótico por luz de estrelas velhas, características de galáxias early-type e em altos redshifts a característica dominante é um excesso de luz no UV, freqüentemente associado com estruturas que estão alinhadas aos eixos das estruturas rádio em grande escala. Inicialmente esse excesso foi interpretado como devido a episódios intensos de formação estelar nas galáxias hospedeiras. Entretanto, as descobertas dos alinhamentos entre as estruturas UV e rádio modificaram essa idéia. Foi proposto que a formação estelar é iniciada pela passagem do jato rádio através do meio interestelar das galáxias hospedeiras. A natureza do excesso UV começou a ser compreendida em um estudo detalhado do continuo ótico da 3C321, onde se concluiu que o contínuo desta galáxia tem origem multicomponente, com contribuições de populações velhas e intermediárias, de luz espalhada oriunda de um quasar obscurecido e do contínuo nebular. No presente trabalho estudamos a população nuclear e extranuclear de uma amostra de 24 rádio-galáxias, utilizando espectros óticos de fenda longa, com alta razão sinal/ruído. Através do método de síntese espectral de populações estelares, foram estimadas as contribuições de populações estelares de diferentes idades (e de um contínuo tipo lei de potência devido a um AGN, FC) para a luz integrada das galáxias, em 4020Å. As principais conclusões deste trabalho são: apenas quatro dos objetos estudados têm contribuições significativas (maiores do que 10%) das populações de 100 milhões de anos ou mais jovens (ou de FC) ao longo da região espacial estudada (6 kpc centrais); nenhuma das rádio-galáxias de tipo FRI estudadas tem contribuição significativa destas populações ao longo desta região; duas (de oito) de tipo FRII tem contribuições significativas da luz que vem do AGN, na região nuclear; uma tem contribuição significativa das populações de 100 milhões de anos e mais jovens ao longo dos 4 kpc centrais, indicando claramente a presença de formação estelar recente. Comparando estes resultados com aqueles obtidos para uma amostra de galáxias não ativas de mesmo tipo de Hubble das rádio, encontramos que a principal diferença entre as duas amostras está na contribuição da população de 1 bilhão de anos, geralmente maior nas rádio-galáxias.

The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.

PubMed

Lidö, Helga Höifödt; Stomberg, Rosita; Fagerberg, Anne; Ericson, Mia; Söderpalm, Bo

2009-07-01

The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.

Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice.

PubMed

Browne, Caleb J; Ji, Xiaodong; Higgins, Guy A; Fletcher, Paul J; Harvey-Lewis, Colin

2017-10-01

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT 2C receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT 2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT 2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT 2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT 2C receptor ligands may have important implications when considering the 5-HT 2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?

PubMed Central

Dépatie, L; Lal, S

2001-01-01

The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis. PMID:11394190

Role of ventral pallidal D2 dopamine receptors in the consolidation of spatial memory.

PubMed

Péczely, László; Ollmann, Tamás; László, Kristóf; Kovács, Anita; Gálosi, Rita; Kertes, Erika; Zagorácz, Olga; Kállai, Veronika; Karádi, Zoltán; Lénárd, László

2016-10-15

The role of dopamine (DA) receptors in spatial memory consolidation has been demonstrated in numerous brain regions, among others in the nucleus accumbens which innervates the ventral pallidum (VP). The VP contains both D1 and D2 DA receptors. We have recently shown that the VP D1 DA receptor activation facilitates consolidation of spatial memory in Morris water maze test. In the present study, the role of VP D2 DA receptors was investigated in the same paradigm. In the first experiment, the D2 DA receptor agonist quinpirole was administered into the VP of male Wistar rats in three doses (0.1, 1.0 or 5.0μg, respectively in 0.4μl physiological saline). In the second experiment, the D2 DA receptor antagonist sulpiride was applied to elucidate whether it can antagonise the effects of quinpirole. The antagonist (4.0μg, dissolved in 0.4μl physiological saline) was microinjected into the VP either by itself or prior to 1.0μg agonist treatment. Control animals received saline in both experiments. The two higher doses (1.0 and 5.0μg) of the agonist accelerated memory consolidation relative to controls and increased the stability of the consolidated memory against extinction. Sulpiride pretreatment antagonised the effects of quinpirole. In addition, the antagonist microinjected into the VP immediately after the second conditioning trial impaired learning functions. The present data provide evidences for the important role of VP D2 DA receptors in the consolidation and stabilization of spatial memory. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

PubMed Central

Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID:27469513

Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat.

PubMed

Pereira, Mariana; Farrar, Andrew M; Hockemeyer, Jörg; Müller, Christa E; Salamone, John D; Morrell, Joan I

2011-01-01

Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A(2A) receptors in striatal areas, including the nucleus accumbens. This study was conducted to determine if adenosine A(2A) receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior. The adenosine A(2A) receptor antagonist MSX-3 (0.25-2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats. Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25-2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol-induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity. Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother-infant relationship.

Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat

PubMed Central

Farrar, Andrew M.; Hockemeyer, Jörg; Müller, Christa E.; Salamone, John D.; Morrell, Joan I.

2011-01-01

Rationale Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A2A receptors in striatal areas, including the nucleus accumbens. Objective This study was conducted to determine if adenosine A2A receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior. Methods The adenosine A2A receptor antagonist MSX-3 (0.25–2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats. Results Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25–2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol-induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity. Conclusions Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother–infant relationship. PMID:20848086

Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Francescutti, Dina M; Sykes, Catherine E; Shah, Mrudang M; Thomas, David M; Kuhn, Donald M

2013-04-01

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. © 2012 International Society for Neurochemistry.

Treatment strategy according to findings on pressure-flow study for women with decreased urinary flow rate.

PubMed

Tanaka, Yoshinori; Masumori, Naoya; Tsukamoto, Taiji; Furuya, Seiji; Furuya, Ryoji; Ogura, Hiroshi

2009-01-01

In women who reported a weak urinary stream, the efficacy of treatment chosen according to the urodynamic findings on pressure-flow study was prospectively evaluated. Twelve female patients with maximum flow rates of 10 mL/sec or lower were analyzed in the present study. At baseline, all underwent pressure-flow study to determine the degree of bladder outlet obstruction (BOO) and status of detrusor contractility on Schäfer's diagram. Distigmine bromide, 10 mg/d, was given to the patients with detrusor underactivity (DUA) defined as weak/very weak contractility, whereas urethral dilatation was performed using a metal sound for those with BOO (linear passive urethral resistance relation 2-6). Treatment efficacy was evaluated using the International Prostate Symptom Score (IPSS), uroflowmetry, and measurement of postvoid residual urine volume. Some patients underwent pressure-flow study after treatment. Urethral dilatation was performed for six patients with BOO, while distigmine bromide was given to the remaining six showing DUA without BOO. IPSS, QOL index, and the urinary flow rate were significantly improved in both groups after treatment. All four of the patients with BOO and one of the three with DUA but no BOO who underwent pressure-flow study after treatment showed decreased degrees of BOO and increased detrusor contractility, respectively. Both BOO and DUA cause a decreased urinary flow rate in women. In the short-term, urethral dilatation and distigmine bromide are efficacious for female patients with BOO and those with DUA, respectively.

Consequences of partial and severe dopaminergic lesion on basal ganglia oscillatory activity and akinesia.

PubMed

Tseng, Kuei Y; Kargieman, Lucila; Gacio, Sebastian; Riquelme, Luis A; Murer, M Gustavo

2005-11-01

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.

Oral penicillin prescribing for children in the UK: a comparison with BNF for Children age-band recommendations

PubMed Central

Saxena, Sonia; Ismael, Zareen; Murray, Macey L; Barker, Charlotte; Wong, Ian CK; Sharland, Mike; Long, Paul F

2014-01-01

Background The British National Formulary for Children (BNFC) recommends dosing oral penicillins according to age-bands, weight-bands, or weight-based calculations. Because of the rising prevalence of childhood obesity, age-band-based prescribing could lead to subtherapeutic dosing. Aim To investigate actual oral penicillin prescribing by GPs in the UK with reference to the current BNFC age-band recommendations. Design and setting Descriptive analysis of UK prescriptions in the 2010 IMS Disease-Analyzer database (IMS-DA). Method A detailed database analysis was undertaken of oral penicillin prescriptions for 0–18 year olds from the 2010 IMS-DA. The prescription analysis included all available data on formulation, strength (mg), prescription quantity unit, package size, prescribed quantity, and volume. Results Considering amoxicillin alone, no infants (aged <1 year) were prescribed the BNFC 2011 edition recommended unit dose (62.5 mg), while the majority received double the dose (125 mg); among children aged 1–5 years, 96% were prescribed the recommended unit dose (125 mg), but 40% of 6–12 year olds and 70% of 12–18 year olds were prescribed unit doses below the BNFC recommendations. For otitis media, only those children aged <1 year received the recommended dose of amoxicillin (40–90 mg/kg/day). Similar variations in dosing across age-bands were observed for phenoxymethylpenicillin and flucloxacillin. Conclusion There is wide variation in the dosing of penicillins for children in UK primary care, with very few children being prescribed the current national recommended doses. There is an urgent need to review dosing guidelines, in relation to the weights of children today. PMID:24686886

Alginate antacid (Gaviscon DA) chewable tablets reduce esophageal acid exposure in Chinese patients with gastroesophageal reflux disease and heartburn symptoms.

PubMed

Yuan, Yao Zong; Fang, Jing Yuan; Zou, Duo Wu; Levinson, Nigel; Jenner, Bartosz; Wilkinson, Joanne

2016-11-01

To assess the efficacy of Gaviscon Double Action (DA) alginate antacid chewable tablets for reducing esophageal acid exposure in Chinese patients with gastroesophageal reflux disease (GERD). Altogether 44 patients reporting moderate to severe heartburn symptoms underwent two pH monitoring visits. The treatment sequence was randomized to patients received DA alginate antacid or placebo at one visit and the alternate treatment 7 days later. After a standardized reflux-provoking meal, patients took four tablets of DA alginate antacid or placebo. Esophageal pH was measured for 4 h post-dosing using an electrode positioned 5 cm above the lower esophageal sphincter. The primary end-point was the percentage of 4-h post-dosing period with pH <4. Secondary end-points were number of acid reflux episodes (pH <4), longest reflux time and DeMeester scores. All 44 patients completed the study and provided data for analysis. With DA alginate antacid, the mean percentage time with pH <4 was 5.1%, significantly less (P = 0.0003) than with placebo (14.8%). DA alginate antacid was statistically significantly superior (P = 0.0290) to placebo (from at least twofold to threefold better) for all other end-points. Two patients reported two mild adverse events (AEs) that resolved within a month of completing the study. No patients had serious and/or severe AEs and none withdrew due to AEs. DA alginate antacid was statistically significantly superior to placebo in reducing post-prandial acid exposure without serious clinically relevant health risks. These findings suggest DA alginate antacid tablets are appropriate for treating acid reflux in Chinese GERD patients with heartburn symptoms. © 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

PubMed Central

Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

2015-01-01

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. PMID:26338332

Customized acrylic implants for reconstruction of extensive skull defects: an exception approach for selected patients.

PubMed

Silva, Rafael Denadai Pigozzi DA; Raposo-Amaral, Cesar Augusto; Guidi, Marcelo Campos; Raposo-Amaral, Cassio Eduardo; Buzzo, Celso Luiz

2017-01-01

to present our experience in the surgical treatment of extensive skullcap defects with customized acrylic implants. we conducted a retrospective analysis of patients with extensive skull defects undergoing acrylic cranioplasties between 2004 and 2013. We carefully selected all patients and classified surgical results based on three scales (craniofacial esthetics, improvement of facial symmetry and need for additional surgery). fifteen patients underwent cranioplasty with intraoperative acrylic implants, whether manually customized (46.67%) or made with prototyped three-dimensional biomodels (53.33%). There were two (13.33%) complications (one infection with implant withdrawal and one seroma). We considered the craniofacial aesthetics excellent (50%), the degree of improvement of craniofacial symmetry satisfactory (57.14%), and the overall mean of surgical results according to the need for new surgeries was 1.5±0.52. cranioplasties of patients with extensive skullcap defects should obey careful and predetermined criteria, both for selection and for the acrylic implant customization method. apresentar nossa experiência no tratamento cirúrgico dos defeitos extensos da calota craniana com implantes de acrílico customizados. análise retrospectiva de pacientes com defeitos extensos da calota craniana submetidos à cranioplastias com acrílico entre 2004 e 2013. Todos os pacientes foram criteriosamente selecionados e os resultados cirúrgicos foram classificados com base em três escalas (estética craniofacial, melhora da simetria facial e necessidade de cirurgia adicional). Quinze pacientes foram submetidos à cranioplastia com implantes de acrílico customizados manualmente no intraoperatório (46,67%) e confeccionados com base em biomodelos tridimensionais prototipados (53,33%). Mesmo respeitando critérios de seleção, houve duas (13,33%) complicações (infecção com retirada do implante e seroma). A estética craniofacial foi considerada excelente (50%), o grau de melhora da simetria craniofacial foi considerado satisfatório (57,14%) e a média global dos resultados cirúrgicos de acordo com a necessidade de novas cirurgias foi 1,5±0,52. as cranioplastias dos pacientes com defeitos da calota craniana extensos devem ser criteriosamente indicadas, obedecendo a critérios pré-determinados de seleção dos pacientes, bem como, do método de customização do implante de acrílico.

Teamwork in nursing: restricted to nursing professionals or an interprofessional collaboration?

PubMed

Souza, Geisa Colebrusco de; Peduzzi, Marina; Silva, Jaqueline Alcântara Marcelino da; Carvalho, Brígida Gimenez

2016-01-01

To understand the nursing professionals' conceptions of teamwork and their elements. A qualitative study conducted in an oncological hospital using a semi-structured interview with 21 nursing professionals. Two conceptions emerged from the accounts: teamwork restricted to nursing professionals and teamwork with interprofessional collaboration with particular importance for interactive dimensions: communication, trust and professional bonds, mutual respect and recognition of the other's work, collaboration, and conflict, with this last subcategory considered as an obstacle to teamwork. Nursing conceives teamwork as an interprofessional practice, which is a result of the quality of interaction among professionals from different areas and involves the recognition and handling of conflicts. Compreender as concepções dos profissionais de enfermagem sobre trabalho em equipe e seus elementos constituintes. Pesquisa qualitativa, realizada em hospital oncológico, por meio de entrevista semiestruturada com 21 profissionais de enfermagem. Duas concepções emergiram dos relatos, trabalho em equipe circunscrito à enfermagem e trabalho em equipe com colaboração interprofissional, com destaque para dimensão interativa: comunicação, confiança e vínculo, respeito mútuo e reconhecimento do trabalho do outro, colaboração e conflito. Esta última subcategoria foi apontada como obstáculo para o trabalho em equipe. A enfermagem concebe majoritariamente o trabalho em equipe como ação interprofissional, e isto decorre da qualidade da interação entre os profissionais das diferentes áreas e o reconhecimento e manejo de conflitos.

Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

PubMed

Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

2014-05-01

In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

Long-term protective effects of methamphetamine preconditioning against single-day methamphetamine toxic challenges.

PubMed

Hodges, A B; Ladenheim, B; McCoy, M T; Beauvais, G; Cai, N; Krasnova, I N; Cadet, J L

2011-03-01

Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH -induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems.

Determining the Shape of the Orbit of Mars in the High School. (Spanish Title: Determinación de la Forma de la Órbita de Marte en la Escuela Secundaria.) Determinando a Forma da Órbita de Marte no Ensino Médio

NASA Astrophysics Data System (ADS)

Dutra, Carlos Maximiliano; Rossini Goulart, Andressa

2014-12-01

In the present work, in order to supply the lacks of practical activities related to the content of Kepler's Laws in high school physics textbooks, we present a practical activity to determine the shape of the orbit of Mars. In this activity the student can experience the discovery the shape of the orbit of Mars in a way similar to that realized by Johannes Kepler combining the physical concepts with geometry. We applied the activity to eighteen high school teachers participating in a Postgraduate Course in Science Education. After two hours of work the group obtained the shape of the orbit of Mars and estimated its orbital parameters with a relative error less than 14%. En el presente trabajo y con el objetivo de reducir la escasez de actividades prácticas relacionadas con el contenido de las leyes de Kepler en libros de texto de física de la escuela secundaria, se presenta una actividad práctica para determinar la forma de la órbita de Marte. En esta actividad el estudiante puede vivir la experiencia de descubrir la forma de la órbita de Marte de una manera similar a la realizada por Johannes Kepler combinando los conceptos físicos con la geometría. Aplicamos la actividad a dieciocho maestros de escuelas secundarias en un Curso de Especialización en Enseñanza de las Ciencias. Después de dos horas de trabajo el grupo obtuvo la forma de la órbita de Marte com error inferior al 14% en los parámetros orbitales. No presente trabalho, visando suprir a deficiência de atividades práticas relacionadas ao conteúdo de Leis de Kepler nos livros-textos de Física do 1º ano do Ensino Médio, apresentamos uma atividade prática de determinação da órbita de Marte. O aluno, combinando conceitos físicos com a geometria poderá vivenciar a experiência da descoberta da forma da órbita de Marte de modo similar ao realizado por Johannes Kepler. Aplicamos a metodologia proposta junto a dezoito professores do Curso de Especialização em Educação em Ciências e obtivemos em um trabalho de duas horas de duração o traçado da órbita de Marte com resultados numéricos médios que reproduzem com erro inferior a 14% os parâmetros orbitais de referência da órbita de Marte.

Biodegradability enhancement and detoxification of cork processing wastewater molecular size fractions by ozone.

PubMed

Santos, Diana C; Silva, Lúcia; Albuquerque, António; Simões, Rogério; Gomes, Arlindo C

2013-11-01

Cork boiling wastewater pollutants were fractionated by sequential use of four ultrafiltration membranes and five fractions were obtained: four retentates (>100, 50-100, 20-50 and 10-20 kDa) and one permeate (<10 kDa); which were used to study the correlation of molecular size with biodegradability and toxicity before and after ozonation. The results show that molecular size is correlated with organic load and restrains biodegradability. The fraction with >100 kDa corresponds to 56% of the organic load and the one with <10 kDa only 8%. The biodegradability of fractions increased 182% with fractions molecular size reduction from >100 to <10 kDa and the chemical oxygen demand (COD) was from 3436 to 386 mg L(-1). For biodegradability enhancement the best outcome of ozonation was obtained with compounds having molecular size >20 kDa and range from 5% up to 175% for applied ozone doses to COD ratios between 0.15 and 0.38. Copyright © 2013 Elsevier Ltd. All rights reserved.

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity.

PubMed

Miner, Nicholas B; Elmore, Josh S; Baumann, Michael H; Phillips, Tamara J; Janowsky, Aaron

2017-12-01

Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2h apart, of MA (2.5, 5, or 10mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects. Published by Elsevier B.V.

Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.

PubMed

Bartoszyk, G D; Van Amsterdam, C; Greiner, H E; Rautenberg, W; Russ, H; Seyfried, C A

2004-02-01

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.

Effects of molindone on central dopaminergic neuronal activity and metabolism: similarity to other neuroleptics.

PubMed

Bunney, B S; Roth, R H; Aghajanian, G K

1975-01-01

The effect of molindone on the activity of dopaminergic (DA) neurons in the rat midbrain and on DA metabolism in the striatum and olfactory tubercles was studied using extracellular single unit recording and biochemical techniques respectively. Molindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine. Possible mechanisms of action of molindone are discussed based on these findings.

ESR dating of Smilodon populator from Toca de Cima dos Pilão, Piauí, Brazil.

PubMed

Kinoshita, Angela; Mollemberg, Michelle; Santana, William; G Figueiredo, Ana Maria; Guidon, Niede; Fátima da Luz, Maria de; Guérin, Claude; Baffa, Oswaldo

2017-02-01

Smilodon is a genus of big cats that lived from the early to the late Pleistocene in regions extending from North to South America. The fossil records of the "saber-toothed cats" are uneven, with some taxa being quite abundant in certain regions. In Brazil, Smilodon populator is a well-known species whose remains, although scarce in comparison to other large mammals, are found all across the country. In particular, there are multiple records of this species in the region of the Serra da Capivara National Park. This area was home to a rich Pleistocene-Holocene fauna, including many mammals. Here, we report on the Electron Spin Resonance dating of a Smilodon populator tooth found in "Toca de Cima dos Pilão", located in the surroundings of the Serra da Capivara National Park. The equivalent dose found after exponential fitting of dose-response curve was (2.7±0.3)x10 2 Gy. Neutron Activation Analysis was used to determine the concentration of radioisotopes present in the sample and in the sediment to calculate the internal and external dose rates. The result of age found is 93±9ka, which confirmed the presence of this species in Serra da Capivara National Park in the late Pleistocene. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trends in asthma mortality in the 0- to 4-year and 5- to 34-year age groups in Brazil.

PubMed

Graudenz, Gustavo Silveira; Carneiro, Dominique Piacenti; Vieira, Rodolfo de Paula

2017-01-01

To provide an update on trends in asthma mortality in Brazil for two age groups: 0-4 years and 5-34 years. Data on mortality from asthma, as defined in the International Classification of Diseases, were obtained for the 1980-2014 period from the Mortality Database maintained by the Information Technology Department of the Brazilian Unified Health Care System. To analyze time trends in standardized asthma mortality rates, we conducted an ecological time-series study, using regression models for the 0- to 4-year and 5- to 34-year age groups. There was a linear trend toward a decrease in asthma mortality in both age groups, whereas there was a third-order polynomial fit in the general population. Although asthma mortality showed a consistent, linear decrease in individuals ≤ 34 years of age, the rate of decline was greater in the 0- to 4-year age group. The 5- to 34-year group also showed a linear decline in mortality, and the rate of that decline increased after the year 2004, when treatment with inhaled corticosteroids became more widely available. The linear decrease in asthma mortality found in both age groups contrasts with the nonlinear trend observed in the general population of Brazil. The introduction of inhaled corticosteroid use through public policies to control asthma coincided with a significant decrease in asthma mortality rates in both subsets of individuals over 5 years of age. The causes of this decline in asthma-related mortality in younger age groups continue to constitute a matter of debate. Apresentar uma atualização das tendências da mortalidade da asma no Brasil em duas faixas etárias: 0-4 anos e 5-34 anos. Dados relativos ao período de 1980 a 2014 referentes à mortalidade da asma, conforme se definiu na Classificação Internacional de Doenças, foram extraídos Sistema de Informação sobre Mortalidade do Departamento de Tecnologia da Informação do Sistema Único de Saúde. Para analisar as tendências temporais das taxas padronizadas de mortalidade da asma, realizou-se um estudo ecológico de séries temporais com modelos de regressão para as faixas etárias de 0 a 4 anos e 5 a 34 anos. Houve uma tendência linear de redução da mortalidade da asma em ambas as faixas etárias e uma tendência polinomial de terceira ordem na população geral. Embora a mortalidade da asma tenha apresentado redução linear consistente em indivíduos com idade ≤ 34 anos, a taxa de declínio foi maior na faixa etária de 0 a 4 anos. A faixa etária de 5 a 34 anos também apresentou redução linear da mortalidade, e essa redução tornou-se mais pronunciada após o ano de 2004, quando o tratamento com corticosteroides inalatórios tornou-se mais amplamente disponível. A redução linear da mortalidade da asma em ambas as faixas etárias contrasta com a tendência não linear observada na população geral do Brasil. A introdução do uso de corticosteroides inalatórios por meio de políticas públicas de controle da asma coincidiu com uma diminuição significativa das taxas de mortalidade da asma em ambos os subgrupos de indivíduos com mais de 5 anos de idade. As causas dessa redução da mortalidade da asma em faixas etárias mais jovens ainda são objeto de debate.

Comparison of (+)-methamphetamine, ±-methylenedioxymethamphetamine, (+)-amphetamine and ±-fenfluramine in rats on egocentric learning in the Cincinnati water maze.

PubMed

Vorhees, Charles V; He, Elizabeth; Skelton, Matthew R; Graham, Devon L; Schaefer, Tori L; Grace, Curtis E; Braun, Amanda A; Amos-Kroohs, Robyn; Williams, Michael T

2011-05-01

(+)-Methamphetamine (MA), (±)-3,4-methylenedioxymethamphetamine (MDMA), (+)-amphetamine (AMPH), and (±)-fenfluramine (FEN) are phenylethylamines with CNS effects. At higher doses, each induces protracted reductions in brain dopamine (DA) and/or serotonin. Chronic MA and MDMA users show persistent monoamine reductions and cognitive impairments. In rats, similar neurochemical effects can be induced, yet cognitive impairments have been difficult to demonstrate. We recently showed that rats treated on a single day with MA (10 mg/kg x 4 at 2 h intervals) exhibit impaired egocentric learning (Cincinnati water maze [CWM]) without affecting spatial learning (Morris water maze [MWM]) (Herring et al., [2008] Psychopharmacology (Berl) 199:637–650). Whether this effect is unique to MA or is a general characteristic of these drugs is unknown. Accordingly, this experiment compared these drugs on CWM performance. Drugs were given s.c. in four doses at 2 h intervals. MA doses were 10 or 12.5 mg/kg/dose, AMPH 25 mg/kg/dose (to match MA12.5-induced hyperthermia), MDMA 15 mg/kg/dose (previously established hyperthermia-inducing dose), and FEN 16.5 mg/kg/dose (equimolar to MA12.5). Two weeks later, rats were tested in the CWM (2 trials/day, 21 days). AMPH and MA (both doses) induced significant increases in CWM errors and latency to reach the goal with no differences in swim speed. MDMA and FEN did not significantly alter learning. Given that FEN selectively and MDMA preferentially affect serotonin whereas AMPH selectively and MA preferentially affect DA, the data suggest that egocentric learning may be predominantly dopaminergically mediated.

Absorption, distribution, metabolism, and excretion of decursin and decursinol angelate from Angelica gigas Nakai.

PubMed

Kim, Kang Min; Kim, Myo Jeong; Kang, Jae Seon

2009-12-01

The pharmacokinetics of decursin and decursinol angelate (D/DA) was investigated in male SD rats following oral and intravenous administration. D/DA and metabolites obtained from in vitro samples were evaluated by LC/MS. The level of D/DA and metabolized decursinol in the blood following oral and intravenous administration declined according to first-order kinetics, with T1/2 values of 56.67, 58.01 and 57.22 h, respectively, being observed after administration of a dose of 2 mg/kg body weight. The large intestine was the major site of disposition following oral administration. These data indicate that D/DA is rapidly absorbed from the gastrointestinal tract. In in vitro experiment utilizing liver microsomal protein, the major metabolic reaction of D/DA occurred to change decursinol. The cumulative biliary, urinary, and fecal excretion of D/DA in bile duct-cannulated rats was 36.10+/-2.9, 25.35+/-3.8, and 34.20+/-3.2%, respectively, at 72 h after administration. These results indicate that the absorption of D/DA is almost complete, and that its metabolites are primarily excreted into feces through the bile. These results indicate that D/DA is subject to enterohepatic circulation.

Effect of β,β-dimethylacrylshikonin on inhibition of human colorectal cancer cell growth in vitro and in vivo.

PubMed

Fan, Yingying; Jin, Shaoju; He, Jun; Shao, Zhenjun; Yan, Jiao; Feng, Ting; Li, Hong

2012-01-01

In traditional Chinese medicine, shikonin and its derivatives, has been used in East Asia for several years for the prevention and treatment of several diseases, including cancer. We previously identified that β,β-dimethylacrylshikonin (DA) could inhibit hepatocellular carcinoma growth. In the present study, we investigated the inhibitory effects of DA on human colorectal cancer (CRC) cell line HCT-116 in vitro and in vivo. A viability assay showed that DA could inhibit tumor cell growth in a time- and dose-dependent manner. Flow cytometry showed that DA blocks the cell cycle at G(0)/G(1) phase. Western blotting results demonstrated that the induction of apoptosis by DA correlated with the induction of pro-apoptotic proteins Bax, and Bid, and a decrease in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. Furthermore, treatment of HCT-116 bearing nude mice with DA significantly retarded the growth of xenografts. Consistent with the results in vitro, the DA-mediated suppression of HCT-116 xenografts correlated with Bax and Bcl-2. Taken together, these results suggest that DA could be a novel and promising approach to the treatment of CRC.

An endogenous 55 kDa TNF receptor mediates cell death in a neural cell line.

PubMed

Sipe, K J; Srisawasdi, D; Dantzer, R; Kelley, K W; Weyhenmeyer, J A

1996-06-01

Tumor necrosis factor-alpha (TNF) is associated with developmental and injury-related events in the central nervous system (CNS). In the present study, we have examined the role of TNF on neurons using the clonal murine neuroblastoma line, N1E-115 (N1E). N1E cells represent a well-defined model for studying neuronal development since they can be maintained as either undifferentiated, mitotically active neuroblasts or as differentiated, mature neurons. Northern and reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that both undifferentiated and differentiated N1Es express transcripts for the 55 kDa TNF receptor (TNFR), but not the 75 kDa TNFR. The biological activity of the expressed TNF receptor was demonstrated by a dose dependent cytotoxicity to either recombinant murine or human TNF when the cells were incubated with the transcriptional inhibitor actinomycin D. The lack of the 75 kDa receptor mRNA expression and the dose dependent response to rHuTNF, an agonist specific for the murine 55 kDa receptor, suggest that the TNF induced cytotoxicity is mediated through the 55 kDa receptor in both the undifferentiated and differentiated N1Es. Light microscopic observations, flow cytometric analysis of hypodiploid DNA, and electrophoretic analysis of nucleosomal DNA fragmentation of N1Es treated with actinomycin D and TNF revealed features characteristic of both necrotic and apoptotic cell death. These findings demonstrate that blast and mature N1E cells express the 55 kDa TNF receptor which is responsible for inducing both necrotic and apoptotic death in these cells. The observation that actinomycin D renders N1E cells susceptible to the cytotoxic effects of TNF indicates that a sensitization step, such as removal of an endogenous protective factor or viral-mediated inhibition of transcription, may be necessary for TNF cytotoxicity in neurons.

Amphetamine Augments Action Potential-Dependent Dopaminergic Signaling in the Striatum in Vivo

PubMed Central

Ramsson, Eric S.; Covey, Daniel P.; Daberkow, David P.; Litherland, Melissa T.; Juliano, Steven A.; Garris, Paul A.

2011-01-01

Amphetamine (AMPH) is thought to disrupt normal patterns of action potential-dependent dopaminergic signaling by depleting dopamine (DA) vesicular stores and promoting non-exocytotic DA efflux. Voltammetry in brain slices concurrently demonstrates these key drug effects, along with competitive inhibition of neuronal DA uptake. Here we perform comparable kinetic and voltammetric analyses in vivo to determine whether AMPH acts qualitatively and quantitatively similar in the intact brain. Fast-scan cyclic voltammetry measured extracellular DA in dorsal and ventral striata of urethane-anesthetized rats. Electrically evoked recordings were analyzed to determine Km and Vmax for DA uptake and vesicular DA release, while background voltammetric current indexed basal DA concentration. AMPH (0.5, 3, and 10 mg/kg i.p.) robustly increased evoked DA responses in both striatal subregions. The predominant contributor to these elevated levels was competitive uptake inhibition, as exocytotic release was unchanged in the ventral striatum and only modestly decreased in the dorsal striatum. Increases in basal DA levels were not detected. These results are consistent with AMPH augmenting action potential-dependent dopaminergic signaling in vivo across a wide, behaviorally relevant dose range. Future work should be directed at possible causes for the distinct in vitro and in vivo pharmacology of AMPH. PMID:21443523

Clinical Validation of the Indicators and Definitions of the Nursing Outcome "Tissue Integrity: Skin and Mucous Membranes" in People With Diabetes Mellitus.

PubMed

Chantal Magalhães da Silva, Natália; de Souza Oliveira-Kumakura, Ana Railka; Moorhead, Sue; Pace, Ana Emília; Campos de Carvalho, Emília

2017-10-01

The study aimed to validate clinically the indicators of the nursing outcome "Tissue Integrity: Skin and Mucous Membranes" and its conceptual and operational definitions in people with diabetes mellitus. A methodological study was conducted with an evaluation of 100 participants for two pairs: one of these pairs used the indicators without the definitions and the other used the indicators with their definitions. The pair who used the definitions presented greater concordance and similarity in the ratings. The indicators and their definitions have been validated clinically. The use of indicators with definitions can contribute to reliable and accurate evaluation of the tissue integrity of the feet in people with diabetes mellitus and, thus, assist in the measurement of the effectiveness of the nursing care provided. Validar clinicamente os indicadores do resultado de enfermagem "Integridade Tissular: pele e mucosas" e suas definições conceituais e operacionais em pessoas com diabetes mellitus. MÉTODOS: Estudo metodológico que consistiu na avaliação de 100 participantes por duas duplas de avaliadores: uma dupla utilizou os indicadores sem as definições e, a outra dupla, os indicadores com suas definições. A dupla que utilizou as definições apresentou maior concordância e similaridade nas avaliações. CONCLUSÃO: Os indicadores e suas definições foram validados clinicamente. IMPLICAÇÕES PARA A PRÁTICA DE ENFERMAGEM: A utilização de indicadores com suas respectivas definições pode contribuir para a avaliação confiável e precisa da integridade tissular dos pés de pessoas com diabetes mellitus e, assim, auxiliar na mensuração da eficácia da assistência de enfermagem. © 2016 NANDA International, Inc.

Influence of the ventilatory mode on acute adverse effects and facial thermography after noninvasive ventilation.

PubMed

Pontes, Suzy Maria Montenegro; Melo, Luiz Henrique de Paula; Maia, Nathalia Parente de Sousa; Nogueira, Andrea da Nóbrega Cirino; Vasconcelos, Thiago Brasileiro; Pereira, Eanes Delgado Barros; Bastos, Vasco Pinheiro Diógenes; Holanda, Marcelo Alcantara

2017-01-01

To compare the incidence and intensity of acute adverse effects and the variation in the temperature of facial skin by thermography after the use of noninvasive ventilation (NIV). We included 20 healthy volunteers receiving NIV via oronasal mask for 1 h. The volunteers were randomly divided into two groups according to the ventilatory mode: bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP). Facial thermography was performed in order to determine the temperature of the face where it was in contact with the mask and of the nasal dorsum at various time points. After removal of the mask, the volunteers completed a questionnaire about adverse effects of NIV. The incidence and intensity of acute adverse effects were higher in the individuals receiving BiPAP than in those receiving CPAP (16.1% vs. 5.6%). Thermographic analysis showed a significant cooling of the facial skin in the two regions of interest immediately after removal of the mask. The more intense acute adverse effects occurred predominantly among the participants in whom the decrease in the mean temperature of the nasal dorsum was lower (14.4% vs. 7.2%). The thermographic visual analysis of the zones of cooling and heating on the face identified areas of hypoperfusion or reactive hyperemia. The use of BiPAP mode was associated with a higher incidence and intensity of NIV-related acute adverse effects. There was an association between acute adverse effects and less cooling of the nasal dorsum immediately after removal of the mask. Cutaneous thermography can be an additional tool to detect adverse effects that the use of NIV has on facial skin. Comparar a incidência e a intensidade de efeitos adversos agudos e a variação da temperatura da pele da face através da termografia após a aplicação de ventilação não invasiva (VNI). Foram incluídos 20 voluntários sadios, de ambos os gêneros, submetidos à VNI com máscara oronasal por 1 h e divididos aleatoriamente em dois grupos de acordo com o modo ventilatório: bilevel positive airway pressure (BiPAP) ou continuous positive airway pressure (CPAP). A termografia da face foi realizada para determinar a temperatura na região de contato da máscara e no dorso do nariz em momentos diferentes. Os voluntários preencheram um questionário de efeitos adversos após a retirada da VNI. A incidência e a intensidade dos efeitos adversos agudos foram maiores naqueles submetidos a BiPAP em relação aos submetidos a CPAP (16,1% vs. 5,6%). A análise termográfica evidenciou um esfriamento significativo da pele facial nas duas regiões de estudo imediatamente após a retirada da máscara. Os efeitos adversos agudos em maior intensidade ocorreram predominantemente no grupo de participantes cuja redução da temperatura média no dorso do nariz foi menor (14,4% vs. 7,2%). A análise visual termográfica de zonas de esfriamento e aquecimento na face identificou regiões de hipoperfusão ou hiperemia reativa. O uso do modo BiPAP associou-se a maior incidência e intensidade de efeitos adversos agudos associados à VNI. Houve associação entre efeitos adversos agudos e menor esfriamento da pele do dorso do nariz imediatamente após a retirada da máscara. A termografia cutânea pode ser uma ferramenta adicional na detecção de efeitos adversos na pele da face associados ao uso da VNI.

Dopamine depletion shifts behavior from activity based reinforcers to more sedentary ones and adenosine receptor antagonism reverses that shift: Relation to ventral striatum DARPP32 phosphorylation patterns.

PubMed

López-Cruz, Laura; San Miguel, Noemí; Carratalá-Ros, Carla; Monferrer, Lidón; Salamone, John D; Correa, Mercè

2018-02-02

The mesolimbic dopamine (DA) system plays a critical role in behavioral activation and effort-based decision-making. DA depletion produces anergia (shifts to low effort options) in animals tested on effort-based decision-making tasks. Caffeine, the most consumed stimulant in the world, acts as an adenosine A 1 /A 2A receptor antagonist, and in striatal areas DA D 1 and D 2 receptors are co-localized with adenosine A 1 and A 2A receptors respectively. In the present work, we evaluated the effect of caffeine on anergia induced by the VMAT-2 inhibitor tetrabenazine (TBZ), which depletes DA. Anergia was evaluated in a three-chamber T-maze task in which animals can chose between running on a wheel (RW) vs. sedentary activities such as consuming sucrose or sniffing a neutral odor. TBZ-caffeine interactions in ventral striatum were evaluated using DARPP-32 phosphorylation patterns as an intracellular marker of DA-adenosine receptor interaction. In the T-maze, control mice spent more time running and much less consuming sucrose or sniffing. TBZ (4.0 mg/kg) reduced ventral striatal DA tissue levels as measured by HPLC, and also shifted preferences in the T-maze, reducing selection of the reinforcer that involved vigorous activity (RW), but increasing consumption of a reinforcer that required little effort (sucrose), at doses that had no effect on independent measures of appetite or locomotion in a RW. Caffeine at doses that had no effect on their own reversed the effects of TBZ on T-maze performance, and also suppressed TBZ-induced pDARPP-32(Thr34) expression as measured by western blot, suggesting a role for D 2 -A 2A interactions. These results support the idea that DA depletion produces anergia, but does not affect the primary motivational effects of sucrose. Caffeine, possibly by acting on A 2A receptors in ventral striatum, reversed the DA depletion effects. It is possible that caffeine, like selective adenosine A2A antagonists, could have some therapeutic benefit for treating effort-related symptoms. Copyright © 2018. Published by Elsevier Ltd.

Antibiofilm and antibacterial effects of specific chitosan molecules on Staphylococcus aureus isolates associated with bovine mastitis

PubMed Central

Asli, Abdelhamid; Brouillette, Eric; Ster, Céline; Ghinet, Mariana Gabriela; Brzezinski, Ryszard; Lacasse, Pierre; Jacques, Mario

2017-01-01

Staphylococcus aureus is one of the major pathogens causing bovine intramammary infections (IMIs) and mastitis. Mastitis is the primary cause for the use of antibiotics in dairy farms but therapeutic failure is often observed. One of the reasons for the lack of effectiveness of antibiotic therapy despite the observed susceptibility of bacterial isolates in vitro are bacterial biofilms. In this study, we used chitosan of well-defined molecular weight (0.4–0.6, 1.3, 2.6 and 4.0 kDa) and investigated their antibiofilm and antibacterial activities in in vitro and in vivo models related to S. aureus IMIs. A chitosan of at least 6 units of glucosamine was necessary for maximum antibacterial activity. The 2.6 and 4.0 kDa forms were able to prevent biofilm production by the biofilm hyperproducer strain S. aureus 2117 and a bovine MRSA (methicillin-resistant S. aureus). The intramammary administration of the 2.6 kDa chitosan showed no adverse effects in mice or in cows, as opposed to the slight inflammatory effect observed in mammary glands with the 4.0 kDa derivative. The 2.6 kDa chitosan killed bacteria embedded in pre-established biofilms in a dose-dependent manner with a >3 log10 reduction in CFU at 4 mg/ml. Also, the 2.6 kDa chitosan could prevent the persistence of the internalized MRSA into the mammary epithelial cell line MAC-T. An in vitro checkerboard assay showed that the 2.6 kDa chitosan produced a synergy with the macrolide class of antibiotics (e.g., tilmicosin) and reduced the MIC of both molecules by 2–8 times. Finally, the intramammary administration of the 2.6 kDa chitosan alone (P<0.01) or in combination with tilmicosin (P<0.0001) reduced the colonization of mammary glands in a murine IMI model. Our results suggest that the use of chitosan alone or in combination with a low dose of a macrolide could help reduce antibiotic use in dairy farms. PMID:28486482

Effect of (+)-Methamphetamine on Path Integration Learning, Novel Object Recognition, and Neurotoxicity in Rats

PubMed Central

Herring, Nicole R.; Schaefer, Tori L.; Gudelsky, Gary A.; Vorhees, Charles V.; Williams, Michael T.

2008-01-01

Rationale Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems, but few associated cognitive effects. Objectives Since, questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. Methods Rats were treated with one of two regimens, one the typical neurotoxic regimen (4 × 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho et al. 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 ×1.67 mg/kg once every 15 min); matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. Results On markers of neurotoxicity, MA showed decreased DA and 5-HT, and increased glial fibrillary acidic protein and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple-T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. Conclusions MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity. PMID:18509623

Effect of +-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats.

PubMed

Herring, Nicole R; Schaefer, Tori L; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

2008-09-01

Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems but few associated cognitive effects. Since questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 x 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161-166, 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 x 1.67 mg/kg once every 15 min) matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. On markers of neurotoxicity, MA showed decreased dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.

Preclinical and Clinical Studies Demonstrate That the Proprietary Herbal Extract DA-5512 Effectively Stimulates Hair Growth and Promotes Hair Health.

PubMed

Yu, Jae Young; Gupta, Biki; Park, Hyoung Geun; Son, Miwon; Jun, Joon-Ho; Yong, Chul Soon; Kim, Jeong Ah; Kim, Jong Oh

2017-01-01

The proprietary DA-5512 formulation comprises six herbal extracts from traditional oriental plants historically associated with therapeutic and other applications related to hair. Here, we investigated the effects of DA-5512 on the proliferation of human dermal papilla cells (hDPCs) in vitro and on hair growth in C57BL/6 mice and conducted a clinical study to evaluate the efficacy and safety of DA-5512. DA-5512 significantly enhanced the viability of hDPCs in a dose-dependent manner ( p < 0.05), and 100 ppm of DA-5512 and 1  μ M minoxidil (MXD) significantly increased the number of Ki-67-positive cells, compared with the control group ( p < 0.05). MXD (3%) and DA-5512 (1%, 5%) significantly stimulated hair growth and increased the number and length of hair follicles (HFs) versus the controls (each p < 0.05). The groups treated with DA-5512 exhibited hair growth comparable to that induced by MXD. In clinical study, we detected a statistically significant increase in the efficacy of DA-5512 after 16 weeks compared with the groups treated with placebo or 3% MXD ( p < 0.05). In conclusion, DA-5512 might promote hair growth and enhance hair health and can therefore be considered an effective option for treating hair loss.

Prenatal exposure to lambda-cyhalothrin alters brain dopaminergic signaling in developing rats.

PubMed

Dhuriya, Yogesh K; Srivastava, Pranay; Shukla, Rajendra K; Gupta, Richa; Singh, Dhirendra; Parmar, Devendra; Pant, Aditya B; Khanna, Vinay K

2017-07-01

The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats. Copyright © 2017 Elsevier B.V. All rights reserved.

[Evaluation of radiation exposure of personnel in an orthopaedic and trauma operation theatre using the new real-time dosimetry system "dose aware"].

PubMed

Müller, M C; Strauss, A; Pflugmacher, R; Nähle, C P; Pennekamp, P H; Burger, C; Wirtz, D C

2014-08-01

There is a positive correlation between operation time and staff exposure to radiation during intraoperative use of C-arm fluoroscopy. Due to harmful effects of exposure to long-term low-dose radiation for both the patient and the operating team it should be kept to a minimum. AIM of this study was to evaluate a novel dosimeter system called Dose Aware® (DA) enabling radiation exposure feedback of the personal in an orthopaedic and trauma operation theatre in real-time. Within a prospective study over a period of four month, DA was applied by the operation team during 104 orthopaedic and trauma operations in which the C-arm fluoroscope was used in 2D-mode. During ten operation techniques, radiation exposure of the surgeon, the first assistant, the theatre nurse and the anaesthesiologist was evaluated. Seventy-three operations were analysed. The surgeon achieved the highest radiation exposure during dorsolumbar spinal osteosynthesis, kyphoplasty and screw fixation of sacral fractures. The first assistant received a higher radiation exposure compared to the surgeon during plate osteosynthesis of distal radius fractures (157 %), intramedullary nailing of pertrochanteric fractures (143 %) and dorsolumbar spinal osteosynthesis (240 %). During external fixation of ankle fractures (68 %) and screw fixation of sacral fractures (66 %) radiation exposure of the theatre nurse exceeded 50 % of the surgeon's radiation exposure. During plate osteosynthesis of distal radius fractures (157 %) and intramedullary splinting of clavicular fractures (115 %), the anaesthesiologist received a higher radiation exposure than the surgeon. The novel dosimeter system DA provides real-time radiation exposure feedback of the personnel in an orthopaedic and trauma operation theatre for the first time. Data of this study demonstrate that radiation exposure of the personnel depends on the operation type. The first assistant, the theatre nurse and the anaesthesiologist might be exposed to higher radiation doses than the surgeon. DA might help to increase awareness concerning irradiation in an orthopaedic and trauma operation theatre and might enhance staff compliance in using radiation protection techniques. Georg Thieme Verlag KG Stuttgart · New York.

Effects of an acute therapeutic or rewarding dose of amphetamine on acquisition of Pavlovian autoshaping and ventral striatal dopamine signaling.

PubMed

Schuweiler, D R; Athens, J M; Thompson, J M; Vazhayil, S T; Garris, P A

2018-01-15

Rewarding doses of amphetamine increase the amplitude, duration, and frequency of dopamine transients in the ventral striatum. Debate continues at the behavioral level about which component of reward, learning or incentive salience, is signaled by these dopamine transients and thus altered in addiction. The learning hypothesis proposes that rewarding drugs result in pathological overlearning of drug-predictive cues, while the incentive sensitization hypothesis suggests that rewarding drugs result in sensitized attribution of incentive salience to drug-predictive cues. Therapeutic doses of amphetamine, such as those used to treat attention-deficit hyperactivity disorder, are hypothesized to enhance the ventral striatal dopamine transients that are critical for reward-related learning and to enhance Pavlovian learning. However, the effects of therapeutic doses of amphetamine on Pavlovian learning are poorly understood, and the effects on dopamine transients are completely unknown. We determined the effects of an acute pre-training therapeutic or rewarding amphetamine injection on the acquisition of Pavlovian autoshaping in the intact rat. We also determined the effects of these doses on electrically evoked transient-like dopamine signals using fast-scan cyclic voltammetry in the anesthetized rat. The rewarding dose enhanced the amplitude and duration of DA signals, caused acute task disengagement, impaired learning for several days, and triggered incentive sensitization. The therapeutic dose produced smaller enhancements in DA signals but did not have similar behavioral effects. These results underscore the necessity of more studies using therapeutic doses, and suggest a hybrid learning/incentive sensitization model may be required to explain the development of addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

Dose-response and histopathological study, with special attention to the hypophysis, of the differential effects of domoic acid on rats and mice.

PubMed

Vieira, Andrés Crespo; Martínez, J Manuel Cifuentes; Pose, Roberto Bermúdez; Queijo, Álvaro Antelo; Posadas, Nuria Alemañ; López, Luis M Botana

2015-05-01

The effects of the neurotoxin domoic acid (DA) in the central nervous system of rodents (essentially rats and mice) after intraperitoneal administration have been profusely studied in the past. These observations have shown that the toxin induces similar symptoms and pathology in both species, but the lethality varies greatly. This article addresses the common and specific histopathological effects in rats and mice and the difference in sensitivity of these species to DA. Various sublethal and lethal doses were employed in mice (from 3 mg/kg to 8 mg/kg) to observe their neurotoxicity by using different histological techniques, and these results were compared with the pathological effects after the administration of LD50 in rats (2.5 mg/kg). Additionally we also detected the presence of this toxin in various tissues by means of immunohistochemistry. Our results showed that rats are more vulnerable than mice to the neurotoxic effects of DA after intraperitoneal inoculation: lethality was extremely high in rats and the toxin produced hippocampal damage in rats surviving the intoxication, while lesions were not observed in DA-inoculated mice. As for similarities between rats and mice, both displayed similar clinical signs and in both the toxin was detected in the hypophysis by immunohistochemistry, a brain region not reported to date as target of the toxin. © 2015 Wiley Periodicals, Inc.

The effects of low-dose X-irradiation on the oxidative burst in stimulated macrophages.

PubMed

Schaue, D; Marples, B; Trott, K R

2002-07-01

Local irradiation with a dose of around 0.5 Gy is an effective treatment of acute necrotizing inflammations. The hypothesis that low doses of X-rays modulate the oxidative burst in activated macrophages, which plays a major role in the acute inflammatory process, was tested. Murine RAW 264.7 macrophages were stimulated with LPS/gammaIFN, PMA or zymosan and oxidative burst was measured using either DCFH-DA or by reduction of cytochrome-C. Radiation doses of 0.3-10 Gy were given shortly before or after stimulation. Low X-ray doses of <1 Gy significantly reduced the oxidative burst in activated macrophages, whereas higher doses had little effect on oxidative burst. The modulation of oxidative burst by low radiation doses may contribute to the therapeutic effectiveness of low-dose radiotherapy of acute necrotizing inflammations.

Toward development of an in vitro model of methamphetamine-induced dopamine nerve terminal toxicity.

PubMed

Kim, S; Westphalen, R; Callahan, B; Hatzidimitriou, G; Yuan, J; Ricaurte, G A

2000-05-01

To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for different periods of time (10-80 min), washed once, then tested for DA transporter function at 37 degrees C. METH produced time- and dose-dependent reductions in the V(max) of DA uptake, without producing any change in K(m). Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.

Subchronic, Low-Level Intraperitoneal Injections of Manganese (IV) Oxide and Manganese (II) Chloride Affect Rat Brain Neurochemistry.

PubMed

Nielsen, Brian S; Larsen, Erik H; Ladefoged, Ole; Lam, Henrik R

Manganese (Mn) is neurotoxic and can induce manganism, a Parkinson-like disease categorized as being a serious central nervous system irreversible neurodegenerative disease. An increased risk of developing symptoms of Parkinson disease has been linked to work-related exposure, for example, for workers in agriculture, horticulture, and people living near areas with frequent use of Mn-containing pesticides. In this study, the focus was placed on neurochemical effects of Mn. Rats were dosed intraperitoneally with 0.9% NaCl (control), 1.22 mg Mn (as MnO 2 )/kg bodyweight (bw)/day, or 2.5 mg Mn (as MnCl 2 )/kg bw/day for 7 d/wk for 8 or 12 weeks. This dosing regimen adds relevant new knowledge about Mn neurotoxicity as a consequence of low-dose subchronic Mn dosing. Manganese concentrations increased in the striatum, the rest of the brain, and in plasma, and regional brain neurotransmitter concentrations, including noradrenaline, dopamine (DA), 5-hydroxytrytamine, glutamate, taurine, and γ-amino butyric acid, and the activity of acetylcholinesterase changed. Importantly, a target parameter for Parkinson disease and manganism, the striatal DA concentration, was reduced after 12 weeks of dosing with MnCl 2 . Plasma prolactin concentration was not significantly affected due to a potentially reduced dopaminergic inhibition of the prolactin release from the anterior hypophysis. No effects on the striatal α-synuclein and synaptophysin protein levels were detected.

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson's disease: an open-label study.

PubMed

Kim, Jong-Min; Chung, Sun Ju; Kim, Jae Woo; Jeon, Beom Seok; Singh, Pritibha; Thierfelder, Stephan; Ikeda, Junji; Bauer, Lars

2015-02-28

Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinson's disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1-4 weeks and maintained for 4-7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinson's Disease Rating Scale (UPDRS) II and III, Parkinson's Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and "off" time. Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in "off" time were observed. The majority (71/88; 81%) improved on PGIC. Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012.

Apomorphine effects on frog locomotor behavior.

PubMed

Chu, Joanne; Wilczynski, Walter

2007-05-16

The neuroanatomical pathways of the DA systems have been shown to be largely conserved across many vertebrate taxa. It is less certain whether the structural similarities seen between mammals and amphibians reflect a similar functional homology. DA is well known for its role in facilitating motor behaviors in mammals. We examined whether a similar role for DA exists in amphibians using the Northern Leopard Frog (Rana pipiens). We investigated the effects of the nonspecific DA agonist, apomorphine (APO) on a complex motor task that included two distinct components known to be differentially modulated by DA in mammals: swimming and climbing. We demonstrated that a high single dose of APO (20 mg/kg, body weight) strongly increased the amount of time spent completing the motor task. Furthermore, we showed that although APO did not significantly alter several aspects of swimming behavior, two aspects of climbing behavior were disrupted. Both climbing speed and climbing ability were impaired by APO treatment. These results increase our understanding of DA function in amphibians and add to our understanding of structure-function homologies of dopamine function across vertebrate taxa.

Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells.

PubMed

Ververis, J; Ku, L; Delafontaine, P

1994-02-01

Insulin-like growth factor I is an important mitogen for vascular smooth muscle cells, and its effects are regulated by several binding proteins. Western ligand blotting of conditioned medium from rat aortic smooth muscle cells detected a 24 kDa binding protein and a 28 kDa glycosylated variant of this protein, consistent with insulin-like growth factor binding protein-4 by size. Low amounts of a glycosylated 38 to 42 kDa doublet (consistent with binding protein-3) and a 31 kDa non-glycosylated protein also were present. Basic fibroblast growth factor markedly increased secretion of the 24 kDa binding protein and its 28 kDa glycosylated variant. This effect was dose- and time-dependent and was inhibited by co-incubation with cycloheximide. Crosslinking of [125I]-insulin-like growth factor I to cell monolayers revealed no surface-associated binding proteins, either basally or after agonist treatment. Induction of binding protein production by fibroblast growth factor at sites of vascular injury may be important in vascular proliferative responses in vivo.

Procedures for measuring and verifying gastric tube placement in newborns: an integrative review.

PubMed

Dias, Flávia de Souza Barbosa; Emidio, Suellen Cristina Dias; Lopes, Maria Helena Baena de Moraes; Shimo, Antonieta Keiko Kakuda; Beck, Ana Raquel Medeiros; Carmona, Elenice Valentim

2017-07-10

to investigate evidence in the literature on procedures for measuring gastric tube insertion in newborns and verifying its placement, using alternative procedures to radiological examination. an integrative review of the literature carried out in the Cochrane, LILACS, CINAHL, EMBASE, MEDLINE and Scopus databases using the descriptors "Intubation, gastrointestinal" and "newborns" in original articles. seventeen publications were included and categorized as "measuring method" or "technique for verifying placement". Regarding measuring methods, the measurements of two morphological distances and the application of two formulas, one based on weight and another based on height, were found. Regarding the techniques for assessing placement, the following were found: electromagnetic tracing, diaphragm electrical activity, CO2 detection, indigo carmine solution, epigastrium auscultation, gastric secretion aspiration, color inspection, and evaluation of pH, enzymes and bilirubin. the measuring method using nose to earlobe to a point midway between the xiphoid process and the umbilicus measurement presents the best evidence. Equations based on weight and height need to be experimentally tested. The return of secretion into the tube aspiration, color assessment and secretion pH are reliable indicators to identify gastric tube placement, and are the currently indicated techniques. investigar, na literatura, evidências sobre procedimentos de mensuração da sonda gástrica em recém-nascidos e de verificação do seu posicionamento, procedimentos alternativos ao exame radiológico. revisão integrativa da literatura nas bases Biblioteca Cochrane, LILACS, CINAHL, EMBASE, MEDLINE e Scopus, utilizando os descritores "intubação gastrointestinal" e "recém-nascido" em artigos originais. dezessete publicações foram incluídas e categorizadas em "método de mensuração" ou "técnica de verificação do posicionamento". Como métodos de mensuração, foram encontrados os de tomada de duas distâncias morfológicas e os de aplicação de duas fórmulas, uma baseada no peso e outra na altura. Para técnicas de verificação do posicionamento, encontrou-se traçado eletromagnético, atividade elétrica do diafragma, detecção de CO2, solução de índigo carmim, ausculta do epigástrio, aspiração de secreção gástrica, inspeção da cor, avaliação de pH, enzimas e bilirrubina. o método de mensuração que utiliza as medidas do nariz ao lóbulo da orelha ao ponto médio entre apêndice xifoide e cicatriz umbilical apresenta melhores evidências. As equações baseadas em peso e altura necessitam ser testadas experimentalmente. O retorno de secreção na aspiração da sonda, avaliação da cor e do pH da secreção são indicadores confiáveis na identificação do posicionamento da sonda gástrica, e são as técnicas atualmente indicadas. investigar, en la literatura, evidencias sobre procedimientos de medición de la sonda gástrica en recién nacidos y de verificación de su posicionamiento, procedimientos alternativos al examen radiológico. revisión integradora de la literatura en las bases Biblioteca Cochrane, LILACS, CINAHL, EMBASE, MEDLINE y Scopus, utilizando los descriptores "intubación gastrointestinal" y "recién nacido" en artículos originales. diecisiete publicaciones fueron incluidas y categorizadas en "método de medición" o "técnica de verificación del posicionamiento". Como métodos de medición, fueron encontrados los de medida de dos distancias morfológicas y los de aplicación de dos fórmulas (una basada en el peso y otra en la altura). Para las técnicas de verificación del posicionamiento, se encontró: trazado electromagnético, actividad eléctrica del diafragma, detección de CO2, solución de índigo carmín, auscultación del epigastrio, aspiración de secreción gástrica, inspección del color, evaluación de pH, enzimas y bilirrubina. el método de medición que utiliza las medidas de la nariz al lóbulo de la oreja al punto medio entre apéndice xifoideo y cicatriz umbilical, presenta las mejores evidencias. Las ecuaciones basadas en peso y altura necesitan ser comprobadas experimentalmente. El retorno de secreción en la aspiración de la sonda, evaluación del color y del pH de la secreción son indicadores confiables en la identificación del posicionamiento de la sonda gástrica, y son las técnicas actualmente indicadas.

Apoptosis induced by β,β-dimethylacrylshikonin is associated with Bcl-2 and NF-κB in human breast carcinoma MCF-7 cells

PubMed Central

XIONG, YAO; MA, XIU-YING; ZHANG, ZIRAN; SHAO, ZHEN-JUN; ZHANG, YUAN-YUAN; ZHOU, LI-MING

2013-01-01

β,β-dimethylacrylshikonin (DA) is a natural naphthoquinone derivative compound of Lithospermum erythrorhizon with various biological activities. The present study aimed to investigate the inhibitory effects and underlying mechanisms of DA in human breast carcinoma MCF-7 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that DA inhibited the proliferation of MCF-7 cells in a dose- and time-dependent manner. The half maximal inhibitory concentration of DA with regard to the proliferation of MCF-7 cells was 0.050±0.016 mM. The characteristics of cell apoptosis, including cell shrinkage, nuclear pyknosis and chromatin condensation, were all observed in DA-treated cells. DA decreased the expression levels of Bcl-2 and increased the expression of Bax and caspase-3 compared with those in the control. DA inhibited the activity of the nuclear factor (NF)-κB pathway, by downregulating the expression of the p65 subunit, and inhibited the Iκb phosphorylation. DA inhibits the proliferation of MCF-7 cells in vitro by inducing apoptosis through the downregulation of Bcl-2, upregulation of Bax and partial inactivation of the NF-κB pathway. PMID:24260077

Role of dopamine D2 receptors in human reinforcement learning.

PubMed

Eisenegger, Christoph; Naef, Michael; Linssen, Anke; Clark, Luke; Gandamaneni, Praveen K; Müller, Ulrich; Robbins, Trevor W

2014-09-01

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.

Role of Dopamine D2 Receptors in Human Reinforcement Learning

PubMed Central

Eisenegger, Christoph; Naef, Michael; Linssen, Anke; Clark, Luke; Gandamaneni, Praveen K; Müller, Ulrich; Robbins, Trevor W

2014-01-01

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well. PMID:24713613

A emissão em 8mm e as bandas de Merrill-Sanford em estrelas carbonadas

NASA Astrophysics Data System (ADS)

de Mello, A. B.; Lorenz-Martins, S.

2003-08-01

Estrelas carbonadas possuem bandas moleculares em absorção no visível e, no infravermelho (IR) as principais características espectrais se devem a emissão de grãos. Recentemente foi detectada a presença de bandas de SiC2 (Merrill-Sanford, MS) em emissão sendo atribuída à presença de um disco rico em poeira. Neste trabalho analisamos uma amostra de 14 estrelas carbonadas, observadas no telescópio de 1.52 m do ESO em 4 regiões espectrais diferentes, a fim de detectar as bandas de MS em emissão. Nossa amostra é composta de estrelas que apresentam além da emissão em 11.3 mm, outra em 8 mm. Esta última emissão, não usual nestes objetos, tem sido atribuída ou a moléculas de C2H2, ou a um composto sólido ainda indefinido. A detecção de emissões de MS e aquelas no IR, simultaneamente, revelaria um cenário mais complexo que o habitualmente esperado para os ventos destes objetos. No entanto como primeiro resultado, verificamos que as bandas de Merrill-Sanford encontram-se em absorção, não revelando nenhuma conexão com a emissão a 8 mm. Assim, temos duas hipóteses: (a) a emissão a 8 mm se deve à molécula C2H2 ou (b) essa emissão é resultado da emissão térmica de grãos. Testamos a segunda hipótese modelando a amostra com grãos não-homogêneos de SiC e quartzo, o qual emite em aproximadamente 8mm. Este grão seria produzido em uma fase evolutiva anterior a das carbonadas (estrelas S) e por terem uma estrutura cristalina são destruídos apenas na presença de campos de radiação ultravioleta muito intensos. Os modelos para os envoltórios utilizam o método de Monte Carlo para descrever o problema do transporte da radiação. As conclusões deste trabalho são: (1) as bandas de Merrill-Sanford se encontram em absorção, sugerindo um cenário usual para os ventos das estrelas da amostra; (2) neste cenário, a emissão em 8 mm seria resultado de grãos de quartzo com mantos de SiC, indicando que o quartzo poderia sobreviver a fase evolutiva S.

Biaxial seismic behaviour of reinforced concrete columns =

NASA Astrophysics Data System (ADS)

Rodrigues, Hugo Filipe Pinheiro

A analise dos efeitos dos sismos mostra que a investigacao em engenharia sismica deve dar especial atencao a avaliacao da vulnerabilidade das construcoes existentes, frequentemente desprovidas de adequada resistencia sismica tal como acontece em edificios de betao armado (BA) de muitas cidades em paises do sul da Europa, entre os quais Portugal. Sendo os pilares elementos estruturais fundamentais na resistencia sismica dos edificios, deve ser dada especial atencao a sua resposta sob acoes ciclicas. Acresce que o sismo e um tipo de acao cujos efeitos nos edificios exige a consideracao de duas componentes horizontais, o que tem exigencias mais severas nos pilares comparativamente a acao unidirecional. Assim, esta tese centra-se na avaliacao da resposta estrutural de pilares de betao armado sujeitos a acoes ciclicas horizontais biaxiais, em tres linhas principais. Em primeiro lugar desenvolveu-se uma campanha de ensaios para o estudo do comportamento ciclico uniaxial e biaxial de pilares de betao armado com esforco axial constante. Para tal foram construidas quatro series de pilares retangulares de betao armado (24 no total) com diferentes caracteristicas geometricas e quantidades de armadura longitudinal, tendo os pilares sido ensaiados para diferentes historias de carga. Os resultados experimentais obtidos sao analisados e discutidos dando particular atencao a evolucao do dano, a degradacao de rigidez e resistencia com o aumento das exigencias de deformacao, a energia dissipada, ao amortecimento viscoso equivalente; por fim e proposto um indice de dano para pilares solicitados biaxialmente. De seguida foram aplicadas diferentes estrategias de modelacao nao-linear para a representacao do comportamento biaxial dos pilares ensaiados, considerando nao-linearidade distribuida ao longo dos elementos ou concentrada nas extremidades dos mesmos. Os resultados obtidos com as varias estrategias de modelacao demonstraram representar adequadamente a resposta em termos das curvas envolventes forca-deslocamento, mas foram encontradas algumas dificuldades na representacao da degradacao de resistencia e na evolucao da energia dissipada. Por fim, e proposto um modelo global para a representacao do comportamento nao-linear em flexao de elementos de betao armado sujeitos a acoes biaxiais ciclicas. Este modelo tem por base um modelo uniaxial conhecido, combinado com uma funcao de interacao desenvolvida com base no modelo de Bouc- Wen. Esta funcao de interacao foi calibrada com recurso a tecnicas de otimizacao e usando resultados de uma serie de analises numericas com um modelo refinado. E ainda demonstrada a capacidade do modelo simplificado em reproduzir os resultados experimentais de ensaios biaxiais de pilares.

Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of β-catenin in dopamine neurons.

PubMed

Diaz-Ruiz, Oscar; Zhang, Yajun; Shan, Lufei; Malik, Nasir; Hoffman, Alexander F; Ladenheim, Bruce; Cadet, Jean Lud; Lupica, Carl R; Tagliaferro, Adriana; Brusco, Alicia; Bäckman, Cristina M

2012-07-20

In the present study, we analyzed mice with a targeted deletion of β-catenin in DA neurons (DA-βcat KO mice) to address the functional significance of this molecule in the shaping of synaptic responses associated with motor learning and following exposure to drugs of abuse. Relative to controls, DA-βcat KO mice showed significant deficits in their ability to form long-term memories and displayed reduced expression of methamphetamine-induced behavioral sensitization after subsequent challenge doses with this drug, suggesting that motor learning and drug-induced learning plasticity are altered in these mice. Morphological analyses showed no changes in the number or distribution of tyrosine hydroxylase-labeled neurons in the ventral midbrain. While electrochemical measurements in the striatum determined no changes in acute DA release and uptake, a small but significant decrease in DA release was detected in mutant animals after prolonged repetitive stimulation, suggesting a possible deficit in the DA neurotransmitter vesicle reserve pool. However, electron microscopy analyses did not reveal significant differences in the content of synaptic vesicles per terminal, and striatal DA levels were unchanged in DA-βcat KO animals. In contrast, striatal mRNA levels for several markers known to regulate synaptic plasticity and DA neurotransmission were altered in DA-βcat KO mice. This study demonstrates that ablation of β-catenin in DA neurons leads to alterations of motor and reward-associated memories and to adaptations of the DA neurotransmitter system and suggests that β-catenin signaling in DA neurons is required to facilitate the synaptic remodeling underlying the consolidation of long-term memories.

Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson's disease.

PubMed

Schapira, A H V; Stocchi, F; Borgohain, R; Onofrj, M; Bhatt, M; Lorenzana, P; Lucini, V; Giuliani, R; Anand, R

2013-02-01

Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD). Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to 'intervention', defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group. Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis). The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

PubMed Central

Grotewold, Susan K.; Wall, Vanessa L.; Goodell, Dayton J.; Hayter, Cassandra

2015-01-01

Rationale Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation. Objectives The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT). Methods Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters. Results ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT. Conclusions Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates. PMID:24553577

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

PubMed

Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

2015-08-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

PubMed Central

Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

2015-01-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists.

PubMed

Worden, Lila T; Shahriari, Mona; Farrar, Andrew M; Sink, Kelly S; Hockemeyer, Jörg; Müller, Christa E; Salamone, John D

2009-04-01

Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A(2A) receptors. Adenosine A(2A) receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. The adenosine A(2A) receptor antagonist MSX-3 (0.5-2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure. MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses. The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A(2A) receptors on the same population of striatal neurons.

Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab' Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity.

PubMed

Chan, Linda J; Ascher, David B; Yadav, Rajbharan; Bulitta, Jürgen B; Williams, Charlotte C; Porter, Christopher J H; Landersdorfer, Cornelia B; Kaminskas, Lisa M

2016-04-04

The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab' as a model. Specifically, the Fab' was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3-4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab' displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab'. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab's against lymph-resident diseases, while no significant benefit is achieved with very large PEGs.

The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity

PubMed Central

Miner, Nicholas B.; O’Callaghan, James P.; Phillips, Tamara J.; Janowsky, Aaron

2017-01-01

The rise in popularity of substituted methcathinones (aka “bath salts”) has increased the focus on their neurotoxic effects. Two commonly abused methcathinones, 3,4-methylenedioxymethcathinone (methylone, MDMC) and 3,4-methylenedioxypyrovalerone (MDPV), are often concomitantly ingested with the illicit drug 3,4-methylenedioxymethamphetamine (MDMA). To examine potential neurotoxic effects of these drug combinations, C57BL/6J mice were administered 4 i.p. injection of the drugs, at 2 h intervals, either singularly: MDMA 15 or 30 mg/kg, methylone 20 mg/kg, MDPV 1 mg/kg; or in combination: methylone/MDMA 20/15 mg/kg, MDPV/MDMA 1/15 mg/kg. Drug effects on thermoregulation were characterized and striatal tissue analyzed after 2 or 7 days for dopamine (DA) and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. Two days following drug administration, DA and TH were decreased only in the MDMA 30 mg/kg group, whereas GFAP expression was dose-dependently increased by MDMA alone. While the combination of the methcathinones with the lower MDMA dose did not affect DA or TH levels, both blocked the MDMA-induced increase in GFAP expression. Seven days following drug administration, there were no significant differences in DA, TH, or GFAP for any treatment group, indicating that changes in DA, TH, and GFAP were transient. Five of the six drug groups exhibited acute hypothermia followed by gradually increasing temperatures. Animals treated with MDPV did not exhibit these biphasic temperature changes, and resembled the saline group. These results indicate that specific effects of both methylone and MDPV on DA depletion or astrocyte activation in the striatum are not additive with effects of MDMA, but block astrogliosis caused by MDMA alone. Additionally, MDPV modulates thermoregulation through a different mechanism than methylone or MDMA. PMID:28212938

The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity.

PubMed

Miner, Nicholas B; O'Callaghan, James P; Phillips, Tamara J; Janowsky, Aaron

2017-05-01

The rise in popularity of substituted methcathinones (aka "bath salts") has increased the focus on their neurotoxic effects. Two commonly abused methcathinones, 3,4-methylenedioxymethcathinone (methylone, MDMC) and 3,4-methylenedioxypyrovalerone (MDPV), are often concomitantly ingested with the illicit drug 3,4-methylenedioxymethamphetamine (MDMA). To examine potential neurotoxic effects of these drug combinations, C57BL/6J mice were administered 4 i.p. injection of the drugs, at 2h intervals, either singularly: MDMA 15 or 30mg/kg, methylone 20mg/kg, MDPV 1mg/kg; or in combination: methylone/MDMA 20/15mg/kg, MDPV/MDMA 1/15mg/kg. Drug effects on thermoregulation were characterized and striatal tissue analyzed after 2 or 7days for dopamine (DA) and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. Two days following drug administration, DA and TH were decreased only in the MDMA 30mg/kg group, whereas GFAP expression was dose-dependently increased by MDMA alone. While the combination of the methcathinones with the lower MDMA dose did not affect DA or TH levels, both blocked the MDMA-induced increase in GFAP expression. Seven days following drug administration, there were no significant differences in DA, TH, or GFAP for any treatment group, indicating that changes in DA, TH, and GFAP were transient. Five of the six drug groups exhibited acute hypothermia followed by gradually increasing temperatures. Animals treated with MDPV did not exhibit these biphasic temperature changes, and resembled the saline group. These results indicate that specific effects of both methylone and MDPV on DA depletion or astrocyte activation in the striatum are not additive with effects of MDMA, but block astrogliosis caused by MDMA alone. Additionally, MDPV modulates thermoregulation through a different mechanism than methylone or MDMA. Published by Elsevier Inc.

Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats.

PubMed

Sahu, Surajit; Ray, Koushik; Yogendra Kumar, M S; Gupta, Shilpa; Kauser, Hina; Kumar, Sanjeev; Mishra, Kshipra; Panjwani, Usha

2012-07-15

The present study was performed to investigate the effects of Valeriana wallichi (VW) aqueous root extract on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats. Electrodes and transmitters were implanted to record EEG and EMG in freely moving condition and the changes were recorded telemetrically after oral administration of VW in the doses of 100, 200 and 300 mg/kg body weight. Sleep latency was decreased and duration of non-rapid eye movement (NREM) sleep was increased in a dose dependent manner. A significant decrease of sleep latency and duration of wakefulness were observed with VW at doses of 200 and 300 mg/kg. Duration of NREM sleep as well as duration of total sleep was increased significantly after treatment with VW at the doses of 200 and 300 mg/kg. VW also increased EEG slow wave activity during NREM sleep at the doses of 200 and 300 mg/kg. Level of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and hydroxy indole acetic acid (HIAA) were measured in frontal cortex and brain stem after VW treatment at the dose of 200mg/kg. NE and 5HT level were decreased significantly in both frontal cortex and brain stem. DA and HIAA level significantly decreased only in cortex. DOPAC level was not changed in any brain region studied. In conclusion it can be said that VW water extract has a sleep quality improving effect which may be dependent upon levels of monoamines in cortex and brainstem. Copyright © 2012 Elsevier GmbH. All rights reserved.

The hypolipidemic effect and antithrombotic activity of Mucuna pruriens protein hydrolysates.

PubMed

Herrera Chalé, Francisco; Ruiz Ruiz, Jorge Carlos; Betancur Ancona, David; Acevedo Fernández, Juan José; Segura Campos, Maira Rubi

2016-01-01

Hydrolysates and peptide fractions (PF) obtained from M. pruriens protein concentrates with commercial and digestive enzymatic systems were studied for their hypolipidemic and antithrombotic activities. Hydrolysates obtained with Pepsin-Pancreatin (PP) and their peptide fractions inhibited cholesterol micellar solubility with a maximum value of 1.83% in PP. Wistar rats were used to evaluate the hypolipidemic effect of hydrolysates and PF. The higher reductions of cholesterol and triglyceride levels were exhibited by PP and both peptide fractions <1 kDa obtained from PP and Alcalase®-Flavourzyme® hydrolysate (AF) at a dose of 15 mg kg(-1) of animal weight. PF > 10 kDa from both hydrolysates showed the maximum antithrombotic activity with values of 33.33% for PF > 10 kDa from AF and 31.72% for PF > 10 kDa from PP. The results suggest that M. pruriens bioactive peptides with the hypolipidemic effect and antithrombotic activity might be utilized as nutraceuticals.

Farmyard Manure and Fertilizer Effects on Seed Potato (Solanum tuberosum L.) Yield in Green House Production

NASA Astrophysics Data System (ADS)

László, M.

2009-04-01

Nowadays is widely well know that the potato is an important vegetable crop at Brazíl. It is grown on about 173.000 ha, with total yield of 2.6 million tons year-1. The average yield is 15 t ha-1. This level is very low because degeneration of crop is rapid under high temperature and high viruses pressure. Therefore seed potato propagation and production is principal on consumption potato production. This is why we found it necessary to develop it. The latossolo vermelho soil-farmyard manure- burnt rice straw-fertilizer 4N:14P:8K greenhouse pot trial was set up at the National Vegetable Crops Research Center, Brasília-DF, Brazíl in 1990. The methods of the experiments were soil x farmyard manure x burnt rice straw, soil x 4N:14P:8K fertilizer and soil x farmyard manure x burnt rice straw x 4N:14P:8K fertilizer on randomized block design in total 29 combination of treatments in 5, 5 and 3 repetitions with in a total parcel of 116. According to chemical analysis of the a., soil, b., farmyard manure and c., burnt rice straw the agrochemistry parameters were as follows (estimated datas): a., latossolo vermelho soil: CaCO3 0.3-0.7%, humo 0.9-1.0%, pH (H2O) 5.3, pH (KCl) 4.5, AL- P2O5 3.2-3.5 mg kg-1, AL- K2O 180 mg kg-1, Mg (KCl) 70 mg kg-1, EDTA-Zn 0.5-0.8 mg kg-1, EDTA-Cu 0.5-0.6 mg kg-1, b., farmyard manure: N 1.8 g kg-1, P2O5 2.0 g kg-1, K2O 4.0 g kg-1, c., burnt rice straw: N 0.8 g kg-1, P2O5 7.0 g kg-1, K2O 4.5 g kg-1. The experimental datas were estimated by analysis of variance, ANOVA and MANOVA. The main conclusions were as follows: 1. Mixture of 80% latossolo vermelho, 10% burnt rice straw and 10% farmyard manure were shown best performance on seed potato productivity. The piece of tubers with a 0-20 mm (consumption seeds) was increased by 77%. 2. Total seed potato number was reached maximum at 10.8 g pot-1 4N:14P:8K fertilizer regarding to average of treatments with a 33%. 3. Dry biomassa production plant-1 was decreased by high dose of 4N:14P:8K fertilizer (18.0 g pot-1) with a hard effect (57%). Our results are shown that it was possible developing of the seed potato production under tropical greenhouse conditions by optimalised soil-organic matter-fertilizer system. This datas should be as indicators to sustainable field potato advisory systems. Keywords: potato (Solanum tuberosum L.), greenhouse, latossolo vermelho soil, farmyard manure, burnt rice straw, 4N:14P:8K fertilizer, sustainability, yield Introducáo: Importância e situação actual em produção da batata no Brazíl A batata é atualmente uma das hortaliças de maior importância no Brasíl (Márton 2000a., 2000b.) com um cultivo annual médio de 173.000 ha e uma produção de 2600000 t. A produtividade médio nacional é de 15 t ha-1, muito baixa se considerar que é possivel a obtenção de rendimentos acima de 40 t ha-1. Observa- se também, que existe variação no produtividade entre regiões e estados. E importante como fonte de alimento pelo seu alto valor nutricional a quantidade produzida muito superior por unidade de área a tempo, se comparada com diversas outras culturas (László 2000b., 2000c.). Os estados que tradicionalmente produzem batata em maior ou menor escala são indicados em seguente: Pernambuco, Ceará, Sergipe, Goiás, Mato Grosso, Mato Grosso do Sul, Rondonia e Acre. Os plantios predominantes são o das águas e das secas, sendo o de inverno bem menos expressivo, pois poucas áreas permitem o seu cultivo, na maioria dos casos necessitando- se de irrigação. Considerando as três épocas de plantio e diferentes condições climaticas brasileiras, podemos definir de um modo geral o plantio de batata no Brasíl da seguinte maneira: Nordeste e Centro- Oeste- plantio de inverno, Sudeste- plantio das águas, secas e inverno, Sul- plantio das aguas, secas e inverno. Sendo este último em áreas muito limitadas. Dentre as hortaliças a batata é uma das culturas mais estudadas actualmente. Os principais problemas que afetam a cultura da batata podem ser de ordem agronómica, economica e comercial. Como exemplos destes podem ser citados: o uso racional de matérias orgânicos, esterco de curral e inorgânico fertilizantes. Efeito de materias orgnicânicos e N, P, K elementos minerais para produção da batata As necessidades em N, P, e K elementos minerais da batata são superidas pela aplicação apropriada de matérias orgânicos, esterco de currals, fertilizantes ao solo, combinada com a ambiente (Márton 2001a., 2001b.), época adequada e posição ideal de aplicá- lo. Efeito da materias orgânicos O suprimento de N á batateira provém principalmente da matéria orgânica do solo e do fertilizante aplicado (László 2000a., Márton et all. 2000.). Embora não seja muito praticado no Brasíl, a incorporação de esterco ao solo é fator de aumento da produção de tuberculos. Este resultado favorável poderia ser atribuído ao melhoramento da estrutura do solo, á maior retenção de água pelo e mesmo favorecendo o melhor desenvolvimento do sistema radicular da planta. A batata pode ser cultivada em todo tipo de solo desde que tenha boa drenagem e seja bem estruturado. Isto é tem que ser bem aerado e permitir o bom desenvolvimento dos órgãos subterráneos da batateira. Sem de matéria orgânicos e esterco de curral a tendencia de determinados solos formar crosta, oferecendo uma alta resisténcia mecánica á emergéncia das plantas, pode ser um determinante de stands desuniformes. A cause primaria da formação de crostas é a destruição dos agregados do solo pela excessiva manipulação mecánica resultando em aeração reduzida e aumento da densidade e coesão das particulas do solo. O encrostamento do solo pode ser reduzido através com matérias orgânicos. De maneira geral, a produção de tuberculos em solo de baixa potencialidade (aqueles em que a penetração das raizes é dificultada pela compactação, textura argilosa ou com camadas no solo) será menor do que nagueles com alta potencialidade (boa textura e adequada retenção de agua). Efeito do nitrogênio No Brazíl em todas regiões onde se cultiva batata é raro encontrar solos com elevado teor de nitrogênio e que não precisam de quantidades desta elemento. É o elemento que governa o padrão de desenvolvimento da planta, estimulando principalmente o crescimento da parte aérea (Kádár et all. 2000., László 2000.). Para se obter rendimento de tubérculos é necessário um rápido e curto periodo de desenvolvimento da parte aérea e uma fase de acúmulo maior possível. Para tanto, devem ser evitadas doses muito altas de nitrogênio e, principalmente, se aplicadas tardiamente, pois haverá demasiado desenvolvimento de folhas que demorarão mais a finalizar seu crescimento e maturação. Isto implicará na redução do periodo de intenso desenvolvimento dos tubérculos e armazenagem do amido, resultando em menor produção. Há risco para a saúde na ingestão de alimentos com altos teores de nitrato e nitrito, havendo preocupação com o efeito de doses mais altas de nitrogênio sobre os teores dos mesmos nos tuberculos. Embora haja diferenças entre cultivares, localidades e períodos de armazenamento, há estudos mostrando que a fertilização com até 150 kg ha-1 de nitrogênio não foi suficiente para propiciar niveis preocupantes de nitrato nos tuberculos colhidos. Efeito do fósforo A grande maioria dos solos brasileiros cultivados com batata apresentam limitações ao bom desenvolvimento e produção da cultura em função dos baixos níveis de fósforo. Isto significa que aumentos de produção quase sempre ocorrem quando o solo recebe adubação fosfatada (László 2001a.). Estes aumentos são mais marcantes em solos nunca antes adubados ou com baixo teor de fósforo. Nestes, dificilmente alcanca- se a produção máxima com níveis reduzidos de fósforo. Não seria exagerado supor níveis de 600 a 800 kg ha-1 de P2O5, como sendo aqueles que iriam proporcionar produção máximas, principalmente em solos mais ácidos e pobres em matéria orgânico. A adubação fosfatada é muito importante no crescimento inicial da planta e, além de aumentar a produção de tuberculos em peso e números, aumenta também a quantidade e qualidade do amido neles contidos e reduz perdas durante o armazenamento dos mesmos. A quantidade de fósforo a aplicar dependerá da análise do solo considerando- se principalmente o nível de P existente e a textura do solo. Solos de textura média e arenosa necessitam maior conteúdo de fósforo do que os de textura argilosa para serem considerandos solos de baixo, médio ou alto teor de fósfato. Efeito da potássica Embora seja o elemento mais absorbido pela batateira, nem sempre há resposta positiva da aduba potássica sobre o rendimento da cultura. Provavelmente isto esteja relacionado com níveis elevados deste elemento no solo (Kurnik et all. 2001.). Entretanto, em solos com médios e baixos teores de potássio, aumentos significativos são conseguidos. Por isto, as recomendações de adubação com potássio, nas diversas regiões do mundo, variam de 50-300 kg ha-1 de K2O. Resultados de trabalhos em brasiléiros têm demonstrado que a aduba potássica pode ser substituída pela aplicação de 150 m3 ha-1 de vinhaça de cana de açúcar. Ao elevar- se a dose de fertilização potássica deverá haver precaução para que a adubação magnesiana seja suficiente. O K além de aumentar a produção, em solos deficientes, aumenta também o tamanho dos tubérculos produzidos, e a proporção de tubérculos grandes. Deficiência no suprimento de potássio á planta pode acarretar produção de tubérculos com elevada susceptibilidade aos danos mecánicos pós-colheita. Os tubérculos injuriados enegrecem facilmente e este enegrecimento é inversamente proporcional á quantidade de potássio nos tuberculos. Ademais, quando fritos dão origem a um produto escuro, de baixa valor comercial. Manejo de adubação Diversos fatores como potencial de produção do solo, modo de aplicação do fertilizante dentre outro fatores afetam a resposta da batateira á aplicação de fertilizantes (Refschneider 1987.). Depreende- se pois que no estabelecimento de um nivel ideal de fertilização as variáveis planta, solo e condições climaticas devem ser visualizadas como um sistema pouco provável de ser homogeneo mesmo em nivel de fazenda. Como tal, generalizações a respeito de doses ou niveis de fertlização são difíceis de serem feitas, recomendações exigem julgamento hábil por parte do fazendeiro ou do tecnico responsavel pela cultura (Márton 2001a., 2001b.). Este julgamento será mais preciso conhecendo- se pontos que serão rápidamente discutidos a seguir. A taxa de absorção de nutrientes é governada pela concentração externa ou suprimento de nutrientes pelo solo e a demanda do nutriente criada pelo desenvolvimento e funcinamento normal dos diversos órgãos das plantas. O nivel de nutrientes na solução do solo deve ser suficiamente alto para que suas taxas de absorção não sejam limitantes ao crescimento. Por outro lado, não deve ser demasiado para causar excessiva absorção de outros nutrientes. Forte associação existe entre a absorção de nutrientes e o desenvolvimento da planta. De maneira geral, a fase de rapido desenvolvimento da cultura é acompanhada por um grande aumento na absorção de nutrientes com a taxa de absorção declinado quando a taxa de crescimento diminuiu. Normalmente todos os fertilizantes potássicos e fosfatados são adicionados ao solo na época do plantio. O nitrogênio normalmente é parcelado. Cerca de 2 por 3 do nível recomendado é colocado no sulco de plantio e o restante adicionado por ocasião da amontoa. É uma prática tradicinal e com pouco suporte experimental no condiõces brasileiras. Espera -se que a aplicação parcelada do nitrogênio e mesmo do potássio possem ser benéficas quando houver chuva excessiva ou irrigações mal executadas principalmente em solos mais arenosos onde poderá ocorrer a lixiviacão dos mesmos (Márton 2001a., 2001b.). O parcelamento poderá também ser benéfico quando elevados níveis de fertilizantes porém recomendandos e a aplicação por feita nos sulcos de plantio, pois evitar-se ia assim, elevada concentração salina em torno dos tubérculos plantados, embora a aplicação á lanco, em toda área, possa ser opção vantajosa. Quantidades corretas de fertilizantes, posição ideal e época certa de aplicação, combinadas adequadamente, definem o programa de adubação da batata. Esse programa é variável de acordo com o solo, a batata e condisões ambientais (Márton 2001a.). A dose de um elemento a ser aplicada em batata, é função da quantidade desse elemento suprida pelo solo e da percentagem de recuperação do elemento adicionado ao solo como fertilizante. Resultados experimentais comparando a aplicação de fertilizante á lanco ou localizado mostram respostas variadas sobre a produção. E possivel encontrar resultados iguais em ambos os métodos, de supremacia da aplicação á lanco ou da aplicação localizada (Kurnik et all. 2001.). Parece que baixas quantidades de fertilizantes são mais eficiemente utilizadas quando aplicação nos sulcos de plantios. Entretanto o potancial de produção pode ser aumentando com alta ou mesmo moderada quantidade de fertilizantes aplicados á lanço. A recomendação geral de colocar o adubo no sulco de plantio da batata merece ser questionada. É uma recomendação válida ao entender- se que a batata responde bastante á aplicação de fósforo, que os solos brasileiros tem alta capacidade de absorção de fósforo e que haverá maior proliferação de raízes na área fertilizada. Uma indagação aparece: um solo com baxa disponibilidade de fósforo fora da zona fertilizada permitiria o desenvolvimento ótimo da planta. Algumas evidéncias mostram, para outras espécies, que grande parte do sistema radicular, deve estar exposta ao fósforo para suprir as necessidades das plantas. Ademais, há um determinado valor de concentração de fósforo, na solução do solo, acima da qual a taxa de absorção não é aumentada. Essas considerações suscitam a possibilidade de questionar se a aplicação de fósforo em sulcos seria a forma mais eficiente de usá-lo quando se pretende alcancar elevadas produções. Deve-se lembrar entretanto, que solos tropicais, ainda com baixos teores fósforo e alta capacidade de adsorção, seria necessária dose muito elevada de P, quando aplicada á lanço, em todo o terreno. Se a aplicação localizada do fósforo pode, em parte, ser explicada, a do nitrogênio e potássio não são facilmente justificadas sob o aspecto de eficiéncia de utilização. Pelo contrário, ela pode ser questionada, principalmente pelas suas caracteristicas de difusão, pelo efeito que altas concentração de amónio e cloreto podem ter sobre a pressão osmotica da solução do solo junto aos tubérculos plantados, pelo efeito negativo do cloreto sobre a absorção de fósforo e também sobre a capacidade produtiva das plantas. Portanto, existe a possibilidade de ocorrer toxidez de amónio e de cloreto ao se aplicar doses altas dos fertilizantes nos sulcos de plantios. Isto pode determinar uma menor eficiéncia no uso dos fertilizantes. Materiais e Metodos: Nos desenvolverémos os três experimentos (i.e.: 1., 2., 3.) para aumentár-se do produção e produtividade da batata (Solanum tuberosum L.) semente pré- básica no casa de vegetação com diferentes doságens do latossolo vermelho novo, do esterco de curral e do adubo fórmula 4N:14P:8K no Empresa Brasileira de Pesquisa Agropecuaria- Centro Nacional de Pesquisas de Hortaliças, da Brazília-DF no 1990. Caracteristicas agroquímicas do solo em faixa arado (dados estimados), e conteudos N, P2O5, K2O do esterco de curral e palha de arroz queimado (dados estimados): a., caracteristicas agroquímicas do solo latossolo vermelho (solo novo: nunca foi usado para produção da batata semente): CaCO3 0.3-0.7%, humo 0.9-1.0%, pH (H2O) 5.3, pH (KCl) 4.5, AL- P2O5 3.2-3.5 mg kg-1, AL- K2O 180 mg kg-1, Mg (KCl) 70 mg kg-1, EDTA-Zn 0.5-0.8 mg kg-1, EDTA-Cu 0.5-0.6 mg kg-1 com abastecer fraco destes elementos, b., conteudos N, P2O5, K2O do esterco de curral (qualidade médio): N 1.8 g kg-1, P2O5 2.0 g kg-1, K2O 4.0 g kg-1, c., conteudos N, P2O5, K2O do palha de arroz queimado (palha de arroz foi queimado em um especial forno): N 0.8 g kg-1, P2O5 7.0 g kg-1, K2O 4.5 g kg-1. Nestas provas usarémos para controle a *mistura padrão. O este tratamento é a composição usual neste programa i.e.: 150 l de solo novo, 50 l de palha de arroz queimado, 50 l de esterco de curral, 350 gramas de cal e 300 gramas de adubo da fórmula 4N:14P:8K. Experimento 1. Efeito de diferentes misturas para produção da batata semente pré- básica em casa de vegetação O experimento foi instalado considerando-se sete misturas de substrato (latossolo vermelho novo, esterco de curral, palha de arroz queimado) em 3000 cm3 volume de capacidade de vasos preto com cinco repetições, no delineamento experimental de blocos ao acaso, na mésas experimentais em caso de vegetação. A cultivar foi a Achat, com plãntulas provenientes de cultura de tecidos. A data de plantio foi 18.04.1990. Plantarémos em cada vaso 3-3 "in vitro" plantulas com raiz embaixo de 4cm de superficie da mistura no vasos. Irrigarémos com 12 mm quantidade da augua 2 vezes por semana. Para produção aplicarémos sistema de proteção de plantas como usados no Brasíl. Ambiente foi controlado com ventilação automatizado. Temperatura médio foi 22 0C e humidade médio foi 68% durante de experimento. A data de colheta foi 04.07.1990. As pesagens foram feitos como peso fresco. Os resultados foram submetidos a analise de variáncia, ANOVA. As misturas do substrato utilizadas foram como a seguir no Tabela 1. Experimento 2. Efeito de adubo 4N:14P:8K para produção da batata semente pré- básica em casa de vegetação O experimento foi instalado considerando-se 9 dosagens de adubo da fórmula 4N:14P:8K com latossolo vermelho novo em 3000 cm3 volume de capacidade de vasos preto com cinco repetições, no delineamento experimental de blocos ao acaso na mésas experimentais em casa de vegetação. O adubo foi posicionando no solo de 4 cm abaixo de superficie do solo. A cultivar foi a Achat, com plãntulas provenientes de cultura de tecidos. A data de plantio foi 18.04.1990. Plantarémos em cada vaso 3-3 "in vitro" plantulas com raiz embaixo de 4cm de superficie da mistura no vasos. Irrigarémos com 12 mm quantidade da augua 2 vezes por semana. Para produção aplicarémos sistema de proteção de plantas como usados no Brasíl. Ambiente foi controlado com ventilação automatizado. Temperatura médio foi 22 0C e humidade médio foi 68% durante de experimento. A data de colheta foi 04.07.1990. As pesagens foram feitos como peso fresco. Os resultados foram submetidos a analise de variáncia, ANOVA. As doságens de adubo foram como a seguir no Tabela 2. Experimento 3. Efeito de latossolo vermelho novo, palha de arroz queimado e adubo 4N:14P:8K para produção da batata semente pré- básica em casa de vegetação Para pesquisar estes efeitos o experimento tipo de (2 x 6) foi instalado considerando-se as combinações entre duas misturas (i.e.: 1., 2.) e seis doságens de adubo complexo 4N:14P:8K, com três repetições, no delineamento experimental de bloco ao acaso, sendo 1 vaso (3000 cm3 volume de capacidade de vasos preto) por parcela na mésas experimentais em casa de vegetação. O adubo foi posicionando no solo de 4 cm abaixo de superficie do solo. A cultivar utilizada foi Baraka e o tamanho de tuberculos foi com 0-20 mm. A data de plantio foi 25.09.1990. Plantarémos em cada vaso 3-3 tuberculos com embaixo de 4cm de superficie da mistura no vasos. Irrigarémos com 12 mm quantidade da augua 2 vezes por semana. Para produção aplicarémos sistema de proteção de plantas como usados no Brasíl. Ambiente foi controlado ventilação automatizado. Temperatura médio foi 21 0C é humidade médio foi 66% durante de experimento. A data de colheta foi 14.12.1990. As pesagens foram feitos como peso fresco e matéria seca. Os resultados foram submetidos a analise de variáncia, MANOVA. Os manejos foram como a seguir no Tabela 3. Resultados e Discuscáo Experimento 1. Efeito de diferentes misturas para produção da batata semente pré- básica em casa de vegetação O tratamento 3. i.e.: mistura de 80% latossolo vermelho novo, 10% palha de arroz queimado e 10% esterco de curral, apresentou os maiores valores para numero de tuberculos com 0-20 mm (tamanho de comercial), peso de tuberculos com 0-20 mm e peso total de tuberculos por vaso. Porém, não houve diferencas significativas para o numero tuberculos comerciais, i.e.: com 0-20 mm, para os tratamentos 2., 3., 4., e 5. Portanto, a mistura poderá ter uma composição entre 60 a 90% de latossolo vermelho novo, 6 a 24% de palha de arroz queimado e de 4 a 16% de esterco de curral. Não houve diferenca significativa entre a mistura padrão utilizada e as misturas incluidas nos extremos indicados anteriormente. Porém, a mistura padrão recebeu adubação quimica de 4N:14P:8K (3.6 grama vaso-1) e calcário na dosagem de 4.2 grama vaso-1, o que não aconteceu com as parcelas das misturas em analise. Experimento 2. Efeito de adubo 4N:14P:8K para produção da batata semente pré- básica em casa de vegetação Há um efeito crescente das dóses de 4N:14P:8K nos caracteres observados. Porém, a maior dóse não chegou a ultrapassar a mistura padrão. Experimento 3. Efeito de latossolo vermelho novo, palha de arroz queimado e adubo 4N:14P:8K para produção da batata semente pré- básica em casa de vegetação Efeitos de misturas As duas misturas (i.e.: 1 e 2) deram resultados significativos mais alto que a mistura padrão, em média 54 %. Entre as misturas 1 e 2, foi melhor a 2. (80% latossolo vermelho novo, 10% palha de arroz queimado, 10% esterco de curral). Examinando-se 15 fatores, entre 11 casos afirmou-se a mistura como para melhor que a mistura 1. (70% latossolo vermelho novo, 20% palha de arroz queimado, 10% esterco de curral). Em caso de número de tuberculos 0-20 mm com a mistura 2. foi possivel aumentar geralmente os números de tuberculos em 77% que a mistura padrão. Efeitos de adubação 1. Área da folhas por planta entre manejo foi melhor de modo significativo a doságem de 3.6 grama vaso-1 adubo complexo (3103 cm2 plantas-1). 2. Peso fresco da folhas e de hastes por plantas as tendencias foram parecidos com o da área de folhas. 3. Peso fresco de raizis por planta até 7.2 grama vaso-1 diminuiu depois aumentou. 4. Peso fresco total de tuberculos por planta as crescentes doságens de um modo forte diminuiram a produção de tuberculos de 0 e 18.0 grama vaso-1 em 160% em os dois caso da mistura. 5. Peso de fitomassa fresco por planta foi melhor a 3.6 g vaso-1 (239 grama planta-1 em médio da dois mistura), depois os dados diminuirám. 6. Produção de biomassa fresco por planta a maxima produção (188 grama planta-1) foi obtida com 3.6 grama vaso-1. Deste ponto de modo forte caiu a produção. 7. Peso da matéria seca de folhas, hastes e raizis por planta somente em caso de mistura padrão o resultado foi significativo em relação aos outros tratamentos. 8. Péso da matéria seca de tuberculos total por planta modo significativo diminuiu a produção (0 e 18.0 grama vaso-1 = 360%) em médio da duas misturas. 9. Biomassa produção de materia seca por planta modo significativo diminuiu para efeito de alta dosagens de adubo complexo (0 e 18.0 grama vaso-1 = 158%) em médio da duas misturas. 10. Peso fresco de tuberculos com 0-20 mm as crescentes dosagens de 0 e 18.0 grama vaso-1 diminuiram a produção em 213% em médio da duas misturas. 11. Peso fresco de tuberculos com 20 mm-1 as crescentes dosagens de 0 e 18.0 grama vaso-1 diminuiram a produção assima de 250% em médio da duas misturas. 12. Numero de tuberculos 0-20 mm e 20 mm- por planta com os manejos de 0 e 18.0 grama vaso-1 foi possível aumentar em media 200% sobre a mistura padrão. Os manejo de 18.0 grama de adubo vaso-1 já causaram importante diminuição em relação caso a absoluto controle. 13. Numero total de tuberculos por planta entre manejos foi melhor a dosagem de 7.2 grama vaso-1 adubo complexo 4N:14P:8K comparando da mistura padrão. Nos verificamos-se que a mistura padrão sempre deu menor rasultados do que as outras misturas (i.e.: 1 e 2). Entre as misturas 1 e 2 a melhor foi a número 2. (80% latossolo vermelho novo, 10% palha de arroz queimado, 10% esterco de curral). Com esta mistura e com relação a mistura padrão, foi possível aumentar o número de tuberculos 0-20 mm com 77%. No caso do adubação, verificamos que grande quantidades de adubo acima de 7.2 grama vaso-1, de modo rigoroso diminuiu a produção de batata-semente pré- básica. Este fato deve ser considerado para a eleição das dosagens de adubos. Deve-se indicar o caso de número de tuberculos acima 20 mm-, onde em relação mistura padrão foi possivel aumentar em média 73% os resultados. Reconhecimento: Esta pesquisa foi apoio da Empresa Brasileira de Pesquisa Agropecuaria- Centro Nacional de Pesquisas de Hortaliças, Brasília-DF e Centro Pesquisa de Solo e Agroquímica do Academia Húngara de Ciências, Budapest References Kádár I-Márton L.-Horváth S. 2000. Mineral fertilisation of potato (Solanum tuberosum L.) on calcareous chernozem soil. Plant Production. 49: 291-306. Kurnik E.-Németh T.-Márton L.-Radimszki L. 2001. Effects of a new environment friendly deep fertilization system on a limy chernozem soil parameters. Agrochemistry and Soil Science. Budapest. In press László M. 2000. Nutrition of potato (Solanum tuberosum L.) on Hungary on a chernozem soil. Acta Agronomica Óváriensis. 42: 81-93. László M. 2001a. Climate change and N, P, K, Mg fertilization effects on potato (Solanum tuberosum L.) yield and quality. EAPR. Hamburg. In press László M. 2001b. Year and fertilization effect analysis in long field term experiments. XLIII. Georgikon Days. University of Veszprém. Keszthely László M.-Imre K.-Jose E.M. 2000a. Effects of Crotalaria juncea L. and Crotalaria spectabilis ROTH. on soil fertility and soil conservation in Hungary. Acta Agronomica Óváriensis. 42: 99-106. László M.-Silva J.C.-Jose A.B. 2000b. Ecological friendly dragée technics on different crops and vegetables seeds. Acta Agronomica Óváriensis. 42: 107-111. László M.-Silva J.B.C.-Jose A.B. 2000c. Ecological friendly dragée technics to sustainable precision agriculture. Fertilization in the Third Millenium. CASISCF. Beijing Márton L. 2000a. Effects of NPK fertilizers on potato (Solanum tuberosum L.) yield. Doctoral Ph.D Dissertation. University of Veszprém, Keszthely Márton L. 2000b. Effects of NPK fertilizers on potato (Solanum tuberosum L.) yield. Doctoral Ph.D Thesis. University of Veszprém, Keszthely Márton L. 2001a. Climete change effets on rye (Secale cereale L.) yield. Agrochemistry and Soil Science. Budapest. In press Márton L. 2001b. Climate change and fertilization effect analysis at the Tisza- river basin on rye yield. SZINET. University of Szent István. Gödöllő Márton L.-Kádár I.-Estáquio M.J. 2000. Effects of Crotalaria juncea L. and Crotalaria spectabilis ROTH on soil fertility and soil conservation. ESSC. Man and Soil at the Third Millennium. Abstract Book. 195. Valencia Reifschneider F.J.B. 1987. Produção de batata. Linha Gráfica e Editora. Brasília. p. 239. Tabela 1. Tratamentos do experimento 1. (Brasília-DF, 1990) ------------------------------------------------------------------ Numero de Composição em % Tratamento Solo novo Palha de arroz queimado Esterco de curral ------------------------------------------------------------------ 1. 100 0 0 2. 90 6 4 3. 80 10 10 4. 70 18 12 5. 60 24 16 6. 50 30 20 7. 40 36 24 ----------------------------------------------------------------- Tabela 2. Tratamentos do experimento 2. (Brasília-DF, 1990) ------------------------------------------------------- Numero de Adubo 4:14:8 N P2O5 K2O Tratamento Grama vaso-1 ------------------------------------------------------- 1. 0.0 0.000 0.000 0.000 2. 1.8 0.072 0.252 0.144 3. 3.6 0.144 0.504 0.288 4. 5.4 0.216 0.756 0.432 5. 7.2 0.288 1.008 0.576 6. 9.0 0.360 1.260 0.720 7. 10.8 0.432 1.512 0.864 8. 12.6 0.504 1.764 1.008 9. 14.4 0.576 2.016 1.152 ------------------------------------------------------- Tabela 3. Tratamentos do experimento 3. (Brasília-DF, 1990) ------------------------------------------------------------------------ Num. de Mistura % Trat. Solo novo Palea de arr. Q Esterco de curral 4N:14P:8K g vaso-1 ------------------------------------------------------------------------ 1. 70 20 10 0.0 2 70 20 10 3.6 3. 70 20 10 7.2 4. 70 20 10 10.8 5. 70 20 10 14.4 6. 70 20 10 18.0 7. 80 10 10 0.0 8. 80 10 10 3.6 9. 80 10 10 7.2 10. 80 10 10 10.8 11. 80 10 10 14.4 12. 80 10 10 18.0 ------------------------------------------------------------------------

A murine model of elastase- and cigarette smoke-induced emphysema.

PubMed

Rodrigues, Rubia; Olivo, Clarice Rosa; Lourenço, Juliana Dias; Riane, Alyne; Cervilha, Daniela Aparecida de Brito; Ito, Juliana Tiyaki; Martins, Milton de Arruda; Lopes, Fernanda Degobbi Tenório Quirino Dos Santos

2017-01-01

To describe a murine model of emphysema induced by a combination of exposure to cigarette smoke (CS) and instillation of porcine pancreatic elastase (PPE). A total of 38 C57BL/6 mice were randomly divided into four groups: control (one intranasal instillation of 0.9% saline solution); PPE (two intranasal instillations of PPE); CS (CS exposure for 60 days); and CS + PPE (two intranasal instillations of PPE + CS exposure for 60 days). At the end of the experimental protocol, all animals were anesthetized and tracheostomized for calculation of respiratory mechanics parameters. Subsequently, all animals were euthanized and their lungs were removed for measurement of the mean linear intercept (Lm) and determination of the numbers of cells that were immunoreactive to macrophage (MAC)-2 antigen, matrix metalloproteinase (MMP)-12, and glycosylated 91-kDa glycoprotein (gp91phox) in the distal lung parenchyma and peribronchial region. Although there were no differences among the four groups regarding the respiratory mechanics parameters assessed, there was an increase in the Lm in the CS + PPE group. The numbers of MAC-2-positive cells in the peribronchial region and distal lung parenchyma were higher in the CS + PPE group than in the other groups, as were the numbers of cells that were positive for MMP-12 and gp91phox, although only in the distal lung parenchyma. Our model of emphysema induced by a combination of PPE instillation and CS exposure results in a significant degree of parenchymal destruction in a shorter time frame than that employed in other models of CS-induced emphysema, reinforcing the importance of protease-antiprotease imbalance and oxidant-antioxidant imbalance in the pathogenesis of emphysema. Descrever um modelo murino de enfisema induzido por exposição a fumaça de cigarro (FC) e instilação de elastase pancreática porcina (EPP). Trinta e oito camundongos C57BL/6 foram aleatoriamente divididos em quatro grupos: controle (uma instilação intranasal de solução salina a 0,9%); EPP (duas instilações intranasais de EPP); FC (exposição a FC durante 60 dias) e FC + EPP (duas instilações intranasais de EPP + exposição a FC durante 60 dias). No fim do protocolo experimental, todos os animais foram anestesiados e traqueostomizados para o cálculo de parâmetros de mecânica respiratória. Em seguida, todos os animais foram sacrificados e seus pulmões foram removidos para a medição da intercepção linear média (Lm) e a determinação do número de células imunorreativas a antígeno macrofágico (MAC)-2, metaloproteinase da matriz (MMP)-12 e glicoproteína glicosilada de 91 kDa (gp91phox) no parênquima pulmonar distal e na região peribrônquica. Embora não tenha havido diferenças entre os quatro grupos quanto aos parâmetros de mecânica respiratória avaliados, houve aumento da Lm no grupo FC + EPP. O número de células positivas para MAC-2 na região peribrônquica e no parênquima pulmonar distal foi maior no grupo FC + EPP do que nos outros grupos, assim como o foi o número de células positivas para MMP-12 e gp91phox, porém somente no parênquima pulmonar distal. Nosso modelo de enfisema induzido por instilação de EPP e exposição a FC resulta em um grau significativo de destruição parenquimatosa em um período de tempo menor que o empregado em outros modelos de enfisema induzido por FC, o que reforça a importância do desequilíbrio entre proteases e antiproteases e entre oxidantes e antioxidantes na patogênese do enfisema.

Ovulation-inducing factor: a protein component of llama seminal plasma

PubMed Central

2010-01-01

Background Previously, we documented the presence of ovulation-inducing factor (OIF) in the seminal plasma of llamas and alpacas. The purpose of the study was to define the biochemical characteristics of the molecule(s) in seminal plasma responsible for inducing ovulation. Methods In Experiment 1, llama seminal plasma was centrifuged using filtration devices with nominal molecular mass cut-offs of 30, 10 and 5 kDa. Female llamas (n = 9 per group) were treated i.m. with whole seminal plasma (positive control), phosphate-buffered saline (negative control), or the fraction of seminal plasma equal or higher than 30 kDa, 10 to 30 kDa, 5 to 10 kDa, or < 5 kDa. In Experiment 2, female llamas (n = 7 per group) were given an i.m. dose of seminal plasma treated previously by: 1) enzymatic digestion with proteinase-K, 2) incubation with charcoal-dextran, 3) heating to 65°C, or 4) untreated (control). In Experiment 3, female llamas (n = 10 per group) were given an i.m. dose of pronase-treated or non-treated (control) seminal plasma. In all experiments, llamas were examined by transrectal ultrasonography to detect ovulation and CL formation. Ovulation rate was compared among groups by Fisher's exact test and follicle and CL diameters were compared among groups by analyses of variance or student's t-tests. Results In Experiment 1, all llamas in the equal or higher than 30 kDa and positive control groups ovulated (9/9 in each), but none ovulated in the other groups (P < 0.001). In Experiment 2, ovulations were detected in all llamas in each treatment group; i.e., respective treatments of seminal plasma failed to inactivate the ovulation-inducing factor. In Experiment 3, ovulations were detected in 0/10 llamas given pronase-treated seminal plasma and in 9/10 controls (P < 0.01). Conclusions We conclude that ovulation-inducing factor (OIF) in llama seminal plasma is a protein molecule that is resistant to heat and enzymatic digestion with proteinase K, and has a molecular mass of approximately equal or higher than 30 kDa. PMID:20462434

Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine.

PubMed

Kong, H; Kuang, W; Li, S; Xu, M

2011-03-10

Memories of learned associations between the rewarding properties of drugs and environmental cues contribute to craving and relapse in humans. The mesocorticolimbic dopamine (DA) system is involved in reward-related learning induced by drugs of abuse. DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas. Genetic and pharmacological studies have shown that DA D3 receptors suppress locomotor-stimulant effects of cocaine and reinstatement of cocaine-seeking behaviors. Activation of the extracellular signal-regulated kinase (ERK) induced by acute cocaine administration is also inhibited by D3 receptors. How D3 receptors modulate cocaine-induced reward-related learning and associated changes in cell signaling in reward circuits in the brain, however, have not been fully investigated. In the present study, we show that D3 receptor mutant mice exhibit potentiated acquisition of conditioned place preference (CPP) at low doses of cocaine compared to wild-type mice. Activation of ERK and CaMKIIα, but not the c-Jun N-terminal kinase and p38, in the nucleus accumbens, amygdala and prefrontal cortex is also potentiated in D3 receptor mutant mice compared to that in wild-type mice following CPP expression. These results support a model in which D3 receptors modulate reward-related learning induced by low doses of cocaine by inhibiting activation of ERK and CaMKIIα in reward circuits in the brain. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Chronic and asymptomatic diseases influence the control of hypertension treatment in primary care.

PubMed

Pierin, Angela Maria Geraldo; Silva, Stael Silvana Bagno Eleutério da; Colósimo, Flávia Cortez; Toma, Gabriela de Andrade; Serafim, Talita de Souza; Meneghin, Paolo

2016-01-01

To identify the association between blood pressure control and the following variables: a) bio-social and lifestyle characteristics of hypertensive patients; and b) factors related to the antihypertensive treatment. This is an exploratory study with 290 people with hypertension from primary care. We used a specific instrument, self-administered, with 21 questions on factors that can hinder treatment, divided into four dimensions: medication, socioeconomic, institutional and personal beliefs. We adopted a significance level of p <0.05. The control of blood pressure was associated (p <0.05) with female gender, Caucasian ethnicity, primary/secondary education, not drinking alcohol, higher income and regular physical activity. Regarding the factors that can hinder treatment, there was association of hypertension control with only two questions: "feel nothing" and "have to do treatment for life". Sociodemographic variables and beliefs concerning the absence of symptoms and chronicity of the disease influenced the control of hypertension and should be considered in the adherence process to the treatment. Identificar a associação entre o controle da pressão arterial e as seguintes variáveis: a) características biossociais e hábitos de vida dos hipertensos; e b) fatores relacionados ao tratamento anti-hipertensivo. Realizou-se estudo exploratório com 290 hipertensos da atenção primária. Utilizou-se de instrumento específico, autoaplicável, com 21 questões sobre fatores que podem dificultar o tratamento, divididas em quatro domínios: medicamentos, socioeconômico, institucional e crenças pessoais. Adotou-se nível de significância de p < 0,05. O controle da pressão arterial se associou (p < 0,05) com sexo feminino, etnia branca, ensino fundamental/médio, não ingerir bebida alcoólica, maior renda e atividade física regular. Quanto aos fatores que podem dificultar o tratamento, houve associação do controle com apenas duas questões: "não sentir nada" e "ter que fazer tratamento para vida toda". Variáveis sociodemográficas e crenças relativas à ausência de sintomatologia e cronicidade da doença influenciaram o controle dos hipertensos e devem ser consideradas no processo de adesão ao tratamento.

Comparison of in vivo and in vitro amphetamine on the synaptosomal uptake of dopamine in mouse striatum

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

Hadfield, M.G.

1985-05-01

Amphetamine (AMPH) produced competitive uptake inhibition of /sup 3/H-dopamine (DA) in synaptosomes obtained from mouse striatum--whether it was injected beforehand into living animals or simply added to the incubation medium. However, the in vivo drug doses required to produce this effect were high (ED50 = 65 mg/kg.) as compared with the in vitro doses (ED50 = 2.5 X 10(-6) M).

Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress.

PubMed

Novick, Andrew M; Forster, Gina L; Hassell, James E; Davies, Daniel R; Scholl, Jamie L; Renner, Kenneth J; Watt, Michael J

2015-10-01

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss through activating microglial NADPH oxidase

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

Wang, Yinxi; Liu, Dan; Zhang, Huifeng

Background: Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. Methods: Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPHmore » oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. Results: In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100 μg/cm{sup 2} induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10 μg/cm{sup 2}) and rotenone (2 nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91{sup phox}, p47{sup phox} and p40{sup phox}); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47{sup phox} and p67{sup phox} translocation assembling active NADPH oxidase. Conclusion: ufCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD. - Graphical abstract: Ultrafine particles and rotenone synergistically induce the assembly of active form NADPH oxidase complex in microglia inducing oxidative damage to dopamine neurons. - Highlights: • Ultrafine carbon black promotes dopaminergic neuronal loss induced by rotenone. • The role and underlying mechanism of ultrafine particles in the pathogenesis of PD • NADPH oxidase is a potential therapeutic target of Parkinson's disease.« less

The genome sequence of Agrotis segetum granulovirus, isolate AgseGV-DA, reveals a new Betabaculovirus species of a slow killing granulovirus.

PubMed

Gueli Alletti, Gianpiero; Eigenbrod, Marina; Carstens, Eric B; Kleespies, Regina G; Jehle, Johannes A

2017-06-01

The European isolate Agrotis segetum granulovirus DA (AgseGV-DA) is a slow killing, type I granulovirus due to low dose-mortality responses within seven days post infection and a tissue tropism of infection restricted solely to the fat body of infected Agrotis segetum host larvae. The genome of AgseGV-DA was completely sequenced and compared to the whole genome sequences of the Chinese isolates AgseGV-XJ and AgseGV-L1. All three isolates share highly conserved genomes. The AgseGV-DA genome is 131,557bp in length and encodes for 149 putative open reading frames, including 37 baculovirus core genes and the per os infectivity factor ac110. Comprehensive investigations of repeat regions identified one putative non-hr like origin of replication in AgseGV-DA. Phylogenetic analysis based on concatenated amino acid alignments of 37 baculovirus core genes as well as pairwise distances based on the nucleotide alignments of partial granulin, lef-8 and lef-9 sequences with deposited betabaculoviruses confirmed AgseGV-DA, AgseGV-XJ and AgseGV-L1 as representative isolates of the same Betabaculovirus species. AgseGV encodes for a distinct putative enhancin, distantly related to enhancins from other granuloviruses. Copyright © 2017. Published by Elsevier Inc.

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion.

PubMed

Khaldy, Hoda; Escames, Germaine; León, Josefa; Bikjdaouene, Leila; Acuña-Castroviejo, Darío

2003-01-01

Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.

Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging

PubMed Central

Schiffer, Wynne K.; Alexoff, David L.; Shea, Colleen; Logan, Jean; Dewey, Stephen L.

2005-01-01

In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound. PMID:15848236

Effects of beta-phenylethylamine on dopaminergic neurons of the ventral tegmental area in the rat: a combined electrophysiological and microdialysis study.

PubMed

Ishida, Kota; Murata, Mikio; Katagiri, Nobuyuki; Ishikawa, Masago; Abe, Kenji; Kato, Masatoshi; Utsunomiya, Iku; Taguchi, Kyoji

2005-08-01

The effects of systemic administration of beta-phenylethylamine (beta-PEA) and microiontophoretically applied beta-PEA on the spontaneous discharge of dopamine (DA) neurons in the ventral tegmental area (VTA) of the anesthetized rat were examined. Intravenous administration of beta-PEA (1.0, 2.5, and 5.0 mg/kg) and microiontophoretic applications of beta-PEA caused inhibitory responses in DA neurons. Systemic administration and microiontophoretic applications of beta-PEA induced dose- or current-dependent responses. The systemic beta-PEA-induced inhibitory responses were reversed by pretreatment with the DA D(2) receptor antagonists haloperidol (0.5 mg/kg i.p.) and sulpiride (10 mg/kg i.p). Pretreatment with reserpine (5 mg/kg i.p. 24 h earlier) did not completely block the systemic administration of beta-PEA (2.5 mg/kg) inhibition. A microdialysis study of freely moving rats demonstrated that the extracellular DA level increased significantly in response to local application of beta-PEA (100 muM) in the VTA via a microdialysis probe, and local application of beta-PEA-stimulated somatodendritic DA release in the VTA. The beta-PEA-induced release of DA was calcium ion-independent and was enhanced by pretreatment with pertussis toxin. These findings indicate that beta-phenylethylamine inhibits DA neuron activity via DA D(2) autoreceptors in the rat VTA and that this inhibitory effect is mediated by the somatodendritic DA release.

Differential impact of pavlovian drug conditioned stimuli on in vivo dopamine transmission in the rat accumbens shell and core and in the prefrontal cortex.

PubMed

Bassareo, Valentina; De Luca, Maria Antonietta; Di Chiara, Gaetano

2007-04-01

Conditioned stimuli (CSs) by pavlovian association with reinforcing drugs (US) are thought to play an important role in the acquisition, maintenance and relapse of drug dependence. The aim of this study was to investigate by microdialysis the impact of pavlovian drug CSs on behaviour and on basal and drug-stimulated dopamine (DA) in three terminal DA areas: nucleus accumbens shell, core and prefrontal cortex (PFCX). Conditioned rats were trained once a day for 3 days by presentation of Fonzies filled box (FFB, CS) for 10 min followed by administration of morphine (1 mg/kg), nicotine (0.4 mg/kg) or saline, respectively. Pseudo-conditioned rats were presented with the FFB 10 h after drug or saline administration. Rats were implanted with microdialysis probes in the shell, core and PFCX. The effect of stimuli conditioned with morphine and nicotine on DA and on DA response to drugs was studied. Drug CSs elicited incentive reactions and released DA in the shell and PFCX but not in the core. Pre-exposure to morphine CS potentiated DA release to morphine challenge in the shell but not in the core and PFCX. This effect was related to the challenge dose of morphine and was stimulus-specific since a food CS did not potentiate the shell DA response to morphine. Pre-exposure to nicotine CS potentiated DA release in the shell and PFCX. The results show that drug CSs stimulate DA release in the shell and medial PFCX and specifically potentiate the primary stimulant drug effects on DA transmission.

P2X1 Receptor-Mediated Ca2+ Influx Triggered by DA-9801 Potentiates Nerve Growth Factor-Induced Neurite Outgrowth.

PubMed

Back, Moon Jung; Lee, Hae Kyung; Lee, Joo Hyun; Fu, Zhicheng; Son, Mi Won; Choi, Sang Zin; Go, Hyo Sang; Yoo, Sungjae; Hwang, Sun Wook; Kim, Dae Kyong

2016-11-16

Nerve growth factor (NGF)-induced neuronal regeneration has emerged as a strategy to treat neuronal degeneration-associated disorders. However, direct NGF administration is limited by the occurrence of adverse effects at high doses of NGF. Therefore, development of a therapeutic strategy to promote the NGF trophic effect is required. In view of the lack of understanding of the mechanism for potentiating the NGF effect, this study investigated molecular targets of DA-9801, a well-standardized Dioscorea rhizome extract, which has a promoting effect on NGF. An increase in intracellular calcium ion level was induced by DA-9801, and chelation of extracellular calcium ions with ethylene-bis(oxyethylenenitrilo)tetraacetic acid (EGTA) suppressed the potentiating effect of DA-9801 on NGF-induced neurite outgrowth. In addition, EGTA treatment reduced the DA-9801-induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), the major mediators of neurite outgrowth. To find which calcium ion-permeable channel contributes to the calcium ion influx induced by DA-9801, we treated PC12 cells with various inhibitors of calcium ion-permeable channels. NF449, a P2X1 receptor selective antagonist, significantly abolished the potentiating effect of DA-9801 on NGF-induced neurite outgrowth and abrogated the DA-9801-induced ERK1/2 phosphorylation. In addition, transfection with siRNA of P2X1 receptor significantly reduced the DA-9801-enhanced neurite outgrowth. In conclusion, calcium ion influx through P2X1 receptor mediated the promoting effect of DA-9801 on NGF-induced neurite outgrowth via ERK1/2 phosphorylation.

Radiation inactivation method provides evidence that membrane-bound mitochondrial creatine kinase is an oligomer

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

Quemeneur, E.; Eichenberger, D.; Goldschmidt, D.

1988-06-30

Lyophilized suspensions of rabbit heart mitochondria have been irradiated with varying doses of gamma rays. Mitochondrial creatine kinase activity was inactivated exponentially with a radiation inactivation size of 352 or 377 kDa depending upon the initial medium. These values are in good agreement with the molecular mass previously deduced from by permeation experiments: 357 kDa. This is the first direct evidence showing that the native form of mitochondrial creatine kinase is associated to the inner membrane as an oligomer, very likely an octamer.

Role of the Dopaminergic System in the Acquisition, Expression and Reinstatement of MDMA-Induced Conditioned Place Preference in Adolescent Mice

PubMed Central

Vidal-Infer, Antonio; Roger-Sánchez, Concepción; Daza-Losada, Manuel; Aguilar, María A.; Miñarro, José; Rodríguez-Arias, Marta

2012-01-01

Background The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood. Methodology/Principal Findings In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed. Conclusions/Significance These results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement. PMID:22916213

Chronic treatment of DA-8159, a new phosphodiesterase type V inhibitor, attenuates endothelial dysfunction in stroke-prone spontaneously hypertensive rat.

PubMed

Choi, Seul Min; Kim, Jee Eun; Kang, Kyung Koo

2006-02-09

This study examined the effects of chronic treatment of a new phosphodiesterase type 5 inhibitor, DA-8159, on endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHR-SP). Six-week-old male SHR-SP were divided into 4 groups; vehicle control, DA-8159 1, 3, and 10 mg/kg/day. During a 32-week experimental period, the animals were administered DA-8159 orally and fed a 4% NaCl-loaded diet. The systolic blood pressure was measured every two weeks throughout the experimental period using the tail-cuff method. At the end of experiments, the vascular function (acetylcholine-induced vasodilation) in the endothelium-intact aortic rings was investigated. In addition, the mortality, the left ventricular hypertrophy index, the plasma parameters and the incidence of a cerebral infarction were assessed. In the DA-8159 treated-rats, the vascular reactivity improved significantly in a dose-dependent manner. Although DA-8159 did not alter the elevation of the systolic blood pressure directly, the 3 and 10 mg/kg/day DA-8159 treatment delayed the early death caused by stroke. DA-8159 significantly reduced the left ventricular heart weight/body weight ratio compared with the vehicle control group. Furthermore, the DA-8159 treatment significantly increased the plasma nitric oxide, cGMP, and the total antioxidative status. The DA-8159 treatment also reduced the occurrence of stroke-associated cerebral damage. These results indicate that DA-8159 can ameliorate an endothelial dysfunction-related vascular injury. Therefore, pharmacological intervention aimed at attenuating an endothelial dysfunction is important and might be useful in both preventing and treating endothelial dysfunction-related complications.

Chemopreventive effects of Korean Angelica vs. its major pyranocoumarins on two lineages of transgenic adenocarcinoma of mouse prostate carcinogenesis

PubMed Central

Tang, Su-Ni; Zhang, Jinhui; Wu, Wei; Jiang, Peixin; Puppala, Manohar; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

2015-01-01

We showed previously that daily gavage of Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited growth of prostate epithelium and neuroendocrine carcinomas (NE-Ca) in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Since decursin (D) and its isomer decursinol angelate (DA) are major pyranocoumarins in AGN extract, we tested the hypothesis that D/DA represented active/prodrug compounds against TRAMP carcinogenesis. Three groups of male C57BL/6 TRAMP mice were gavage-treated daily with excipient vehicle, AGN (5 mg per mouse) or equimolar D/DA (3 mg per mouse) from 8 weeks to 16 or 28 weeks of age. Measurement of plasma and NE-Ca D, DA and their common metabolite decursinol indicated similar retention from AGN vs. D/DA dosing. The growth of TRAMP dorsolateral prostate (DLP) in AGN-and D/DA-treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28 weeks, respectively. Survival of mice bearing NE-Ca to 28 weeks was improved by AGN, but not by D/DA. Nevertheless, AGN-and D/DA-treated mice had lower NE-Ca burden. Immunohistochemical and mRNA analyses of DLP showed AGN and D/DA exerted similar inhibition of TRAMP epithelial lesion progression and key cell cycle genes. Profiling of NE-Ca mRNA showed a greater scope of modulating angiogenesis, epithelial-mesenchymal-transition, invasion-metastasis and inflammation genes by AGN than D/DA. The data therefore support D/DA as probable active/prodrug compounds against TRAMP epithelial lesions, and they cooperate with non-pyranocoumarin compounds to fully express AGN efficacy against NE-Ca. PMID:26116406

Chemopreventive Effects of Korean Angelica versus Its Major Pyranocoumarins on Two Lineages of Transgenic Adenocarcinoma of Mouse Prostate Carcinogenesis.

PubMed

Tang, Su-Ni; Zhang, Jinhui; Wu, Wei; Jiang, Peixin; Puppala, Manohar; Zhang, Yong; Xing, Chengguo; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

2015-09-01

We showed previously that daily gavage of Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited growth of prostate epithelium and neuroendocrine carcinomas (NE-Ca) in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Because decursin (D) and its isomer decursinol angelate (DA) are major pyranocoumarins in AGN extract, we tested the hypothesis that D/DA represented active/prodrug compounds against TRAMP carcinogenesis. Three groups of male C57BL/6 TRAMP mice were gavage treated daily with excipient vehicle, AGN (5 mg per mouse), or equimolar D/DA (3 mg per mouse) from 8 weeks to 16 or 28 weeks of age. Measurement of plasma and NE-Ca D, DA, and their common metabolite decursinol indicated similar retention from AGN versus D/DA dosing. The growth of TRAMP dorsolateral prostate (DLP) in AGN- and D/DA-treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28 weeks, respectively. Survival of mice bearing NE-Ca to 28 weeks was improved by AGN, but not by D/DA. Nevertheless, AGN- and D/DA-treated mice had lower NE-Ca burden. Immunohistochemical and mRNA analyses of DLP showed that AGN and D/DA exerted similar inhibition of TRAMP epithelial lesion progression and key cell-cycle genes. Profiling of NE-Ca mRNA showed a greater scope of modulating angiogenesis, epithelial-mesenchymal transition, invasion-metastasis, and inflammation genes by AGN than D/DA. The data therefore support D/DA as probable active/prodrug compounds against TRAMP epithelial lesions, and they cooperate with non-pyranocoumarin compounds to fully express AGN efficacy against NE-Ca. ©2015 American Association for Cancer Research.

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats.

PubMed

Arnt, J; Hyttel, J

1985-01-01

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig.

PubMed

Hussain, Zahid; Rhee, Kwang Won; Lee, Young Ju; Park, Hyojin

2016-07-30

Opioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig. The ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig. DA-9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 μg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles. DA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD.

Infectivity titration of a prototype strain of hepatitis E virus in cynomolgus monkeys.

PubMed

Tsarev, S A; Tsareva, T S; Emerson, S U; Yarbough, P O; Legters, L J; Moskal, T; Purcell, R H

1994-06-01

The infectivity titer of a standard stock of the SAR-55 strain of hepatitis E virus (HEV) was determined in cynomolgus macaques (Macaca fascicularis) and the effect of dose on the course of the infection was examined by weekly monitoring of alanine aminotransferase (ALT) and anti-HEV levels. Antibody to HEV (anti-HEV) was measured with ELISAs based on ORF-2 recombinant antigens consisting of either a 55 kDa region expressed in insect cells or shorter regions expressed as fusion proteins in bacteria. The ELISA based on the 55 kDa antigen was generally more sensitive. The infectivity titer of SAR-55 was 10(6) cynomolgus 50% infectious doses per gram of feces. The infectivity titer corresponded to the HEV genome titer of the inoculum as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Anti-HEV IgM was detected in only a portion of the animals that had an anti-HEV IgG response. Biochemical evidence of hepatitis was most prominent in animals that were inoculated with the higher concentrations of virus and the incubation period to seroconversion was prolonged in animals that received the lower doses.

Arabinogalactan for hepatic drug delivery.

PubMed

Groman, E V; Enriquez, P M; Jung, C; Josephson, L

1994-01-01

Arabinogalactan, a polysaccharide from the tree Larix occidentalis, has been purified and its biological and physical properties described. Intravenous injection of radiolabeled arabinogalactan (4 mg/kg) in rats resulted in 52.5% of the dose being present in the liver, while prior injection of asialofetuin (100 mg/kg) reduced hepatic radioactivity to 3.54%. Gel chromatography indicates arabinogalactan is a single species of 19 kDa, while light scattering gave a molecular weight of 40 kDa. Glycosyl linkage analysis of arabinogalactan is consistent with a highly branched structure comprising a backbone of 1,3-linked galactopyranose connected by 1,3-glycosidic linkages, comprised of 3,4,6-,3,6-, and 3,4- as well as 3-linked residues. In the carbon-13 NMR spectra, the major resonances of arabinogalactan are assigned to beta-galactopyranose, beta-arabinofuranose, and beta-arabinopyranose. Arabinogalactan produced no adverse reactions in single intravenous dose (mouse, 5000 mg/kg) and repeat dose toxicity studies (rats, 500 mg/kg/day, 90 days). When tritiated arabinogalactan was injected, radioactivity cleared from the liver with a half-life of 3.42 days. Arabinogalactan has properties that make it suitable as a carrier for delivering diagnostic or therapeutic agents to hepatocytes via the asialoglycoprotein receptor.

Da-Chaihu-Tang alters the pharmacokinetics of nifedipine in rats and a treatment regimen to avoid this.

PubMed

He, Ju-Xiu; Ohno, Kenji; Tang, Jun; Hattori, Masao; Tani, Tadato; Akao, Teruaki

2014-11-01

To investigate the influence of co-administrated Da-Chaihu-Tang (DCT; a traditional Chinese formulation) on the pharmacokinetics of nifedipine, as well as the safe optimal dosing interval to avoid the adverse interactions. A single dose of DCT was administered with nifedipine simultaneously, 2 h before, 30 min before or 30 min after nifedipine administration. Pharmacokinetics of nifedipine with or without DCT were compared. The influences of DCT on nifedipine intestinal mucosal and hepatic metabolism were studied by using rat in-vitro everted jejunal sac model and hepatic microsomes. A simultaneous co-administration of DCT significantly increased the area under concentration-time curve from time zero to infinity (AUC0-inf ) of nifedipine. In-vitro mechanism investigations revealed that DCT inhibited both the intestinal and the hepatic metabolism of nifedipine. Further study on the optimal dosing interval for nifedipine and DCT revealed that administration of DCT 30 min before or after nifedipine did not significantly change the AUC of nifedipine. The bioavailability of nifedipine is significantly increased by a simultaneous oral co-administration of DCT. This increase is caused by the inhibitory effect of DCT on both the intestinal mucosal and the hepatic metabolism of nifedipine. The dose interval between DCT and nifedipine needs to be set for over 30 min to avoid such drug-drug interactions. © 2014 Royal Pharmaceutical Society.

Bacterial Heat Shock Protein GroEL (Hsp64) Exerts Immunoregulatory Effects on T Cells by Utilizing Apoptosis

PubMed Central

Nalbant, Ayten; Kant, Melis

2016-01-01

Aggregatibacter actinomycetemcomitans (Aa) expresses a 64-kDa GroEL protein belonging to the heat shock family of proteins. This protein has been shown to influence human host cells, but the apoptotic capacity of the GroEL protein regarding T cells is not yet known. The purpose of this study was to investigate the ability of A. actinomycetemcomitans GroEL (AaGroEL) protein to induce human peripheral blood T-cell apoptosis. Endogenous, purified AaGroEL protein was used as an antigen. In AaGroEL-treated T cells, the data indicated that phosphatidylserine exposure, an early apoptotic event, was dose- and time-dependent. The AaGroEL-treated T cells were also positive for active caspase-3 in a dose-dependent manner. The rate of AaGroEL-induced apoptosis was suppressed by the addition of the general caspase inhibitor Z-VAD-FMK. Furthermore, cleaved caspase-8 bands (40/36 kDa and 23 kDa) were identified in cells responding to AaGroEL. DNA fragmentation was also detected in the AaGroEL-treated T cells. Overall, we demonstrated that the endogenous GroEL from A. actinomycetemcomitans has the capacity to induce T-cell apoptosis. PMID:27736933

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions.

PubMed

Arnt, J

1985-08-26

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.

Development policy for the Brazilian health industry and qualification of national public laboratories.

PubMed

Viana, Ana Luiza d'Ávila; Silva, Hudson Pacifico da; Ibañez, Nelson; Iozzi, Fabíola Lana

2016-11-03

Technological innovations play a decisive role in societies' development by contributing to economic growth and the population's welfare. The state has a key role in this process by inducing innovative behavior, strategies, and decisions. This study addresses Brazil's current policy for development of the health industry and its effects on qualification of national public laboratories by contextualizing different cycles of interaction between health policy and the industrial base, discussing the government's development strategy and the transfer and absorption of health technology (through Industrial Development Partnerships), and presenting two current partnerships involving public laboratories in the production of medicines and vaccines. Resumo: As inovações tecnológicas jogam papel decisivo no processo de desenvolvimento das sociedades, visto que contribuem para gerar crescimento econômico e bem-estar da população. O Estado possui grande importância e centralidade nesse processo, pois pode induzir fortemente o comportamento, as estratégias e as decisões relativas à inovação. O presente artigo tem por objetivo investigar a atual política de desenvolvimento produtivo em saúde no Brasil e seus reflexos sobre a capacitação dos laboratórios públicos nacionais. Para essa finalidade, contextualiza os diferentes ciclos de interação entre a política de saúde e a sua base produtiva, discute a estratégia do governo brasileiro para o desenvolvimento, a transferência e a absorção de tecnologia na área da saúde (as parcerias para o desenvolvimento produtivo) e apresenta duas parcerias vigentes envolvendo laboratórios públicos para a produção de medicamentos e vacinas.

ALTERNATIVE TECHNIQUE FOR CHOLECYSTECTOMY COMPARABLE TO SINGLE PORT.

PubMed

Sabbag, Carlos; Blitzckow, Ana

2017-01-01

With the advancement of laparoscopic surgery, new techniques have been proposed and disseminated in order to reduce the surgical aggression and get better cosmetic results. To present alternative technique for videocholecystectomy comparable to single port technique using conventional material for laparoscopic surgery. Introduction of laparoscopic devices using two incisions; gallbladder traction with thread, exposition of Calot triangle, and ligature of cystic pedicle with polymer clips. Nine operations were carried out with this method, without complications and no increase in operative time, being compared to conventional videocholecistectomy, however vastly superior in aesthetic results. The technique is feasible, reproducible, showing benefits to patient´s safety. Com o avanço da cirurgia laparoscópica, novas técnicas têm sido propostas e difundidas com o objetivo de diminuir a agressão cirúrgica e obter melhores resultados estéticos. Apresentar técnica alternativa para videocolecistectomia similar à técnica de single port, contudo utilizando material convencional para cirurgia laparoscópica. Procedimento de videocolecistectomia com uso de duas incisões, exposição do trígono de Calot por tração da vesícula biliar com fio e ligadura dos elementos do hilo cístico com clipes de polímero. Foram realizadas nove operações com esse método, não se observando complicações e nem aumento do tempo operatório em relação à videocolecistectomia convencional, contudo com resultado estético grandemente superior. A técnica é factível, reprodutível e mostra benefícios e segurança ao paciente.

A 21-35 kDa Mixed Protein Component from Helicobacter pylori Activates Mast Cells Effectively in Chronic Spontaneous Urticaria.

PubMed

Tan, Ran-Jing; Sun, He-Qiang; Zhang, Wei; Yuan, Han-Mei; Li, Bin; Yan, Hong-Tao; Lan, Chun-Hui; Yang, Jun; Zhao, Zhuo; Wu, Jin-Jin; Wu, Chao

2016-12-01

Helicobacter pylori (H. pylori) seem to involve in the etiology of chronic spontaneous urticaria (CSU). But studies of the pathogenic mechanism are very little. In this study, we detected the serum-specific anti-H. pylori IgG and IgE antibodies in 211 CSU and 137 normal subjects by enzyme-linked immunosorbent assay (ELISA), evaluated the direct activation effects of H. pylori preparations and its protein components on human LAD 2 mast cell line in vitro, and analyzed the specific protein ingredients and functions of the most effective H. pylori mixed protein component using liquid chromatography-mass spectrometry and ELISA assay. In CSU patients, the positive rate of anti-H. pylori IgG positive rate was significantly higher than that in normal controls, and the anti-H. pylori IgE levels had no statistical difference between H. pylori-infected patients with and without CSU. Further studies suggested that H. pylori preparations can directly activate human LAD 2 mast cell line in a dose-dependent manner and its most powerful protein component was a mixture of 21-35 kDa proteins. Moreover, the 21-35 kDa mixed protein component mainly contained 23 kinds of proteins, which can stimulate the release of histamine, TNF-a, IL-3, IFN-γ, and LTB4 by LAD 2 cells in a dose-dependent or time-dependent manner. A 21-35 kDa mixed protein component should be regarded as the most promising pathogenic factor contributing to the CSU associated with H. pylori infection. © 2016 John Wiley & Sons Ltd.

Impact of diatomite on the slightly polluted algae-containing raw water treatment process using ozone oxidation coupled with polyaluminum chloride coagulation.

PubMed

Hu, Wenchao; Wu, Chunde; Jia, Aiyin; Zhang, Zhilin; Chen, Fang

2014-01-01

The impact of adding diatomite on the treatment performance of slightly polluted algae-containing raw water using ozone pre-oxidation and polyaluminum chloride (PAC) coagulation was investigated. Results demonstrated that the addition of diatomite is advantageous due to reduction of the PAC dose (58.33%) and improvement of the removal efficiency of algae, turbidity, and dissolved organic matter (DOM) in raw water. When the ozone concentration was 1.0 mg L⁻¹ and the PAC dosage was 2.5 mg L⁻¹, the removal rates of algae, turbidity, UV254, and TOC were improved by 6.39%, 7.06%, 6.76%, and 4.03%, respectively, with the addition of 0.4 g L⁻¹ diatomite. It has been found that the DOM presented in the Pearl River raw water mainly consisted of small molecules (<1 kDa) and large ones (> 50 kDa). After adding diatomite (0.4 g L⁻¹), the additional removal of 5.77% TOC and 14.82% UV254 for small molecules (<1 kDa) of DOM, and 8.62% TOC and 7.33% UV254 for large ones (>50 kDa) could be achieved, respectively, at an ozone concentration of 1.0 mg L⁻¹ and a PAC dose of 2.5 mg L⁻¹. The growth of anabaena flos-aquae (A.F.) was observed by an atomic force microscope (AFM) before and after adding diatomite. AFM images demonstrate that diatomite may have a certain adsorption on A.F.

A noninterventional study evaluating the effectiveness of rotigotine and levodopa combination therapy in younger versus older patients with Parkinson's disease.

PubMed

Woitalla, Dirk; Dunac, Antoine; Safavi, Ali; Ceravolo, Maria-Gabriella; Gomez Esteban, Juan Carlos; Pavese, Nicola; Asgharnejad, Mahnaz; Joeres, Lars; Schuller, Jan-Christof; Chaudhuri, K Ray

2018-06-19

PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson's disease (PD) patients. Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP). 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose. At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals. Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.

Subchronic nandrolone administration reduces cocaine-induced dopamine and 5-hydroxytryptamine outflow in the rat nucleus accumbens.

PubMed

Kurling-Kailanto, Sanna; Kankaanpää, Aino; Seppälä, Timo

2010-04-01

The abuse of anabolic androgenic steroids (AASs) is not only a problem in the world of sports but is associated with the polydrug use of nonathletes. Investigations of the neurochemical effects of AAS have focused in part on the monoaminergic systems, involving, among other things, the development of dependence. We have previously shown that pretreatment with nandrolone decanoate attenuates dose-dependently the increase in extracellular dopamine (DA) concentration evoked by amphetamine and 3,4-methylenedioyxymethamphetamine in the nucleus accumbens (NAc). The aim of this study was to investigate whether the nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of cocaine in rats and whether the effects are long lasting. DA, 5-hydroxytryptamine (5-HT), and their metabolites were measured from samples collected from the NAc by microdialysis. The behavior of the animals was recorded. The present study demonstrates that five injections of nandrolone (5 and 20 mg/kg) inhibited cocaine-evoked DA and 5-HT outflow in the NAc, locomotor activity (LMA), and stereotyped behavior in experimental animals, and that these effects are seen even after elimination of nandrolone from bloodstream. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior, is related to gratification of stimulant drugs, this study suggests that nandrolone, at the doses tested, has a significant effect on the pleasurable properties of cocaine. Furthermore, because neurochemical and behavioral responses were still attenuated after a fairly long recovery period, it seems that nandrolone may induce long-lasting changes in the brains of rat.

Dopaminergic modulation of striatal acetylcholine release in rats depleted of dopamine as neonates.

PubMed

Johnson, B J; Bruno, J P

1995-02-01

A repeated sessions, in vivo microdialysis design was used to determine the D1- and D2-like receptor modulation of striatal ACh efflux in intact adult rats and those depleted of DA on postnatal Day 3. Systemic administration of the D1-like agonist SKF 38393 (1.0 or 10.0 mg/kg, or the D2-like antagonist clebopride (1.0 or 10.0 mg/kg) increased ACh efflux in both controls and DA-depleted animals. Systemic administration of the D1-like antagonist SCH 23390 (0.05 or 0.2 mg/kg) or D2-like agonist quinpirole (0.5 or 1.0 mg/kg) decreased ACh efflux in both groups of animals. DA-depleted animals exhibited a larger response than did controls to the lower doses of these drugs. Intrastriatal administration of clebopride (10 microM) increased ACh efflux in DA-depleted animals. Finally, basal and clebopride-stimulated ACh efflux were unaffected by the repeated microdialysis sessions. These data demonstrate that the reciprocal modulation of striatal ACh efflux, seen in controls and in rats depleted of DA as adults, is also present in adults depleted of DA as neonates. Because the roles of D1- and D2-receptors in the expression of motor behavior differ between rats depleted of DA as adults vs as neonates, these data suggest that alterations in the dopaminergic modulation of striatal ACh release do not underlie the sparing from motoric deficits seen in animals depleted of DA as neonates.

Socioeconomic and regional differences in active transportation in Brazil.

PubMed

Sá, Thiago Hérick de; Pereira, Rafael Henrique Moraes; Duran, Ana Clara; Monteiro, Carlos Augusto

2016-06-27

To present national estimates regarding walking or cycling for commuting in Brazil and in 10 metropolitan regions. By using data from the Health section of 2008's Pesquisa Nacional por Amostra de Domicílio (Brazil's National Household Sample Survey), we estimated how often employed people walk or cycle to work, disaggregating our results by sex, age range, education level, household monthly income per capita, urban or rural address, metropolitan regions, and macro-regions in Brazil. Furthermore, we estimated the distribution of this same frequency according to quintiles of household monthly income per capita in each metropolitan region of the country. A third of the employed men and women walk or cycle from home to work in Brazil. For both sexes, this share decreases as income and education levels rise, and it is higher among younger individuals, especially among those living in rural areas and in the Northeast region of the country. Depending on the metropolitan region, the practice of active transportation is two to five times more frequent among low-income individuals than among high-income individuals. Walking or cycling to work in Brazil is most frequent among low-income individuals and the ones living in less economically developed areas. Active transportation evaluation in Brazil provides important information for public health and urban mobility policy-making. Apresentar estimativas nacionais sobre o deslocamento a pé ou de bicicleta no trajeto casa-trabalho no Brasil e em 10 de suas regiões metropolitanas. Utilizando dados do Suplemento sobre Saúde da Pesquisa Nacional por Amostra de Domicílios de 2008, estimamos a frequência de pessoas empregadas que se deslocam a pé ou de bicicleta no trajeto casa-trabalho estratificada por sexo, e segundo faixa etária, escolaridade, renda domiciliar per capita, residência em área urbana ou rural, regiões metropolitanas e macrorregiões do país. Adicionalmente, estimamos a distribuição da mesma frequência segundo quintos da distribuição da renda domiciliar per capita em cada região metropolitana. Um terço dos homens e mulheres empregados desloca-se a pé ou de bicicleta de casa para o trabalho no Brasil. Em ambos os sexos, esta proporção diminui com o aumento da renda e da escolaridade e é maior entre os mais jovens, entre os que residem em área rural e naqueles residentes na região Nordeste. A depender da região metropolitana, a prática de deslocamento ativo entre os mais pobres é de duas a cinco vezes maior do que entre os mais ricos. O deslocamento a pé ou de bicicleta para o trabalho no Brasil é mais frequente entre os mais pobres e entre pessoas que vivem em áreas e regiões economicamente menos desenvolvidas. A avaliação do deslocamento ativo no País traz informações importantes para a discussão de políticas públicas de mobilidade.

A brief history of levodopa.

PubMed

Hornykiewicz, Oleh

2010-11-01

This article highlights some landmarks in the history of levodopa, beginning with its isolation in 1910-13 from seedlings of Vicia faba to the demonstration, in 1961, of its "miraculous" effect in patients with Parkinson's disease (PD). Midway between these two time points, in 1938, L: -dopa decarboxylase was discovered, the enzyme that produces dopamine (DA) from levodopa. In 1957, DA was shown to occur in the brain, and in 1959 it was found to be enriched in the basal ganglia. At that time the striatal localization of DA, together with studies done in 1957-58 in naive and reserpine-treated animals regarding DA in the brain and the central effects of levodopa, suggested its possible involvement in "extrapyramidal control" and "reserpine parkinsonism". Following these discoveries, a study of (postmortem) brains of patients with basal ganglia disorders, including PD, was started, demonstrating, in 1960, a severe striatal DA deficit specifically in PD, thus furnishing a rational basis for the concept of "DA replacement therapy" with levodopa. Accordingly, in 1961, the first highly successful clinical trial with i.v. levodopa was carried out. In 1963, the DA deficit in the PD substantia nigra was found, indicative of a nigrostriatal DA pathway in the human brain, subsequently established in animal studies in 1964-65. In 1967, the chronic, high dose oral levodopa regimen was introduced in treatment of PD. Besides the above highlights in the history of levodopa, the article also cites critical opinions of world authorities in brain research of the time, harmful to the cause of DA, levodopa and PD. Today, the concept of DA replacement with levodopa is uncontested, with levodopa being the "gold standard" of modern drug treatment of PD.

Observações das explosões cósmicas de raios gama GRB021004 e GRB021211 com o satélite HETE

NASA Astrophysics Data System (ADS)

Braga, J.; Ricker, G.; Hurley, K.; Lamb, D.; Grew, G.; et al.

2003-08-01

O High Energy Transient Explorer (HETE) é o primeiro satélite inteiramente dedicado ao estudo das explosões cósmicas de raios gama (ECRGs). Lançado em 9 de outubro de 2000, o HETE possui instrumentação capaz de observar as ECRGs desde o UV até raios gama e localizá-las com precisão de ~ 1-10 minutos de arco. As localizações das ECRGs detectadas são disseminadas rapidamente (em alguns segundos) pela Internet através de uma rede de estações de recepção ao longo do equador. A participação brasileira nesse projeto se dá através da montagem e operação de uma estação de recepção em Natal, RN, e da participação na equipe científica da missão. Neste trabalho são apresentados resultados da observação pelo HETE de duas ECRGs: GRB 021004 e GRB 021211. A GRB021004 foi detectada em raios gama pelo HETE em 4 de outubro de 2002 e localizada em raios-X em apenas 48 s, quando a emissão de raios gama ainda estava se processando. A explosão, relativamente brilhante e longa, durou aproximadamente 100 s. Um transiente óptico de magnitude 15 foi detectado no local da explosão nove minutos após o evento, e observações realizadas após 7 horas determinaram um desvio para o vermelho de absorção de 1,6. O GRB021004 foi o burst mais bem observado até o momento e suas observações em vários comprimentos de onda têm sido fundamentais para o aprimoramento dos modelos de ECRGs. O GRB21211, um burst brilhante e rico em raios-X, foi detectado em 11 de dezembro de 2002 e localizado em raios-X em 22 s após o início do evento. A duração do burst foi de 2,3 s em altas energias (85 a 400 keV) e de 8,5 s em baixas energias (2 a 10 keV). Caso essa explosão não tivesse sido rapidamente localizada pelo HETE, ela teria sido classificada como "opticamente escura", já que o transiente óptico decaiu rapidamente de R < 14 a R»19 dentro dos primeiros 20 minutos e já estava mais fraco do que R»23 depois de 24 horas da ocorrência do burst. Serão discutidas as implicações desse resultado nos modelos de afterglows de ECRGs.

Modified technique for preparation of venous circulation resin casts in the cirrhotic liver.

PubMed

Vasconcelos, José Olímpio Maia DE; Batista, Laécio Leitão; Pitta, Guilherme Benjamin Brandão; Lacerda, Cláudio Moura

2016-01-01

This study describes two major adaptations for the preparation of resin casts in human cirrhotic liver, harvested at the time of transplantation. The first is the way of fixing the catheter in the ostia of the hepatic and portal veins through a cerclage, so as to prevent displacement of the catheter and / or leakage of the resin during its injection. The second is the extension of corrosion time in the NaOH solution, averaging 6.8 days, with daily replacement the solution until complete removal of parenchymal tissue. We applied the method in 14 cirrhotic livers, with good filling and coloring of the portal and hepatic vein territories, using different colors. This allows an anatomical study of these vessels, able to complement the knowledge of the histopathology in research work, and the planning of therapeutic procedures, such as the Trans-Jugular Intrahepatic Port-Systemic Shunt (TIPS). RESUMO Este estudo descreve duas importantes adaptações para o preparo de moldes de resina em fígado humano cirrótico, captado no momento do transplante: a primeira, é a maneira de fixação dos cateteres nos "óstios" das veias hepáticas e porta, através de uma "cerclagem" dos mesmos, de modo a evitar o deslocamento do cateter e/ou extravasamento da resina durante sua injeção, e a segunda, é o prolongamento do tempo de corrosão na solução de NaOH, atingindo a média de 6,8 dias, com a substituição diária da solução, até a remoção completa do tecido parenquimatoso. O método foi empregado em 14 fígados cirróticos com bom preenchimento e coloração dos territórios das veias porta e hepáticas, utilizando cores distintas. Isto permite um estudo anatômico desses vasos, capaz de complementar os conhecimentos da histopatologia em trabalhos de pesquisa, e planejar procedimentos terapêuticos como a derivação porto-sistêmica intra-hepática transjugular (TIPS - Transjugular Intrahepatic Postosystemic Shunt).

Comprehensiveness and humanization of nursing care management in the Intensive Care Unit.

PubMed

Medeiros, Adriane Calvetti de; Siqueira, Hedi Crecencia Heckler de; Zamberlan, Claudia; Cecagno, Diana; Nunes, Simone Dos Santos; Thurow, Mara Regina Bergmann

2016-01-01

Identifying the elements that promote comprehensiveness and humanization of nursing care management in the Intensive Care Unit, with an ecosystemic approach. A documentary qualitative study. The method of documentary analysis was used for data analysis. Four pre-established categories were identified - Technical; Organizational; Technological; and Humanizing Dimensions. Data resulted in forming two sub-categories that integrate the humanizing dimension category, namely 'Comprehensiveness in healthcare actions' and 'Integrating processes and promoters of humanization,' bringing forth implications and challenges in forms of managing health work processes, enabling organizational, structural and managerial changes to the provided healthcare. It was considered that all structural elements in managing nursing care with a focus on the needs of users should be in line with public policies and the principles of comprehensiveness and humanization, thus possessing strong potential for transforming health practices. Identificar os elementos capazes de promover a integralidade e a humanização na gestão do cuidado de enfermagem na Unidade de Terapia Intensiva, com enfoque ecossistêmico. Pesquisa documental, de natureza qualitativa. Para a análise dos dados utilizou-se do método da análise documental. SForam identificadas quatro categorias preestabelecidas ‒ Dimensões: Técnica; Organizacional; Tecnológica e Humanizadora. Os dados resultantes das duas subcategorias que integraram a categoria Dimensão Humanizadora, Integralidade nas ações do cuidado e Processos integradores e promotores de humanização, trazem implicações e desafios nos modos de gerir os processos de trabalho em saúde, o que possibilita transformações organizacionais, estruturais e gerenciais na produção do cuidado. Considera-se que na gestão do cuidado de enfermagem todos os elementos estruturantes, com enfoque nas necessidades dos usuários, devem estar em consonância com as políticas públicas e os princípios da integralidade e da humanização e possuir forte potencial para a transformação das práticas em saúde.

Brain dialysis: in vivo metabolism of dopamine and serotonin by monoamine oxidase A but not B in the striatum of unrestrained rats.

PubMed

Kato, T; Dong, B; Ishii, K; Kinemuchi, H

1986-04-01

A dialysis cannula was implanted into rat striatum while the animals were anesthetized, and the area was perfused with Ringer solution while the animals were unanesthetized after at least 3 days following surgery. Concentrations of the metabolites of 3,4-dihydroxyphenylethylamine (DA) and 5-hydroxytryptamine (5-HT) in the perfusate were determined by HPLC with electrochemical detection. Levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perfusate significantly decreased after pargyline administration (50 mg/kg i.p.), which may inhibit not only monoamine oxidase (MAO)-B but also MAO-A in these high doses. The level of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) also decreased after pargyline treatment, although change in the relative level of 5-HIAA was less than that of DOPAC or HVA. To clarify the mechanisms for the metabolism of monoamines in rat striatum, highly specific MAO-A and -B inhibitors were used in the following experiments. Treatment with l-deprenyl (10 mg/kg), a specific inhibitor for MAO-B, did not cause any statistically significant change in DOPAC, HVA, and 5-HIAA levels. No significant change was found in rat striatal homogenates at 2 h after the same treatment with l-deprenyl. In contrast, low-dose treatment (1 mg/kg) with clorgyline, a specific inhibitor for MAO-A, caused a significant decrease in levels of these three metabolites in both the perfusates and tissue homogenates. In addition to the above three metabolites, the level of 3-methoxytyramine, which is an indicator of the amount of DA released, greatly increased after treatment with a low dose (1 mg/kg) of clorgyline.(ABSTRACT TRUNCATED AT 250 WORDS)

The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats.

PubMed

Galaj, Ewa; Manuszak, Monica; Babic, Sandra; Ananthan, Subramaniam; Ranaldi, Robert

2015-11-01

Because the role of dopamine (DA) D3 receptors has been investigated primarily in relation to cocaine-related behaviors little is known of the role of these receptors in heroin seeking. To investigate the effect of the selective DA D3 receptor antagonist, SR 21502, on cue-induced reinstatement of heroin seeking and heroin conditioned place preference (CPP). In experiment 1, rats were trained to self-administer intravenous heroin for 15 days followed by extinction. Following extinction animals were treated with one of several SR 21502 doses (0, 7.5, 10 or 15mg/kg) and a cue-induced reinstatement test was conducted. In experiment 2, animals were conditioned to experience heroin in one compartment of a CPP apparatus and saline in the other. On the test day animals were treated with 0, 3.75, 7.5, 10 or 15mg/kg of SR 21502 and tested for their CPP. The results from experiment 1 showed a significant dose-related reduction in cue-induced reinstatement of active lever pressing in the 7.5 and 10mg groups and an absence of the reinstatement effect in the 15mg group. In experiment 2, animals treated with vehicle or 3.75mg of SR 21502 showed significant heroin place preferences but those treated with the higher doses showed no CPP. Our findings suggest that DA D3 receptors play a significant role in heroin approach behaviors driven by conditioned stimuli. As such, we propose that SR 21502 holds potential as an effective pharmacotherapeutic agent for relapse prevention and should be studied further. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.

PubMed

El-Khuffash, Afif; Jain, Amish; Corcoran, David; Shah, Prakesh S; Hooper, Christopher W; Brown, Naoko; Poole, Stanley D; Shelton, Elaine L; Milne, Ginger L; Reese, Jeff; McNamara, Patrick J

2014-09-01

We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

A Preliminary Investigation of the Effect of Acute Alcohol on Dopamine Transmission as Assessed by [11 C]-(+)-PHNO.

PubMed

Thiruchselvam, Thulasi; Wilson, Alan A; Boileau, Isabelle; Le Foll, Bernard

2017-06-01

Previous positron emission tomography (PET) studies exploring the effect of acute alcohol on dopamine (DA) levels have yielded inconsistent results, with only some studies suggesting increased synaptic DA levels after an alcohol challenge. The D 2 /D 3 agonist radiotracer, [ 11 C]-(+)-propyl-hexahydro-naphtho-oxazin ([ 11 C]-(+)-PHNO), has greater sensitivity to synaptic DA fluctuation than previously used antagonist radiotracers and is in principle more suitable for imaging alcohol-induced changes in DA. Its high affinity for the D 3 receptor also enables measuring changes in D 3 -rich brain areas which have previously been unexplored. The aim of this study was to investigate whether alcohol reduces [ 11 C]-(+)-PHNO binding in the striatum and in D 3 -rich extra-striatal areas. Eight healthy drinkers underwent 2 [ 11 C]-(+)-PHNO PET scans following alcohol and placebo in a randomized, single-blind, crossover design. [ 11 C]-(+)-PHNO binding in the striatum and in the extra-striatal regions were compared between the 2 scans. Acute alcohol administration did not significantly reduce [ 11 C]-(+)-PHNO binding in either the limbic striatum (d = 0.64), associative striatum (d < 0.20), or the sensorimotor striatum (d < 0.15). Similarly, there were no changes in binding in the D 3 -rich areas of the ventral pallidum (d = 0.53), substantia nigra (d < 0.15), or globus pallidus (d < 0.15). However, greater percent change in [ 11 C]-(+)-PHNO binding (ΔBP ND ) between scans was related to lower blood alcohol levels. Using the agonist radiotracer, [ 11 C]-(+)-PHNO, our preliminary findings suggest that alcohol is not associated with robust changes in tracer binding in striatal or extra-striatal regions. However, we found that changes in [ 11 C]-(+)-PHNO binding following alcohol are dependent on blood alcohol levels suggesting that increases in DA may occur at lower stimulating doses. The effect of lower doses of alcohol on DA warrants further investigation in a larger study. Copyright © 2017 by the Research Society on Alcoholism.

Development and validation of a method for measuring depth of understanding in constructivist learning

NASA Astrophysics Data System (ADS)

Guarino, Lucia Falsetti

A method for measuring depth of understanding of students in the middle-level science classroom was developed and validated. A common theme in the literature on constructivism in science education is that constructivist pedagogy, as opposed to objectivist pedagogy, results in a greater depth of understanding. Since few instruments measuring this construct exist at the present time, the development of such a tool to measure this construct was a significant contribution to the current body of assessment technologies in science education. The author's Depth of Understanding Assessment (DUA) evolved from a writing measure originally designed as a history assessment. The study involved 230 eighth grade science students studying a chemical change unit. The main research questions were: (1) What is the relationship between the DUA and each of the following independent variables: recall, application, and questioning modalities as measured by the Cognitive Preference Test; deep, surface, achieving, and deep-achieving approaches as measured by the Learning Process Questionnaire; achievement as measured by the Chemical Change Quiz, and teacher perception of student ability to conceptualize science content? (2) Is there a difference in depth of understanding, as measured by the DUA, between students who are taught by objectivist pedagogy and students who are taught by constructivist pedagogy favoring the constructivist group? (3) Is there a gender difference in depth of understanding as measured by the DUA? (4) Do students who are taught by constructivist pedagogy perceive their learning environment as more constructivist than students who are taught by objectivist pedagogy? Six out of nine hypothesis tests supported the validity of the DUA. The results of the qualitative component of this study which consisted of student interviews substantiated the quantitative results by providing additional information and insights. There was a significant difference in depth of understanding between the two groups favoring the constructivist group, however, since only two teachers and their students participated in the study, the significance of this result is limited. There was a significant gender difference in depth of understanding favoring females. Students in the constructivist group perceived their learning environment to be more constructivist than students in the objectivist group.

Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users.

PubMed

Cruz, Hans G; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M; Dingemanse, Jasper

2014-04-01

Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

A estabilidade dos PAHS em função da energia da radiação interestelar nas faixas UV e raios-X

NASA Astrophysics Data System (ADS)

Pinotti, R.; Costa, R. K.; Boechat-Roberty, H. M.; Lago, A.; Souza, G. B.

2003-08-01

A nebulosa CRL 618, uma proto-nebulosa planetária cuja nuvem molecular espessa envolve uma estrela B0, contém uma grande quantidade de C2H2 e CH4. Estas moléculas são consideradas os tijolos da criação de grandes moléculas carbonadas como os Hidrocarbonetos Policíclicos Aromáticos (PAHs). Esta nebulosa, por estar exposta a intensos campos de UV e Raios-X, é uma região de fotodissociação molecular que propicia a formação de novas moléculas, confirmada pela presença de C4H2 e C6H6 (Benzeno), que é a unidade básica dos PAHs. Atribui-se a esta família de moléculas orgânicas duas propriedades fundamentais, a resistência para sobreviver ao campo de radiação UV interestelar e a geração das bandas de emissão não identificadas (UIR) observadas no infravermelho. No entanto, alguns autores questionam a resistência dos PAHs ao campo de radiação UV interestelar. Empregando a técnica de Espectrometria de Massas por Tempo de Vôo, no modo de coincidência fotoelétron-fotoíon, estudamos a ionização e fragmentação das seguintes moléculas: Benzeno, Benzeno deuterado, Naftaleno, Antraceno e Fenantreno. Utilizamos uma fonte de Hélio monocromática em 21,21 eV (584,5 Å) e a radiação Síncroton do Laboratório Nacional de Luz Síncroton (LNLS) em diferentes energias nas proximidades da borda do C 1s ( 290 eV). Comprovamos a estabilidade dos PAHs sob ação de UV (21,21 eV), onde eles apresentam um baixo nível de fotodissociação, produzindo fragmentos ionizados com rendimento total na ordem de 5 por cento em relação ao íon molecular pai. Entretanto, em altas energias, na faixa de Raios-X, a quebra destas moléculas torna-se mais intensa, com a produção de muitos fragmentos. Como uma das rotas de fragmentação do Naftaleno é [(C10H8) = > (C6H6+) + (C4H2) + (e-)], e como temos as evidências observacionais da existência do C4H2 e C6H6 na nebulosa CRL 618, sugerimos que este ambiente também possui o Naftaleno.

Dopamine D3 Receptors Mediate the Discriminative Stimulus Effects of Quinpirole in Free-Feeding Rats

PubMed Central

Baladi, Michelle G.; Newman, Amy H.

2010-01-01

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine. PMID:19797621

Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats.

PubMed

Baladi, Michelle G; Newman, Amy H; France, Charles P

2010-01-01

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine.

The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists

PubMed Central

Worden, Lila T.; Shahriari, Mona; Farrar, Andrew M.; Sink, Kelly S.; Hockemeyer, Jörg; Müller, Christa E.

2010-01-01

Rationale Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A2A receptors. Objective Adenosine A2A receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. Materials and methods The adenosine A2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure. Results MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses. Conclusions The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A2A receptors on the same population of striatal neurons. PMID:19048234

High Throughput Determinations of Critical Dosing Parameters (IVIVE workshop)

EPA Science Inventory

High throughput toxicokinetics (HTTK) is an approach that allows for rapid estimations of TK for hundreds of environmental chemicals. HTTK-based reverse dosimetry (i.e, reverse toxicokinetics or RTK) is used in order to convert high throughput in vitro toxicity screening (HTS) da...

Characterization of three novel adhesins of Leptospira interrogans.

PubMed

Siqueira, Gabriela H; Atzingen, Marina V; Alves, Ivy J; de Morais, Zenaide M; Vasconcellos, Silvio A; Nascimento, Ana L T O

2013-12-01

We report cloning, expression, purification, and characterization of three predicted leptospiral membrane proteins (LIC11360, LIC11009, and LIC11975). In silico analysis and proteinase K accessibility data suggest that these proteins might be surface exposed. We show that proteins encoded by LIC11360, LIC11009 and LIC11975 genes interact with laminin in a dose-dependent and saturable manner. The proteins are referred to as leptospiral surface adhesions 23, 26, and 36 (Lsa23, Lsa26, and Lsa36), respectively. These proteins also bind plasminogen and generate active plasmin. Attachment of Lsa23 and Lsa36 to fibronectin occurs through the involvement of the 30-kDa and 70-kDa heparin-binding domains of the ligand. Dose-dependent, specific-binding of Lsa23 to the complement regulator C4BP and to a lesser extent, to factor H, suggests that this protein may interfere with the complement cascade pathways. Leptospira spp. may use these interactions as possible mechanisms during the establishment of infection.

Characterization of Three Novel Adhesins of Leptospira interrogans

PubMed Central

Siqueira, Gabriela H.; Atzingen, Marina V.; Alves, Ivy J.; de Morais, Zenaide M.; Vasconcellos, Silvio A.; Nascimento, Ana L. T. O.

2013-01-01

We report cloning, expression, purification, and characterization of three predicted leptospiral membrane proteins (LIC11360, LIC11009, and LIC11975). In silico analysis and proteinase K accessibility data suggest that these proteins might be surface exposed. We show that proteins encoded by LIC11360, LIC11009 and LIC11975 genes interact with laminin in a dose-dependent and saturable manner. The proteins are referred to as leptospiral surface adhesions 23, 26, and 36 (Lsa23, Lsa26, and Lsa36), respectively. These proteins also bind plasminogen and generate active plasmin. Attachment of Lsa23 and Lsa36 to fibronectin occurs through the involvement of the 30-kDa and 70-kDa heparin-binding domains of the ligand. Dose-dependent, specific-binding of Lsa23 to the complement regulator C4BP and to a lesser extent, to factor H, suggests that this protein may interfere with the complement cascade pathways. Leptospira spp. may use these interactions as possible mechanisms during the establishment of infection. PMID:23958908

Polysaccharides from Arctium lappa L.: Chemical structure and biological activity.

PubMed

Carlotto, Juliane; de Souza, Lauro M; Baggio, Cristiane H; Werner, Maria Fernanda de P; Maria-Ferreira, Daniele; Sassaki, Guilherme L; Iacomini, Marcello; Cipriani, Thales R

2016-10-01

The plant Arctium lappa L. is popularly used to relieve symptoms of inflammatory disorders. A crude polysaccharide fraction (SAA) resulting of aqueous extraction of A. lappa leaves showed a dose dependent anti-edematogenic activity on carrageenan-induced paw edema, which persisted for up to 48h. Sequential fractionation by ultrafiltration at 50kDa and 30kDa cut-off membranes yielded three fractions, namely RF50, RF30, and EF30. All these maintained the anti-edematogenic effect, but RF30 showed a more potent action, inhibiting 57% of the paw edema at a dose of 4.9mg/kg. The polysaccharide RF30 contained galacturonic acid, galactose, arabinose, rhamnose, glucose, and mannose in a 7:4:2:1:2:1 ratio and had a Mw of 91,000g/mol. Methylation analysis and NMR spectroscopy indicated that RF30 is mainly constituted by a type I rhamnogalacturonan branched by side chains of types I and II arabinogalactans, and arabinan. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-frequency electrotherapy for female patients with detrusor underactivity due to neuromuscular deficiency.

PubMed

Xu, Dan-Feng; Zhang, Shen; Wang, Cun-Zhou; Li, Jun; Qu, Chuang-Yu; Cui, Xin-Gang; Zhao, Sheng-Jia

2012-08-01

The aim of the study was to assess the efficacy of low-frequency electrotherapy (LFE) for female patients with early-stage detrusor underactivity (DUA) due to neuromuscular deficiency. A total of 102 female patients were divided randomly into four groups: LFE-NC (normal compliance), LFE-LC (low compliance), CON (control)-NC and CON-LC. Patients in the LFE-NC and LFE-LC groups received LFE, and those in the CON-NC and CON-LC groups received conservative treatment. Urodynamic evaluation was performed before and after treatment. After treatment, 82 % of the LFE-NC regained detrusor contractility, whereas only 2 (8 %) of the CON-NC had normal detrusor contraction. None of LFE-LC or CON-LC regained detrusor contractility (p < 0.01). The per cent of LFE-NC who relied on catheterization for bladder emptying decreased by 43 % (p < 0.01). Those in the LFE-LC, CON-NC and CON-LC groups decreased by only 4, 12 or 0 % (p > 0.05). LFE was more effective for DUA patients with normal compliance; these patients benefited from LFE, but DUA patients with low compliance did not.

Pulmonary Impairment and Risk Assessment in a Diacetyl-Exposed Population: Microwave Popcorn Workers.

PubMed

Park, Robert M; Gilbert, Stephen J

2018-06-01

The butter flavoring additive, diacetyl (DA), can cause bronchiolitis obliterans (BO) by inhalation. A risk assessment was performed using data from a microwave popcorn manufacturing plant. Current employees' medical history and pulmonary function tests together with air sampling over a 2.7-year period were used to analyze forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). The exposure responses for declining pulmonary function and for possible early onset of BO were estimated using multiple regression methods. Several exposure metrics were investigated; benchmark dose and excess lifetime risk of impairment were calculated. Forty-six percent of the population had less than 6 months exposure to DA. Percent-of-predicted FEV1 declined with cumulative exposure (0.40 per ppm-yr, P < 10) as did percent FEV1/FVC (0.13 per ppm-yr, P = 0.0004). Lifetime respiratory impairment prevalence of one per thousand resulted from 0.005 ppm DA and one per thousand lifetime incidence of impairment was predicted for 0.002 ppm DA. DA exposures, often exceeding 1 ppm in the past, place workers at high risk of pulmonary impairment.

Transport of nattokinase across the rat intestinal tract.

PubMed

Fujita, M; Hong, K; Ito, Y; Misawa, S; Takeuchi, N; Kariya, K; Nishimuro, S

1995-09-01

Intraduodenal administration of nattokinase (NK) at a dose of 80 mg/kg, resulted in the degradation of fibrinogen in plasma suggesting transport of NK across the intestinal tract in normal rats. The action of NK on the cleavage of fibrinogen in the plasma from blood samples drawn at intervals after intraduodenal administration of the enzyme was investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis with an anti-fibrinogen gamma chain antibody. The 270 kDa fragment carrying antigenic sites for the binding of the anti-fibrinogen gamma chain antibody appeared within 0.5 h and was then degraded gradually to a 105 kDa fragment via a 200 kDa fragment. This suggests that fibrinogen was degraded to a 105 kDa fragment via several intermediates (270 and 200 kDa). In parallel with the degradation process, plasma recalcification times were remarkably prolonged NK was also detected in the plasma from blood samples drawn 3 and 5 h after administration of the enzyme by SDS-PAGE and Western blotting analysis with an anti-NK antibody. The results indicate that NK is absorbed from the rat intestinal tract and that NK cleaves fibrinogen in plasma after intraduodenal administration of the enzyme.

Bioactivity guided isolation of antipsychotic constituents from the leaves of Rauwolfia tetraphylla L.

PubMed

Gupta, Shikha; Khanna, Vinay Kumar; Maurya, Anupam; Bawankule, Dnyaneshwar Umrao; Shukla, Rajendra Kumar; Pal, Anirban; Srivastava, Santosh Kumar

2012-09-01

This study was undertaken to ascertain the antipsychotic properties of Rauwolfia tetraphylla L. leaves and to isolate and characterize the antipsychotic constituents. Among the MeOH extract and some alkaloidal fractions at different pHs, the alkaloidal CHCl(3) fraction at pH-9 (2C) showed the highest antipsychotic activity against dopaminergic (DA-D(2)) and serotonergic (5-HT(2A)) receptors in-vitro and amphetamine induced hyperactive mouse model in-vivo. The activity guided isolation of CHCl(3) fraction (2C) afforded six indole alkaloids: 10-methoxytetrahydroalstonine (1), isoreserpiline (2), an isomeric mixture of 11-demethoxyreserpiline (3) and 10-demethoxyreserpiline (4), α-yohimbine (5) and reserpiline (6). Given orally, alkaloids 3-6 showed significant antipsychotic activity in a dose dependent manner. None of the extract, alkaloidal fractions or alkaloids showed any extra pyramidal symptoms at the tested doses. It was also observed that MeOH extract was behaving similar to other clinically used novel atypical antipsychotics in having 5-HT(2A) occupancy greater than the DA-D(2) receptor at the tested doses. Further toxicity and safety evaluation studies of MeOH extracts of R. tetraphylla leaves at different doses (10, 100, 300 and 2000 mg/kg) on female Swiss albino mice showed that MeOH extract is non toxic. The isolated alkaloids, 3-6 could serve as a promising lead structure for drug development of treating psychotic conditions in human. Copyright © 2012 Elsevier B.V. All rights reserved.

2012 update in the treatment of prolactinomas.

PubMed

Maiter, Dominique; Primeau, Vanessa

2012-04-01

New information has been provided over the last years regarding treatment of prolactinomas and will be reviewed in this update. Medical treatment with a dopamine agonist (DA) remains the cornerstone of therapy and cabergoline is the first choice, due to its high efficacy and good tolerability profile. Prolonged remission after discontinuation of DA may be observed if treatment has been given for at least two years, normal prolactin has been obtained with a low dose and tumoral diameter has been reduced by at least 50%. Although the risk of restrictive cardiac valve disease is low at the standard doses of cabergoline used for the treatment of hyperprolactinaemia, long-term echocardiographic surveillance is however indicated, in particular in resistant patients who need higher doses of cabergoline (2.0 mg/week or more). Neurosurgical treatment of prolactinomas is less effective than medical therapy and recurrence of hyperprolactinaemia is frequent. Besides classical indications such as drug intolerance, resistance or acute complications, new indications have emerged such as young patients with a high likelihood of complete tumour resection and who do not wish to take prolonged medical treatment, or patients who require high doses of cabergoline, in whom surgical debulking may significantly improve postoperative hormonal control. Finally, recent data indicate that cabergoline is safe for the developing foetus and for the mother, and therefore should not be preventively withdrawn in a young woman wishing to become pregnant. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

PubMed

Huang, Mei; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

2015-11-01

Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Teicher, B.A.; Holden, S.A.; Northey, D.

The perfluorochemical emulsion Fluosol-DA plus carbogen breathing has been shown to increase the effectiveness of radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly. The authors hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly. In the present study, the [alpha]/[beta] agonist ephedrine, the Ca[sup 2+] channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested. Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA [+-] carbogen antitumormore » effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus carbogen and the radiation plus Fluosol-DA/carbogen in both emulsion was given rapidly. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and carbogen breathing prior to and during radiation therapy using growth delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses. These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by carbogen breathing and radiation therapy. 45 refs., 4 figs.« less

Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse.

PubMed

Feltenstein, Matthew W; Altar, C Anthony; See, Ronald E

2007-03-01

Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.

Effects of amphetamine on striatal dopamine release, open-field activity, and play in Fischer 344 and Sprague-Dawley rats.

PubMed

Siviy, Stephen M; McDowell, Lana S; Eck, Samantha R; Turano, Alexandra; Akopian, Garnik; Walsh, John P

2015-12-01

Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague-Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague-Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period.

Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain

PubMed Central

Baumann, Michael H.; Clark, Robert D.; Rothman, Richard B.

2008-01-01

(±)-3,4-Methylenedioxymethamphetmine (MDMA, or Ecstasy) is an illicit drug that evokes transporter-mediated release of monoamines, including serotonin (5-HT) and dopamine (DA). Here we monitored the effects of MDMA on neurochemistry and motor activity in rats, as a means to evaluate relationships between 5-HT, DA, and behavior. Male rats undergoing in vivo microdialysis were housed in chambers equipped with photobeams for measurement of ambulation (i.e., forward locomotion) and stereotypy (i.e., head weaving and forepaw treading). Microdialysis probes were placed into the n. accumbens, striatum or prefrontal cortex in separate groups of rats. Dialysate samples were assayed for 5-HT and DA by microbore HPLC-ECD. Rats received two i.v. injections of MDMA, 1 mg/kg followed by 3 mg/kg 60 min later; neurochemical and locomotor parameters were measured concurrently. MDMA produced dose-related elevations in extracellular 5-HT and DA in all regions, with the magnitude of 5-HT release always exceeding that of DA release. MDMA-induced ambulation was positively correlated with dialysate DA levels in all regions (P<0.05-0.0001) and with dialysate 5-HT in striatum and cortex (P<0.001-0.0001). Stereotypy was strongly correlated with dialysate 5-HT in all areas (P<0.001-0.0001) and with dialysate DA in accumbens and striatum (P<0.001-0.0001). These data support previous work and suggest the complex spectrum of behaviors produced by MDMA involves 5-HT and DA in a region- and modality-specific manner. PMID:18403002

Bacillus Calmette-Guerin Vaccine-Mediated Neuroprotection Is Associated With Regulatory T-Cell Induction in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson’s Disease

PubMed Central

Laćan, Goran; Dang, Hoa; Middleton, Blake; Horwitz, Marcus A.; Tian, Jide; Melega, William P.; Kaufman, Daniel L.

2018-01-01

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination’s neuroprotective effects in this model. We found that a dose of 1 × 106 cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases. PMID:23907992

Evidence that central dopamine receptors modulate sympathetic neuronal activity to the adrenal medulla to alter glucoregulatory mechanisms.

PubMed

Arnerić, S P; Chow, S A; Bhatnagar, R K; Webb, R L; Fischer, L J; Long, J P

1984-02-01

Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2 or sectioning the greater splanchnic nerve blocked apomorphine-induced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce hyperglycemia.

Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice.

PubMed

Billes, Sonja K; Cowley, Michael A

2007-04-01

Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.

Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine.

PubMed

Stolyarova, Alexandra; O'Dell, Steve J; Marshall, John F; Izquierdo, Alicia

2014-09-01

Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules. Copyright © 2014 Elsevier B.V. All rights reserved.

Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning.

PubMed

Anastasaki, Corina; Woo, Albert S; Messiaen, Ludwine M; Gutmann, David H

2015-06-15

Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Quantitative determination of decursin, decursinol angelate, and decursinol in mouse plasma and tumor tissue using liquid-liquid extraction and HPLC.

PubMed

Li, Li; Zhang, Jinhui; Shaik, Ahmad Ali; Zhang, Yong; Wang, Lei; Xing, Chengguo; Kim, Sung-Hoon; Lü, Junxuan

2012-02-01

The pyranocoumarin compound decursin and its isomer decursinol angelate (DA) are the major hydrophobic phytochemicals in the root of Angelica gigas Nakai (AGN, Korean Angelica), a major traditional medicinal herb. The ethanol extract of AGN and especially the purified decursin and DA have been shown to exhibit antitumor activities by our collaborative team and others. Although decursinol has been identified as a major hydrolysis metabolite of decursin and DA in vivo in previous pharmacokinetic studies with mouse and rat, other recently published results sharply disputed this conclusion. In this study, we set up a practical method for the concurrent analysis of decursin, DA, and decursinol in mouse plasma and tumor tissues by liquid-liquid extraction and HPLC-UV and applied the method to several animal experiments. Plasma or tumor homogenate was extracted directly with ethyl acetate. The extraction efficiency for decursin/DA (quantitated together) and decursinol was between 82-95 % in both mouse plasma and tumor homogenate. The lower limit of quantitation (LLOQ) was approximately 0.25 µg/mL for decursin/DA and 0.2 µg/mL for decursinol in mouse plasma. In a pilot pharmacokinetic study, male C57BL/6 mice were given a single dose of 4.8 mg decursin/DA mixture (~240 mg/kg) per mouse either by oral gavage or intraperitoneal injection. Maximum plasma concentrations for decursin/DA and decursinol were 11.2 and 79.7 µg/mL, respectively, when decursin/DA was administered via intraperitoneal injection, and 0.54 and 14.9 µg/mL via oral gavage. Decursin/DA and decursinol contents in the tumor tissues from nude mouse xenografts correlated very well with those in plasma. Overall, our results confirm the conclusion that the majority of decursin/DA hydrolyze to decursinol in rodent models with a tiny fraction remaining as the intact compounds administered. © Georg Thieme Verlag KG Stuttgart · New York.

The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

PubMed

Maia, Tiago V; Conceição, Vasco A

2017-09-15

Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Infusions of ascorbic acid into the medial preoptic area facilitate appetitive sexual behavior in the female rat.

PubMed

Graham, M Dean; Pfaus, James G

2013-10-02

Ascorbic acid (AA), also known as Vitamin C, enhances dopamine (DA) transmission in mesolimbic and nigrostriatal terminals and augments DA-mediated behaviors. It is not yet known whether AA has a similar influence in other DA terminals, in particular terminals of the incertohypothalamic system that modulate the function of the medial preoptic area (mPOA). In female rats, DA in the mPOA plays a critical role in the generation of appetitive sexual responses, notably solicitations, hops, and darts, and we have shown previously that the role of DA in this region on female sexual behavior changes depending on the hormonal profile of the female. Since AA has often been used as a vehicle control in the examination of rat sexual behavior, the present study examined the effect of infusions of AA to the mPOA of sexual experienced ovariectomized rats under two hormonal conditions: partially-primed with estradiol benzoate (EB) alone or fully-primed with EB and progesterone. Relative to saline baselines, females under both hormonal conditions displayed a significant increase in appetitive sexual behaviors following infusions of AA. No difference in lordosis behavior was observed following AA infusions relative to saline baselines. We suggest that the mechanism by which AA infusions to the mPOA increase appetitive sexual behaviors in female rats may be through dose-dependent DA receptor interactions, possibly through both presynaptic release mechanisms and postsynaptic DA D1-related messenger systems. © 2013.

Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting.

PubMed

Hsu, Ching-Yun; Yang, Shih-Chun; Sung, Calvin T; Weng, Yi-Han; Fang, Jia-You

2017-01-01

Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5-125 μg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions.

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

PubMed Central

Sable, Helen J. K.; Monaikul, Supida; Poon, Emily; Eubig, Paul A.; Schantz, Susan L.

2010-01-01

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest developmental PCB exposure can alter the interoceptive cues of psychostimulants. PMID:20933596

The development of communication skills and the teacher's performance in the nursing student's perspective.

PubMed

Oliveira, Karime Rodrigues Emilio de; Braga, Eliana Mara

2016-06-01

To understand experiences in the development of communication skills and the teacher's role in this teaching-learning process under the perspective of undergraduate nursing students by considering two types of curriculum organization. Descriptive study with a qualitative approach conducted in two public schools located in São Paulo state, Brazil. Data were collected by means of self-completed forms from 81 students in the second and fourth years of the undergraduate program. Results were analyzed in light of Content Analysis. Results showed that the development of such skills is related to: students' individual characteristics, patients' characteristics, those of the health-disease process, the health-care team's profile and the theoretical knowledge acquired on communication in health-care provision and nursing. The teacher's role was perceived as one that supports and encourages interactions with patients and health-care teams by teaching and providing orientation about interpersonal communication. Students identify and value the importance of their teachers' performance in the development and acquisition of communication skills. Additionally, students who experience active teaching-learning methodologies acknowledge the teacher as essential to provide opportunities for students to express their knowledge and thoughts. Compreender, sob a ótica de graduandos de enfermagem, as experiências no desenvolvimento de habilidades comunicativas e a atuação do professor neste processo de ensino-aprendizagem, considerando dois tipos de organização curricular. Pesquisa descritiva com abordagem qualitativa, realizada em duas instituições de ensino públicas, situadas no interior do estado de São Paulo, Brasil. A coleta dos dados foi realizada pelo autopreenchimento de formulário por 81 alunos de segundo e quartos anos da graduação. Os resultados foram analisados à luz da Análise de Conteúdo. Revelaram que o desenvolvimento desta habilidade está relacionado à: características individuais dos alunos, dos pacientes, do processo saúde-doença, perfil da equipe e dos conhecimentos teóricos sobre comunicação em saúde e em enfermagem. O papel do professor foi percebido apoiando e incentivando as interações com pacientes e equipes de saúde e ensinando e orientando sobre comunicação interpessoal. Os alunos identificam e valorizam a importância da atuação de seus professores no desenvolvimento e aquisição de habilidades comunicativas. Além disso, os estudantes que vivenciaram as metodologias ativas de ensino-aprendizagem reconhecem o docente essencial para oportunizar a expressão de conhecimentos e pensamentos dos alunos.

Is there any link between accreditation programs and the models of organizational excellence?

PubMed

Berssaneti, Fernando Tobal; Saut, Ana Maria; Barakat, Májida Farid; Calarge, Felipe Araujo

2016-01-01

To evaluate whether accredited health organizations perform better management practices than non-accredited ones. The study was developed in two stages: a literature review, and a study of multiple cases in 12 healthcare organizations in the state of São Paulo, Brazil. It surveyed articles comparing hospital accreditation with the EFQM (European Foundation for Quality Management) model of excellence in management. According to the pertinent literature, the accreditation model and the EFQM model are convergent and supplementary in some aspects. With 99% confidence, one can say that there is evidence that accredited organizations scored better in the evaluation based on the EFQM model in comparison to non-accredited organizations. This result was also confirmed in the comparison of results between the categories Facilitators and Results in the EFQM model. There is convergence between the accreditation model and the EFQM excellence model, suggesting that accreditation helps the healthcare sector to implement the best management practices already used by other business sectors. Avaliar se as organizações de saúde acreditadas possuem melhores práticas de gestão do que as não acreditadas. A pesquisa foi dividida em duas etapas: revisão da literatura e estudo de casos múltiplos com 12 organizações de saúde, localizadas no estado de São Paulo ‒ Brasil. Foram pesquisados artigos que comparavam a acreditação hospitalar com o modelo de excelência em gestão da EFQM (European Foundation for Quality Management), sendo que a literatura pertinente considera que o modelo de acreditação e o modelo da EFQM são convergentes e, ao mesmo tempo, complementares em determinados aspectos. Com 99% de confiança, pode-se afirmar que há evidência de que as organizações com acreditação obtiveram uma pontuação maior na avaliação baseada no modelo EFQM comparativamente às organizações não acreditadas. Este resultado também se confirmou na comparação dos resultados das categorias Facilitadores e Resultados do modelo EFQM. Há uma convergência entre o modelo de acreditação e o modelo de excelência da EFQM, sugerindo que a acreditação contribui para o setor de saúde implementar as melhores práticas de gestão já difundidas em outros setores de negócio.

Effects of auriculotherapy on labour pain: a randomized clinical trial.

PubMed

Mafetoni, Reginaldo Roque; Shimo, Antonieta Keiko Kakuda

2016-01-01

Assessing the effects of auriculotherapy in pain control and its outcomes on the duration of labour. This is a randomized, controlled, double-blind trial with preliminary data. Thirty pregnant women with gestational age ≥ 37 weeks, cervical dilatation ≥ 4 cm and two or more contractions in 10 minutes were selected and randomly divided into three groups: auriculotherapy, placebo and control. Auriculotherapy was applied using crystal beads on four strategic points. No statistical significance was found between the groups with regard to pain; however, the women from the auriculotherapy group had lower intensity and less perception of pain at 30, 60 and 120 minutes of treatment. The average duration of labour was shorter in the auriculotherapy group (248.7 versus placebo 414.8 versus control 296.3 minutes); caesarean section rates were higher in the placebo group (50%) and the same in the other groups (10%). Mothers who received auriculotherapy presented a tendency for greater pain control and shorter labour duration; however, caesarean section rates in this group were similar to the control group. This trial precedes a larger study in progress. Registration of Brazilian Clinical Trials: RBR-47hhbj. Avaliar os efeitos da auriculoterapia no controle da dor e seus desfechos na duração do trabalho de parto. Trata-se de um ensaio controlado, randomizado e duplo-cego, com dados preliminares. Foram selecionadas 30 parturientes com idade gestacional ≥ 37 semanas, dilatação cervical ≥ 4 cm e duas ou mais contrações em 10 minutos, divididas aleatoriamente em três grupos: auriculoterapia, placebo ou controle. A auriculoterapia foi aplicada com microesferas de cristais em quatro pontos estratégicos. Não houve significância estatística entre os grupos com relação à dor; no entanto, as mulheres do grupo de auriculoterapia, apresentaram menor intensidade e menor percepção da dor aos 30, 60 e 120 minutos do tratamento. A média de duração do trabalho de parto foi menor no grupo de auriculoterapia (248,7 versus placebo 414,8 versus controle 296,3 minutos); a taxa de cesárea foi maior no grupo placebo (50%) e igual nos outros (10%). As parturientes que receberam auriculoterapia apresentaram tendência a um maior controle da dor e menor duração do trabalho de parto, porém a taxa de cesárea neste grupo foi semelhante à do grupo controle. Este ensaio precede um estudo maior, em andamento. Registro Brasileiro de Ensaio Clínico: RBR-47hhbj.

S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose

PubMed Central

Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M.; Li, Hong; Shibata, Masayuki; Azzam, Edouard I.

2015-01-01

The covalent addition of nitric oxide (NO•) onto cysteine thiols, or S-nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S-nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S-nitrosylation by the “biotin switch” assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137Cs γ rays. Analysis of modulated S-nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S-nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S-nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S-nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric oxide synthase signaling pathway was differentially modulated by low- and high-dose γ-irradiation. PMID:26317069

S-Nitrosylation in Organs of Mice Exposed to Low or High Doses of γ-Rays: The Modulating Effect of Iodine Contrast Agent at a Low Radiation Dose.

PubMed

Nicolas, Fadia; Wu, Changgong; Bukhari, Salwa; de Toledo, Sonia M; Li, Hong; Shibata, Masayuki; Azzam, Edouard I

2015-04-28

The covalent addition of nitric oxide (NO • ) onto cysteine thiols, or S -nitrosylation, modulates the activity of key signaling proteins. The dysregulation of normal S -nitrosylation contributes to degenerative conditions and to cancer. To gain insight into the biochemical changes induced by low-dose ionizing radiation, we determined global S -nitrosylation by the "biotin switch" assay coupled with mass spectrometry analyses in organs of C57BL/6J mice exposed to acute 0.1 Gy of 137 Cs γ-rays. The dose of radiation was delivered to the whole body in the presence or absence of iopamidol, an iodinated contrast agent used during radiological examinations. To investigate whether similar or distinct nitrosylation patterns are induced following high-dose irradiation, mice were exposed in parallel to acute 4 Gy of 137 Cs γ rays. Analysis of modulated S -nitrosothiols (SNO-proteins) in freshly-harvested organs of animals sacrificed 13 days after irradiation revealed radiation dose- and contrast agent-dependent changes. The major results were as follows: (i) iopamidol alone had significant effects on S -nitrosylation in brain, lung and liver; (ii) relative to the control, exposure to 0.1 Gy without iopamidol resulted in statistically-significant SNO changes in proteins that differ in molecular weight in liver, lung, brain and blood plasma; (iii) iopamidol enhanced the decrease in S -nitrosylation induced by 0.1 Gy in brain; (iv) whereas a decrease in S -nitrosylation occurred at 0.1 Gy for proteins of ~50 kDa in brain and for proteins of ~37 kDa in liver, an increase was detected at 4 Gy in both organs; (v) mass spectrometry analyses of nitrosylated proteins in brain revealed differential modulation of SNO proteins (e.g., sodium/potassium-transporting ATPase subunit beta-1; beta tubulins; ADP-ribosylation factor 5) by low- and high-dose irradiation; and (vi) ingenuity pathway analysis identified major signaling networks to be modulated, in particular the neuronal nitric oxide synthase signaling pathway was differentially modulated by low- and high-dose γ-irradiation.

Effects of methylphenidate during emotional processing in amphetamine users: preliminary findings.

PubMed

Bottelier, M A; Schouw, M L J; de Ruiter, M B; Ruhe, H G; Lindauer, R J L; Reneman, L

2015-12-01

D-amphetamine (dAMPH) and methylphenidate (MPH) are stimulants used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Preclinical studies have shown that in healthy animals, dAMPH induces dopamine (DA) dysfunction, as evidenced for instance by loss of DA levels and its transporters. It has also been suggested that DA plays an important role in emotional processing, and that altered DA-ergic intervention may modulate amygdala function. To explore the role of the DA system in emotional processing we examined emotional processing using functional magnetic resonance imaging (fMRI) in eight male recreational users of dAMPH and eight male healthy controls. We compared brain activation between both groups during an emotional face-processing task with and without an oral MPH challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1½ hours after receiving an oral dose of 35 mg MPH. A significant Valence*Group interaction (p = .037) indicated amygdala hyperreactivity to fearful facial expressions in dAMPH users that was robust against adjustment for age (p = .015). Furthermore, duration of amphetamine use in years was positively correlated with amygdala reactivity in dAMPH users (r = .76; p = .029). These exploratory findings are in line with previous findings suggesting that DA plays a role in emotional processing.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

PubMed Central

El-Khuffash, Afif; Jain, Amish; Corcoran, David; Shah, Prakesh S.; Hooper, Christopher W.; Brown, Naoko; Poole, Stanley D.; Shelton, Elaine L.; Milne, Ginger L.; Reese, Jeff

2015-01-01

BACKGROUND We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). METHODS Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2–6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. RESULTS Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 μmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). CONCLUSION The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro. PMID:24941212

Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase.

PubMed

Block, M L; Wu, X; Pei, Z; Li, G; Wang, T; Qin, L; Wilson, B; Yang, J; Hong, J S; Veronesi, B

2004-10-01

The contributing role of environmental factors to the development of Parkinson's disease has become increasingly evident. We report that mesencephalic neuron-glia cultures treated with diesel exhaust particles (DEP; 0.22 microM) (5-50 microg/ml) resulted in a dose-dependent decrease in dopaminergic (DA) neurons, as determined by DA-uptake assay and tyrosine-hydroxylase immunocytochemistry (ICC). The selective toxicity of DEP for DA neurons was demonstrated by the lack of DEP effect on both GABA uptake and Neu-N immunoreactive cell number. The critical role of microglia was demonstrated by the failure of neuron-enriched cultures to exhibit DEP-induced DA neurotoxicity, where DEP-induced DA neuron death was reinstated with the addition of microglia to neuron-enriched cultures. OX-42 ICC staining of DEP treated neuron-glia cultures revealed changes in microglia morphology indicative of activation. Intracellular reactive oxygen species and superoxide were produced from enriched-microglia cultures in response to DEP. Neuron-glia cultures from NADPH oxidase deficient (PHOX-/-) mice were insensitive to DEP neurotoxicity when compared with control mice (PHOX+/+). Cytochalasin D inhibited DEP-induced superoxide production in enriched-microglia cultures, implying that DEP must be phagocytized by microglia to produce superoxide. Together, these in vitro data indicate that DEP selectively damages DA neurons through the phagocytic activation of microglial NADPH oxidase and consequent oxidative insult.

Cytotoxicity and expression of c-fos, HSP70, and GADD45/153 proteins in human liver carcinoma (HepG2) cells exposed to dinitrotoluenes.

PubMed

Glass, Konsuela Y; Newsome, Cecilia R; Tchounwou, Paul B

2005-08-01

Dinitrotoluenes (DNTs) are byproducts of the explosive trinitrotoluene (TNT), and exist as a mixture of 2 to 6 isomers, with 2,4-DNT and 2,6-DNT being the most significant. The main route of human exposure at ammunition facilities is inhalation. The primary targets of DNTs toxicity are the hematopoietic system, cardiovascular system, nervous system and reproductive system. In factory workers, exposure to DNTs has been linked to many adverse health effects, including: cyanosis, vertigo, headache, metallic taste, dyspnea, weakness and lassitude, loss of appetite, nausea, and vomiting. Other symptoms including pain or parasthesia in extremities, abdominal discomfort, tremors, paralysis, chest pain, and unconsciousness have been documented. An association between DNTs exposure and increased risk of hepatocellular carcinomas and subcutaneous tumors in rats, as well as renal tumors in mice, has been established. This research was therefore designed targeting the liver to assess the cellular and molecular responses of human liver carcinoma cells following exposure to 2,4-DNT and 2,6-DNT. Cytotoxicity was evaluated using the MTT assay. Upon 48 hrs of exposure, LC50 values of 245 +/- 14.724 microg/mL, and 300 +/- 5.92 microg/mL were recorded for 2,6-DNT and 2,4-DNT respectively, indicating that both DNTs are moderately toxic, and 2,6-DNT is slightly more toxic to HepG2 cells than 2,4-DNT. A dose response relationship was recorded with respect to the cytotoxicity of both DNTs. Western blot analysis resulted in a significant expression (p<0.05) of the 70-kDa heat shock protein in 2,6-DNT-treated cells compared to the control cells and at the 200 microg/mL dose for 2,4-DNT. A statistically significant expression in c-fos was also observed at the 200 and 250 microg/mL treatment level for 2,4- and 2,6-DNT, respectively. However, no statistically significant expression of this protooncogene-related protein was observed at the doses of 0, 100, or 300 microg/mL or within the dose range of 0-200 microg/mL for 2,6-DNT. The 45-kDa growth arrest and damage protein was significantly expressed at the dose range of 200 - 250 microg/mL for 2,6-DNT and at the dose range of 200 - 400 microg/mL for 2,4-DNT. Expression of 153-kDa growth arrest and DNA damage protein was significant at the 100, 200, and 250 microg/mL doses for 2,6-DNT and at the 200 microg/mL dose for 2,4-DNT. Overall, these results indicate the potential of DNTs to induce cytotoxic, proteotoxic (HSP70), and genotoxic (GADD45/153) effects, as well as oxidative stress and pro-inflammatory reactions (c-fos).

Biological and molecular properties of yellow venom of the Amazonian coral snake Micrurus surinamensis.

PubMed

Oliveira, Fabiana da Rocha; Noronha, Maria das Dores Nogueira; Lozano, Jorge Luis Lopez

2017-01-01

The coral snake Micrurus surinamensis, which is widely distributed throughout Amazonia, has a neurotoxic venom. It is important to characterize the biological and molecular properties of this venom in order to develop effective antitoxins. Toxins from the venom of M. surinamensis were analyzed by two-dimensional polyacrylamide gel electrophoresis and their neurotoxic effects in vivo were evaluated. Most proteins in the venom had masses < 14kDa, low phospholipase A2 activity, and no proteolytic activity. The toxins inhibited the coagulation cascade. The venom had neurotoxic effects in mice, with a median lethal dose upon intravenous administration of 700 µg/kg. Immunogenic studies revealed abundant cross-reactivity of antielapidic serum with 14kDa toxins and limited cross-reactivity with toxins < 10kDa. These results indicate that antielapidic serum against M. surinamensis venom has weak potency (0.35mg/ml) in mice.

Ulex europaeus I lectin induces activation of matrix-metalloproteinase-2 in endothelial cells.

PubMed

Gomez, D E; Yoshiji, H; Kim, J C; Thorgeirsson, U P

1995-11-02

In this report, we show that the lectin Ulex europaeus agglutinin I (UEA I), which binds to alpha-linked fucose residues on the surface of endothelial cells, mediates activation of the 72-kDa matrix metalloproteinase-2 (MMP-2). A dose-dependent increase in the active 62-kDa form of MMP-2 was observed in conditioned medium from monkey aortic endothelial cells (MAEC) following incubation with concentrations of UEA I ranging from 2 to 100 micrograms/ml. The increase in the 62-kDa MMP-2 gelatinolytic activity was not reflected by a rise in MMP-2 gene expression. The UEA I-mediated activation of MMP-2 was blocked by L-fucose, which competes with UEA I for binding to alpha-fucose. These findings may suggest that a similar in vivo mechanism exists, whereby adhesive interactions between tumor cell lectins and endothelial cells can mediate MMP-2 activation.

The metabolism of 14C-cyclohexylamine in mice and two strains of rat.

PubMed

Roberts, A; Renwick, A G

1985-06-01

After administration of 14C-cyclohexylamine (35-500 mg/kg) to male mice and rats, 80% of the dose of 14C was excreted in the urine, mostly within the first 24 h after dosing. In Wistar rats, 7-9% of the 14C in the 0-24 h urine was present as cis-4-aminocyclohexanol, with a similar amount as the corresponding 3-isomers. In the DA rat, only 1-2% of the 14C, and in mouse less than 1% of the 14C was present in the urine as aminocyclohexanols; unchanged cyclohexylamine accounted for about 95% of the activity. The extent of metabolism was not affected by either dose or route of administration. The species differences in metabolism may be implicated in the differences in toxicity during chronic high-dose administration.

Conscious Sedation Procedures Using Intravenous Midazolam for Dental Care in Patients with Different Cognitive Profiles: A Prospective Study of Effectiveness and Safety

PubMed Central

Collado, Valérie; Faulks, Denise; Nicolas, Emmanuel; Hennequin, Martine

2013-01-01

The use of midazolam for dental care in patients with intellectual disability is poorly documented. This study aimed to evaluate the effectiveness and safety of conscious sedation procedures using intravenous midazolam in adults and children with intellectual disability (ID) compared to dentally anxious patients (DA). Ninety-eight patients with ID and 44 patients with DA programmed for intravenous midazolam participated in the study over 187 and 133 sessions, respectively. Evaluation criteria were success of dental treatment, cooperation level (modified Venham scale), and occurrence of adverse effects. The mean intravenous dose administered was 8.8±4.9 mg and 9.8±4.1 mg in ID and DA sessions respectively (t-test, NS). 50% N2O/O2 was administered during cannulation in 51% of ID sessions and 61% of DA sessions (NS, Fisher exact test). Oral or rectal midazolam premedication was administered for cannulation in 31% of ID sessions and 3% of DA sessions (p<0,001, Fisher exact test). Dental treatment was successful in 9 out of 10 sessions for both groups. Minor adverse effects occurred in 16.6% and 6.8% of ID and DA sessions respectively (p = 0.01, Fisher exact test). Patients with ID were more often very disturbed during cannulation (25.4% ID vs. 3.9% DA sessions) and were less often relaxed after induction (58.9% ID vs. 90.3% DA) and during dental treatment (39.5% ID vs. 59.7% DA) (p<0.001, Fisher exact test) than patients with DA. When midazolam sedation was repeated, cooperation improved for both groups. Conscious sedation procedures using intravenous midazolam, with or without premedication and/or inhalation sedation (50% N2O/O2), were shown to be safe and effective in patients with intellectual disability when administered by dentists. PMID:23940729

A 32 kDa viral attachment protein of lymphocystis disease virus (LCDV) specifically interacts with a 27.8 kDa cellular receptor from flounder (Paralichthys olivaceus).

PubMed

Zhong, Ying; Fei, Chenjie; Tang, Xiaoqian; Zhan, Wenbin; Sheng, Xiuzhen

2017-06-01

The 27.8 kDa protein in flounder gill (FG) cells was previously proved to be a receptor specific for lymphocystis disease virus (LCDV) entry and infection. In this paper, a 32 kDa viral attachment protein (VAP) of LCDV specifically binding to the 27.8 kDa receptor (27.8R) was found by far-Western blotting coupled with monoclonal antibodies (MAbs) against 27.8R. The 32 kDa protein was confirmed to be encoded by the open reading frame (ORF) 038 gene in LCDV-C, and predicted to contain a putative transmembrane region, multiple N-myristoylation and glycosylation sites and phosphorylation motifs. The expression plasmid of pET-32a-ORF038 was constructed and the recombinant VAP (rVAP) was obtained. Rabbit polyclonal antibodies against the rVAP were prepared and could recognize the rVAP and 32 kDa protein in LCDV. Immunogold electron microscopy showed that the 32 kDa protein was located on the surface of LCDV particles. Immunofluorescence assay demonstrated that the rVAP could bind to the 27.8R on the cell membrane of the FG monolayer and the anti-27.8R MAbs could block the rVAP binding. Pre-incubation of the rVAP with FG cells before LCDV infection, or pre-incubation of LCDV with the antibodies against the rVAP, could significantly decrease the LCDV copy numbers (P<0.05) and delay the emergence of cytopathic effects in FG cells in a dose-dependent manner. These results indicated for the first time that the 32 kDa protein functioned as an attachment protein for the initial attachment and entry of LCDV, and the interaction of the 32 kDa VAP with the 27.8R-initiated LCDV infection.

Impact of respiratory therapy in vital capacity and functionality of patients undergoing abdominal surgery.

PubMed

Fernandes, Shanlley Cristina da Silva; Santos, Rafaella Souza Dos; Giovanetti, Erica Albanez; Taniguchi, Corinne; Silva, Cilene Saghabi de Medeiros; Eid, Raquel Afonso Caserta; Timenetsky, Karina Tavares; Carnieli-Cazati, Denise

2016-01-01

To evaluate the vital capacity after two chest therapy techniques in patients undergoing abdominal surgical. A prospective randomized study carried out with patients admitted to the Intensive Care Unit after abdominal surgery. We checked vital capacity, muscular strength using the Medical Research Council scale, and functionality with the Functional Independence Measure the first time the patient was breathing spontaneously (D1), and also upon discharge from the Intensive Care Unit (Ddis). Between D1 and Ddis, respiratory therapy was carried out according to the randomized group. We included 38 patients, 20 randomized to Positive Intermittent Pressure Group and 18 to Volumetric Incentive Spirometer Group. There was no significant gain related to vital capacity of D1 and Ddis of Positive Intermittent Pressure Group (mean 1,410mL±547.2 versus 1,809mL±692.3; p=0.979), as in the Volumetric Incentive Spirometer Group (1,408.3mL±419.1 versus 1,838.8mL±621.3; p=0.889). We observed a significant improvement in vital capacity in D1 (p<0.001) and Ddis (p<0.001) and in the Functional Independence Measure (p<0.001) after respiratory therapy. The vital capacity improvement was not associated with gain of muscle strength. Chest therapy, with positive pressure and volumetric incentive spirometer, was effective in improving vital capacity of patients submitted to abdominal surgery. Avaliar a capacidade vital comparando duas técnicas de fisioterapia respiratória em pacientes submetidos à cirurgia abdominal. Estudo prospectivo e randomizado realizado com pacientes admitidos em Unidade de Terapia Intensiva após cirurgia abdominal. Verificamos a capacidade vital, a força muscular por meio da escala do Medical Research Council e funcionalidade pela Medida de Independência Funcional no primeiro momento em que o paciente encontrava-se em respiração espontânea (D1) e na alta da Unidade de Terapia Intensiva (Dalta). Entre D1 e Dalta, foi realizada a fisioterapia respiratória, conforme o grupo randomizado. Foram incluídos 38 pacientes, sendo 20 randomizados para Grupo Pressão Positiva Intermitente e 18 para o Grupo Incentivador Inspiratório a Volume. A capacidade vital entre o D1 e Dalta do Grupo Pressão Positiva Intermitente não teve ganho significativo (média de 1.410mL±547,2 versus 1.809mL±692,3; p=0,979), assim como no Grupo Incentivador Inspiratório a Volume (1.408,3mL±419,1 versus 1.838,8mL±621,3; p=0,889). Houve melhora significativa da capacidade vital no D1 (p<0,001) e na Dalta (p<0,001) e da Medida de Independência Funcional (p<0,001) após a fisioterapia respiratória. A melhora da capacidade vital não apresentou relação com o ganho da força muscular. A fisioterapia respiratória, por meio de pressão positiva ou de incentivador inspiratório a volume, foi eficaz na melhora da capacidade vital em pacientes submetidos à cirurgia abdominal.

Effect of repeated oral therapeutic doses of methylphenidate on food intake and growth rate in rats.

PubMed

Alam, Nausheen; Najam, Rahila

2015-01-01

Central nervous system stimulants are known to produce anorexia. Previous data suggest that methylphenidate can have variable effects on caloric intake and growth rate. A dose-response study was performed to monitor caloric intake, liquid intake and growth rate in rats following repeated administration of human oral therapeutic doses 2 mg/kg/day, 5mg/kg/day and 8mg/kg/day of methylphenidate. We found that food intake and water intake, increased in all weeks and at all doses used in the study. Growth rate increased more at higher dose (8mg/kg/day) and at low dose (2mg/kg/day) of methylphenidate in 1(st) and 2(nd) week whereas more decreased by the above doses in 3(rd) week, suggesting that food stimulation leads to initial increase in growth rate but long term administration of methylphenidate attenuate growth rate that is not due to modulation of appetite but may be due to anxiety and increased activity produce by stimulants. A possible role of DA, 5HT receptors in modulation of appetite and anxiety is discussed.

Ultrasound-guided intrapleural positioning of pleural catheters: influence on immediate lung expansion and pleurodesis in patients with recurrent malignant pleural effusion.

PubMed

Araujo, Pedro Henrique Xavier Nabuco de; Terra, Ricardo Mingarini; Santos, Thiago da Silva; Chate, Rodrigo Caruso; Paiva, Antonio Fernando Lins de; Pêgo-Fernandes, Paulo Manuel

2017-01-01

To evaluate the role of intrapleural positioning of a pleural catheter in early lung expansion and pleurodesis success in patients with recurrent malignant pleural effusion (RMPE). This was a retrospective study nested into a larger prospective cohort study including patients with RMPE recruited from a tertiary university teaching hospital between June of 2009 and September of 2014. The patients underwent pleural catheter insertion followed by bedside pleurodesis. Chest CT scans were performed twice: immediately before pleurodesis (iCT) and 30 days after pleurodesis (CT30). Catheter positioning was categorized based on iCT scans as posterolateral, anterior, fissural, and subpulmonary. We used the pleural volume on iCT scans to estimate early lung expansion and the difference between the pleural volumes on CT30 and iCT scans to evaluate radiological success of pleurodesis. Clinical pleurodesis success was defined as no need for any other pleural procedure. Of the 131 eligible patients from the original study, 85 were included in this nested study (64 women; mean age: 60.74 years). Catheter tip positioning was subpulmonary in 35 patients (41%), anterior in 23 (27%), posterolateral in 17 (20%), and fissural in 10 (12%). No significant differences were found among the groups regarding early lung expansion (median residual pleural cavity = 377 mL; interquartile range: 171-722 mL; p = 0.645), radiological success of pleurodesis (median volume = 33 mL; interquartile range: -225 to 257 mL; p = 0.923), and clinical success of pleurodesis (85.8%; p = 0.676). Our results suggest that the position of the tip of the pleural catheter influences neither early lung expansion nor bedside pleurodesis success in patients with RMPE. Avaliar o papel do posicionamento intrapleural do cateter pleural na expansão pulmonar precoce e no sucesso da pleurodese em pacientes com derrame pleural maligno recorrente (DPMR). Trata-se de um estudo retrospectivo aninhado em um estudo prospectivo de coorte maior com pacientes com DPMR recrutados em um hospital-escola universitário terciário entre junho de 2009 e setembro de 2014. Os pacientes foram submetidos a inserção de cateter pleural e, em seguida, pleurodese à beira do leito. A TC de tórax foi realizada duas vezes: imediatamente antes da pleurodese (TCi) e 30 dias após a pleurodese (TC30). Com base na TCi, a posição do cateter foi classificada em posterolateral, anterior, fissural e subpulmonar. Usamos o volume pleural na TCi para estimar a expansão pulmonar precoce e a diferença entre os volumes pleurais na TC30 e na TCi a fim de avaliar o sucesso radiológico da pleurodese. Considerou-se que a pleurodese teve êxito clínico quando não foi necessário realizar nenhum outro procedimento pleural. Dos 131 pacientes elegíveis do estudo original, 85 foram incluídos neste estudo aninhado (64 mulheres; média de idade: 60,74 anos). A posição da ponta do cateter foi subpulmonar em 35 pacientes (41%), anterior em 23 (27%), posterolateral em 17 (20%) e fissural em 10 (12%). Não houve diferenças significativas entre os grupos quanto à expansão pulmonar precoce (mediana da cavidade pleural residual = 377 ml; intervalo interquartil: 171-722 ml; p = 0,645), sucesso radiológico da pleurodese (mediana do volume = 33 ml; intervalo interquartil: -225 a 257 ml; p = 0,923) e sucesso clínico da pleurodese (85,8%; p = 0,676). Nossos resultados sugerem que a posição da ponta do cateter pleural não influencia nem a expansão pulmonar precoce nem o sucesso da pleurodese à beira do leito em pacientes com DPMR.

Role of D2 dopamine receptors of the ventral pallidum in inhibitory avoidance learning.

PubMed

Lénárd, László; Ollmann, Tamás; László, Kristóf; Kovács, Anita; Gálosi, Rita; Kállai, Veronika; Attila, Tóth; Kertes, Erika; Zagoracz, Olga; Karádi, Zoltán; Péczely, László

2017-03-15

In our present experiments, the role of D2 dopamine (DA) receptors of the ventral pallidum (VP) was investigated in one trial step-through inhibitory avoidance paradigm. Animals were shocked 3 times in the conditioning trial, with 0.5mA current for 1s. Subsequently bilateral microinjection of the D2 DA receptor agonist quinpirole was administered into the VP in three doses (0.1μg, 1.0μg or 5.0μg in 0.4μl saline). We also applied the D2 DA receptor antagonist sulpiride (0.4μg in 0.4μl saline) alone or 15min prior to the agonist treatment to elucidate whether the agonist effect was specific for the D2 DA receptors. Control animals received saline. In a supplementary experiment, it was also investigated whether application of the same conditioning method leads to the formation of short-term memory in the experimental animals. In the experiment with the D2 DA receptor agonist, only the 0.1μg quinpirole increased significantly the step-through latency during the test trials: retention was significant compared to the controls even 2 weeks after conditioning. The D2 DA receptor antagonist sulpiride pretreatment proved that the effect was due to the agonist induced activation of the D2 DA receptors of the VP. The supplementary experiment demonstrated that short-term memory is formed after conditioning in the experimental animals, supporting that the agonist enhanced memory consolidation in the first two experiments. Our results show that the activation of the D2 DA receptors in the VP facilitates memory consolidation as well as memory-retention in inhibitory avoidance paradigm. Copyright © 2017 Elsevier B.V. All rights reserved.

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

PubMed

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

Running wheel exercise before a binge regimen of methamphetamine does not protect against striatal dopaminergic damage.

PubMed

O'dell, Steven J; Marshall, John F

2014-09-01

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" dosing regimen produces long-lasting damage to forebrain dopaminergic nerve terminals as measured by decreases in tissue dopamine (DA) content and levels of the plasmalemmal DA transporter (DAT). However, the midbrain cell bodies from which the DA terminals arise survive, and previous reports show that striatal DA markers return to control levels by 12 months post-mAMPH, suggesting long-term repair or regrowth of damaged DA terminals. We previously showed that when rats engaged in voluntary aerobic exercise for 3 weeks before and 3 weeks after a binge regimen of mAMPH, exercise significantly ameliorated mAMPH-induced decreases in striatal DAT. However, these data left unresolved the question of whether exercise protected against the initial neurotoxicity from the mAMPH binge or accelerated the repair of the damaged DA terminals. The present experiments were designed to test whether exercise protects against the mAMPH-induced injury. Adult male Sprague-Dawley rats were allowed to run in wheels for 3 weeks before an acute binge regimen of mAMPH or saline, then placed into nonwheel cages for an additional week before autoradiographic determination of striatal DAT binding. The autoradiographic findings showed that prior exercise provided no protection against mAMPH-induced damage to striatal DA terminals. These results, together with analyses from our previous experiments, suggest that voluntary exercise may accelerate the repair of mAMPH-damaged DA terminals and that voluntary exercise may be useful as therapeutic adjunct in the treatment mAMPH addicts. © 2014 Wiley Periodicals, Inc.

Self-expanding stent effects on radiation dosimetry in esophageal cancer.

PubMed

Francis, Samual R; Anker, Christopher J; Wang, Brian; Williams, Greg V; Cox, Kristen; Adler, Douglas G; Shrieve, Dennis C; Salter, Bill J

2013-07-08

It is the purpose of this study to evaluate how self-expanding stents (SESs) affect esophageal cancer radiation planning target volumes (PTVs) and dose delivered to surrounding organs at risk (OARs). Ten patients were evaluated, for whom a SES was placed before radiation. A computed tomography (CT) scan obtained before stent placement was fused to the post-stent CT simulation scan. Three methods were used to represent pre-stent PTVs: 1) image fusion (IF), 2) volume approximation (VA), and 3) diameter approximation (DA). PTVs and OARs were contoured per RTOG 1010 protocol using Eclipse Treatment Planning software. Post-stent dosimetry for each patient was compared to approximated pre-stent dosimetry. For each of the three pre-stent approximations (IF, VA, and DA), the mean lung and liver doses and the estimated percentages of lung volumes receiving 5 Gy, 10 Gy, 20 Gy, and 30 Gy, and heart volumes receiving 40 Gy were significantly lower (p-values < 0.02) than those estimated in the post-stent treatment plans. The lung V5, lung V10, and heart V40 constraints were achieved more often using our pre-stent approximations. Esophageal SES placement increases the dose delivered to the lungs, heart, and liver. This may have clinical importance, especially when the dose-volume constraints are near the recommended thresholds, as was the case for lung V5, lung V10, and heart V40. While stents have established benefits for treating patients with significant dysphagia, physicians considering stent placement and radiation therapy must realize the effects stents can have on the dosimetry.

Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting

PubMed Central

Sung, Calvin T; Weng, Yi-Han; Fang, Jia-You

2017-01-01

Pathogens usually invade hair follicles when skin infection occurs. The accumulated bacteria in follicles are difficult to eradicate. The present study aimed to assess the cutaneous and follicular delivery of chloramphenicol (Cm)-loaded liposomes and the antibacterial activity of these liposomes against methicillin-resistant Staphylococcus aureus (MRSA). Skin permeation was conducted by in vitro Franz diffusion cell. The anti-MRSA potential was checked using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), a well diffusion test, and intracellular MRSA killing. The classic, dimyristoylphosphatidylcholine (DMPC), and deoxycholic acid (DA) liposomes had a vesicle size of 98, 132, and 239 nm, respectively. The incorporation of DMPC or DA into the liposomes increased the bilayer fluidity. The malleable vesicles containing DMPC and DA showed increased follicular Cm uptake over the control solution by 1.5- and 2-fold, respectively. The MIC and MBC of DA liposomes loaded with Cm were 62.5 and 62.5–125 μg/mL, comparable to free Cm. An inhibition zone about 2-fold higher was achieved by DA liposomes as compared to the free control at a Cm dose of 0.5 mg/mL. DA liposomes also augmented antibacterial activity on keratinocyte-infected MRSA. The deformable liposomes had good biocompatibility against keratinocytes and neutrophils (viability >80%). In vivo administration demonstrated that DA liposomes caused negligible toxicity on the skin, based on physiological examination and histology. These data suggest the potential application of malleable liposomes for follicular targeting and the treatment of MRSA-infected dermatologic conditions. PMID:29184410

Effects of copper and tributyltin on stress protein abundance in the rotifer Brachionus plicatilis.

PubMed

Cochrane, B J; Irby, R B; Snell, T W

1991-01-01

1. Exposure of the rotifer Brachionus plicatilis to elevated temperature resulted in the synthesis of a number of proteins, including a prominent one of 58,000 Da (SP58). 2. This protein is immunologically crossreactive with the 65,000 Da heat shock protein of the moth Heliothis virescens, which is a member of a highly conserved family of mitochondrial proteins. 3. Exposure of rotifers to sublethal doses of CuSO4 leads to a 4-5-fold increase in abundance of SP58, with maximum increase occurring at a dose that is approximately 5% of the LC50 for that compound. 4. A similar response was seen with tributyl tin (TBT). Kinetics of induction were sigmoidal, with induction occurring in the range of 20-30 micrograms/l. 5. No response was observed when rotifers were exposed to aluminum chloride, mercury chloride, pentachlorophenol, sodium arsenite, sodium azide, sodium dodecyl sulfate, or zinc chloride. 6. These results indicate that changes in stress protein abundance may prove useful as a biomarker of exposure to particular toxicants.

Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines.

PubMed

Roz, Netta; Rehavi, Moshe

2004-10-22

Hyperforin, a phloroglucinol derivative found in Hypericum perforatum (St. John's wort) extracts has antidepressant properties in depressed patients. Hyperforin has a unique pharmacological profile and it inhibits uptake of biogenic monoamines as well as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by hyperforin is related to its ability to dissipate the pH gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In the present study we demonstrate that hyperforin induces dose-dependent efflux of preloaded [3H]5HT and [3H]DA from rat brain slices. Moreover, we show that hyperforin attenuates depolarization- dependent release of monoamines, while increasing monoamine release by amphetamine or fenfluramine. It is also demonstrated that preincubation of brain slices with reserpine is associated with dose- dependent blunting of efflux due to hyperforin. Our data indicate that hyperforin-induced efflux of [3H]5HT and [3H]DA reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines. Copyright 2004 Elsevier Inc.

Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys.

PubMed

Czoty, Paul W

2015-08-01

Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self-administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3-4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). Monkeys self-administered cocaine (0.0-1.0mg/kg/injection, i.v.) under a 300-s fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: 1h, 5 days/week with daily intake equaling 2.0g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0-1.0g/kg. i.v.) prior to cocaine self-administration sessions (n=4). In five of six monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self-administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in two of three monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparative neurobiological effects of ibogaine and MK-801 in rats.

PubMed

Baumann, M H; Rothman, R B; Ali, S F

2000-05-01

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

Fear of falling in older adults living at home: associated factors.

PubMed

Vitorino, Luciano Magalhães; Teixeira, Carla Araujo Bastos; Boas, Eliandra Laís Vilas; Pereira, Rúbia Lopes; Santos, Naiana Oliveira Dos; Rozendo, Célia Alves

2017-04-10

To identify the factors associated with the fear of falling in the older adultliving at home. Cross-sectional study with probabilistic sampling of older adultenrolled in two Family Health Strategies (FHS). The fear of falling was measured by the Brazilian version of the Falls Efficacy Scale-International and by a household questionnairethat contained the explanatory variables. Multiple Linear Regression using the stepwise selection technique and the Generalized Linear Models were used in the statistical analyses. A total of170 older adultsparticipated in the research, 85 from each FHS. The majority (57.1%) aged between 60 and 69; 67.6% were female; 46.1% fell once in the last year. The majority of the older adults(66.5%) had highfear of falling. In the final multiple linear regression model, it was identified that a higher number of previous falls, female gender, older age, and worse health self-assessment explained 37% of the fear of falling among the older adult. The findings reinforce the need to assess the fear of falling among the older adultliving at home, in conjunction with the development and use ofstrategies based on modifiable factors by professionalsto reduce falls and improve health status, which may contribute to the reduction of the fear of falling among the older adult. Identificar os fatores associados ao medo de cair em idosos residentes no domicílio. Estudo transversal com amostragem probabilística de idosos cadastrados em duas Estratégias Saúde da Família (ESF). O medo de cair foi avaliado pela versão brasileira da escala Falls Efficacy Scale International e por um inquérito domiciliar que continha as variáveis explicativas.A Regressão Linear Múltipla por meio da técnica stepwise selectione osModelos Lineares Generalizados foram utilizados nas análises estatísticas. Participaram da pesquisa170 idosos, 85 de cada ESF. A maioria (57,1%) tinha entre 60 e 69 anos de idade; 67,6% eram do sexo feminino; 46,1% tiveram queda no último ano. A maioria dos idosos (66,5%) tinha elevado medo de cair. No modelo final de regressão multivariada, identificou-se que maior número de quedas anteriores, sexo feminino, idade mais avançada, e pior autoavaliação de saúde explicaram 37% do medo de cair entre os idosos. Os achados reforçam a necessidade da avaliação do medo de cair entre os idosos que residem no próprio domicílio, assim como o desenvolvimento e a utilização de estratégias pelos profissionais voltadas para os fatores modificáveis,de modo a reduzir as quedas e melhorar o estado de saúde, o que pode contribuir para a diminuição do medo de cair entre os idosos.

Molecular Simulation of Receptor Occupancy and Tumor Penetration of an Antibody and Smaller Scaffolds: Application to Molecular Imaging.

PubMed

Orcutt, Kelly D; Adams, Gregory P; Wu, Anna M; Silva, Matthew D; Harwell, Catey; Hoppin, Jack; Matsumura, Manabu; Kotsuma, Masakatsu; Greenberg, Jonathan; Scott, Andrew M; Beckman, Robert A

2017-10-01

Competitive radiolabeled antibody imaging can determine the unlabeled intact antibody dose that fully blocks target binding but may be confounded by heterogeneous tumor penetration. We evaluated the hypothesis that smaller radiolabeled constructs can be used to more accurately evaluate tumor expressed receptors. The Krogh cylinder distributed model, including bivalent binding and variable intervessel distances, simulated distribution of smaller constructs in the presence of increasing doses of labeled antibody forms. Smaller constructs <25 kDa accessed binding sites more uniformly at large distances from blood vessels compared with larger constructs and intact antibody. These observations were consistent for different affinity and internalization characteristics of constructs. As predicted, a higher dose of unlabeled intact antibody was required to block binding to these distant receptor sites. Small radiolabeled constructs provide more accurate information on total receptor expression in tumors and reveal the need for higher antibody doses for target receptor blockade.

18. Evenamide, a Putative Antipsychotic, Targets Abnormal Electrical Activity and Glutamatergic Abnormalities to Improve Psychotic Symptoms in Patients With Schizophrenia: Results From a Phase II, Placebo-Controlled Trial

PubMed Central

Anand, Ravi; Hartman, Richard; Graham, Stephen; Forrest, Emma; Faravelli, Laura

2017-01-01

Abstract Background: Increasing evidence implicates hippocampal hyperactivity and glutamatergic (Glu) dysfunction in the dysregulation of excitatory and inhibitory circuits leading to positive/negative symptoms and cognitive deficits associated with schizophrenia (SCZ). Existing antipsychotic drugs that target dopaminergic/serotoninergic (DA/5-HT) transmission are associated with a large proportion of patients experiencing inadequate therapeutic benefit. Evenamide, a new, highly selective, voltage-gated Na+ channel antagonist, reduces hyperexcitability, inhibits Glu release, and shows antipsychotic efficacy in multiple animal models of psychiatric disease in monotherapy and as an add-on to 1st and 2nd generation antipsychotics. Addition of evenamide to marketed antipsychotics would lead to reduction of hippocampal hyperactivity and Glu dysfunction, with modulation of mesolimbic and mesocortical DA/5-HT activity, thus providing unique benefits. Methods: This double-blind, 28-day, placebo-controlled, Phase 2 study evaluated safety, tolerability, and preliminary evidence of efficacy of evenamide as an add-on to a stable dose of risperidone or aripiprazole in SCZ outpatients. Selected patients (CGI-Severity of mild to moderately severe; PANSS total score <80) received placebo or evenamide (15–25 mg bid). Dose escalation from 15–20 to 25 mg bid was done weekly in an inpatient setting, based on tolerability. These doses are associated with plasma levels that overlap exposures (>20 ng/ml) measured at effective doses in animal models. Evaluations of vital signs, ECGs, extra-pyramidal symptom (EPS), and laboratory tests were performed weekly, and plasma levels of evenamide were measured at each dose level to determine PK–PD relationships. Preliminary evidence of efficacy was assessed by changes from baseline on the PANSS total score, CGI-Severity and Change, and the Strauss-Carpenter Level of Functioning scale. Results: Ninety patients were randomized at 5 centers (United States-2; India-3). Most patients tolerated evenamide, based on an absence of severe side-effects, as well as the high proportion of patients able to achieve and maintain the highest dose level. There are no reports of EPS, sedation, weight gain, cardiac changes, or sexual dysfunction. Conclusion: Despite the lack of interactions with DA/5-HT systems, evenamide improves positive/negative symptoms in preclinical models of psychiatric diseases, independent of the stimulus used to produce the perturbation. The combination of evenamide as an add-on to marketed antipsychotics in patients showing inadequate response would combine reduction of aberrant electrical activity and Glu transmission, with blockade of 5HT2/D2 receptors, thus producing a novel therapeutic option. Results from the Phase II trial will be presented.

Avian pathogenic Escherichia coli bind fibronectin and laminin.

PubMed

Ramírez, Rosa María; Almanza, Yolanda; González, Rafael; García, Santos; Heredia, Norma

2009-04-01

Avian colisepticemia frequently occurs after respiratory tract damage, the primary site for infection allows bacteria to encounter an exposed basement membrane, where laminin and fibronectin are important components. We investigated the ability of an isolate of avian pathogenic Escherichia coli to bind fibronectin and laminin. Using Far-western dot blot analysis, we demonstrated the ability of this microorganism to bind basement membrane proteins fibronectin and laminin. Results from an ELISA-based approach indicate that the binding to these membrane proteins was bacterial-dose dependent. Furthermore, two specific E. coli polypeptides, of 32 kDa and 130 kDa, reacted with laminin and fibronectin, respectively. Further evaluation of these potential bacterial adhesins may provide insights into the pathogenesis of colibacillosis.

Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study.

PubMed

Mattos, Beatriz Piva E; Scolari, Fernando Luís; Torres, Marco Antonio Rodrigues; Simon, Laura; Freitas, Valéria Centeno de; Giugliani, Roberto; Matte, Úrsula

2016-09-01

Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations. Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families. Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals. In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation. Mutações em genes do sarcômero são encontradas em 60-70% dos indivíduos com formas familiares de cardiomiopatia hipertrófica. (CMH). Entretanto, essa estimativa refere-se a populações de países do hemisfério norte. O perfil genético-molecular da CMH foi tema de poucos estudos no Brasil, particularmente na região sul do país. Realizar a pesquisa de mutações dos genes sarcoméricos MYH7, MYBPC3 e TNNT2 numa coorte de CMH estabelecida no extremo sul do Brasil, assim como avaliar as associações genótipo-fenótipo. Sequenciamento direto do DNA de todas as regiões codificantes dos três genes sarcoméricos foi realizada em 43 indivíduos consecutivos de dez famílias não-relacionadas. Mutações para CMH foram encontradas em 25 (58%) indivíduos de sete (70%) das dez famílias estudadas, sendo 14 (56%) deles fenótipo-positivos. Todas as mutações eram missense, quatro (66%) no gene MYH7 e duas (33%) no gene MYBPC3. Não foram encontradas mutações no gene TNNT2. Mutações em MYH7 foram identificadas em 20 (47%) indivíduos de seis (60%) famílias. Duas delas não haviam sido previamente relatadas. Mutações de MYBPC3 foram detectadas em sete (16%) membros de duas (20%) famílias. Dois (5%) indivíduos apresentaram dupla heterozigose com mutações em ambos os genes. As mutações acometeram distintos domínios das proteínas codificadas e produziram expressão fenotípica variável. História familiar de CMH foi identificada em todos os indivíduos genótipo-positivos. Nessa primeira análise genético-molecular da CMH realizada no sul do Brasil, foram encontradas mutações nos genes sarcoméricos MYH7 e MYBPC3 em 58% dos indivíduos. Doença relacionada ao gene MYH7 foi identificada na maioria dos casos com mutação.

Novel materials based on chitosan, its derivatives and cellulose fibres

NASA Astrophysics Data System (ADS)

Fernandes, Susana Cristina de Matos

O presente trabalho tem como principal objectivo o desenvolvimento de novos materiais baseados em quitosano, seus derivados e celulose, na forma de nanofibras ou de papel. Em primeiro lugar procedeu-se a purificacao das amostras comerciais de quitosano e a sua caracterizacao exaustiva em termos morfologicos e fisicoquimicos. Devido a valores contraditorios encontrados na literatura relativamente a energia de superficie do quitosano, e tendo em conta a sua utilizacao como precursor de modificacoes quimicas e a sua aplicacao em misturas com outros materiais, realizou-se tambem um estudo sistematico da determinacao da energia de superficie do quitosano, da quitina e seus respectivos homologos monomericos, por medicao de ângulos de contacto Em todas as amostras comerciais destes polimeros identificaram-se impurezas nao polares que estao associadas a erros na determinacao da componente polar da energia de superficie. Apos a remocao destas impurezas, o valor da energia total de superficie (gs), e em particular da sua componente polar, aumentou consideravelmente. Depois de purificadas e caracterizadas, algumas das amostras de quitosano foram entao usadas na preparacao de filmes nanocompositos, nomeadamente dois quitosanos com diferentes graus de polimerizacao, correspondentes derivados soluveis em agua (cloreto de N-(3-(N,N,N-trimetilamonio)-2- hidroxipropilo) de quitosano) e nanofibras de celulose como reforco (celulose nanofibrilada (NFC) e celulose bacteriana (BC). Estes filmes transparentes foram preparados atraves de um processo simples e com conotacao 'verde' pela dispersao homogenea de diferentes teores de NFC (ate 60%) e BC (ate 40%) nas solucoes de quitosano (1.5% w/v) seguida da evaporacao do solvente. Os filmes obtidos foram depois caracterizados por diversas tecnicas, tais como SEM, AFM, difraccao de raio-X, TGA, DMA, ensaios de traccao e espectroscopia no visivel. Estes filmes sao altamente transparentes e apresentam melhores propriedades mecânicas e maior estabilidade termica do que os correspondentes filmes sem reforco. Outra abordagem deste trabalho envolveu o revestimento de folhas de papel de E. globulus com quitosano e dois derivados, um derivado fluorescente e um derivado soluvel em agua, numa maquina de revestimentos ('maquina de colagem') a escala piloto. Este estudo envolveu inicialmente a deposicao de 1 a 5 camadas do derivado de quitosano fluorescente sobre as folhas de papel de forma a estudar a sua distribuicao nas folhas em termos de espalhamento e penetracao, atraves de medicoes de reflectância e luminescencia. Os resultados mostraram que, por um lado, a distribuicao do quitosano na superficie era homogenea e que, por outro lado, a sua penetracao atraves dos poros do papel cessou apos tres deposicoes. Depois da terceira camada verificou-se a formacao de um filme continuo de quitosano sobre a superficie do papel. Estes resultados mostram que este derivado de quitosano fluorescente pode ser utilizado como marcador na optimizacao e compreensao de mecanismos de deposicao de quitosano em papel e outros substratos. Depois de conhecida a distribuicao do quitosano nas folhas de papel, estudou-se o efeito do revestimento de quitosano e do seu derivado soluvel em agua nas propriedades finais do papel. As propriedades morfologicas, mecânicas, superficiais, opticas, assim como a permeabilidade ao ar e ao vapor de agua, a aptidao a impressao e o envelhecimento do papel, foram exaustivamente avaliadas. De uma forma geral, os revestimentos com quitosano e com o seu derivado soluvel em agua tiveram um impacto positivo nas propriedades finais do papel, que se mostrou ser dependente do numero de camadas depositadas. Os resultados tambem mostraram que os papeis revestidos com o derivado soluvel em agua apresentaram melhores propriedades opticas, aptidao a impressao e melhores resultados em relacao ao envelhecimento do que os papeis revestidos com quitosano. Assim, o uso de derivados de quitosano soluveis em agua em processos de revestimento de papel representa uma estrategia bastante interessante e sustentavel para o desenvolvimento de novos materiais funcionais ou na melhoria das propriedades finais dos papeis. Por fim, tendo como objectivo valorizar os residuos e fraccoes menos nobres da quitina e do quitosano provenientes da industria transformadora, estes polimeros foram convertidos em poliois viscosos atraves de uma reaccao simples de oxipropilacao. Este processo tem tambem conotacao "verde" uma vez que nao requer solvente, nao origina subprodutos e nao exige nenhuma operacao especifica (separacao, purificacao, etc) para isolar o produto da reaccao. As amostras de quitina e quitosano foram pre-activadas com KOH e depois modificadas com um excesso de oxido de propileno (PO) num reactor apropriado. Em todos os casos, o produto da reaccao foi um liquido viscoso composto por quitina ou quitosano oxipropilados e homopolimero de PO. Estas duas fraccoes foram separadas e caracterizadas.

Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition.

PubMed

Stocchi, F; Vacca, L; Grassini, P; De Pandis, M F; Battaglia, G; Cattaneo, C; Fariello, R G

2006-10-10

In an open pilot study, doses of safinamide (100, 150, and 200 mg once a day, higher than previously tested) were administered to 13 parkinsonian patients along with a stable dose of dopamine (DA) agonist, causing a significant progressive improvement in motor performance as evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III over an 8-week period (4.2 points; P < 0.001). In association with levodopa, the same doses of safinamide in another group of patients (N = 11) induced a significant decrease in motor fluctuations (UPDRS part IV, 2.1 points; P < 0.001), accompanied by a dose-proportional increase of the levodopa AUC, up to 77% from baseline. Because MAO-B was fully inhibited (95%) at all doses tested, we suggest that these biochemical and symptomatic dose-dependent effects must be related to additional mechanisms of action, such as inhibition of glutamate release, increased dopamine release, or inhibition of dopamine re-uptake. These hypotheses are under investigation and will pursue confirmation in controlled clinical trials.

Analysis of astronomy knowledge of the students in the Federal Institute Sao Paulo

NASA Astrophysics Data System (ADS)

Moraes, A. C.; Voelzke, M. R.

2014-08-01

Este trabalho é parte integrante da pesquisa de mestrado acadêmico em ensino de ciências. Nele, busca-se apresentar os resultados da pesquisa realizada entre os 106 alunos do curso superior de tecnologia em automação industrial do Instituto Federal de Educação, Ciência e Tecnologia de São Paulo campus Cubatão, divididos em cinco turmas, duas no período matutino e três no período noturno. A análise dos resultados deste pré questionárioconstatou a falta de conhecimento básico dos discentes, sobre assuntos relacionados à astronomia, o que pode ser atribuído ao ineficiente processo de aprendizado pelo qual eles passaram tanto no ensino médio como no ensino fundamental, em escolas municipais, estaduais e particulares onde estudaram. No ensino de astronomia, têm-se diagnosticado constantemente diversas dificuldades conceituais tanto por parte de alunos como de professores de todas as áreas e níveis de ensino e poucos de fato a compreendem (ALBRECHT; VOELZKE, 2010). Demonstra-se as duas etapas concluídas do trabalho. A primeira etapa indica a análise dos conhecimentos prévios sobre conceitos astronômicos, através do questionário com 25 perguntas. A fim de corrigir as falhas constatadas, experimentalmente ministrou-se, externo ao conteúdo programático, um curso básico em astronomia, com diferentes estratégias de ensino, tais como, utilização de aulas expositivas dialogadas, recursos audiovisuais e palestras, para corrigir as dificuldades diagnosticadas. Essas estratégias de ensino se comprovaram adequadas às necessidades dos alunos e os conceitos foram finalmente compreendidos. Ao término do curso, completado o interstício de 120 dias, para caracterizar que houve a aprendizagem significativa, realizou-se uma nova pesquisa, quando, exatamente os mesmos 106 alunos responderam as mesmas 25 questões aplicadas na primeira etapa. Constata-se na segunda etapa, após análise, que em todas as questões, houve maior compreensão dos assuntos abordados e os alunos obtiveram uma melhora significativa no aprendizado dos conceitos relacionados à astronomia. Nota-se que a astronomia está presente e é elemento importante dos parâmetros curriculares nacionais e que há muito interesse por parte dos alunos com relação ao tema. Diante dos resultados obtidos no pós-curso, pode-se afirmar que o curso básico em astronomia, realizado na própria escola, mas externo ao conteúdo programático, proporcionou uma integração entre os alunos, estreitando os laços de amizade e do conhecimento entre eles não importando a turma ou o período pois a dificuldade inicial foi vencida por todos, com muita dedicação e comprometimento entre todos; hoje estes alunos podem seguramente continuar estudando estes conceitos de astronomia. ALBRECHT, E.; VOELZKE, M. R.Teaching of Astronomy and scientific literacy. Journal of Science Education, v. 11, n. 1, p.35-38, 2010.

Fall and its association with the frailty syndrome in the elderly: systematic review with meta-analysis.

PubMed

Fhon, Jack Roberto Silva; Rodrigues, Rosalina Aparecida Partezani; Neira, Wilmer Fuentes; Huayta, Violeta Magdalena Rojas; Robazzi, Maria Lucia do Carmo Cruz

2016-01-01

To analyze the prevalence of falls and frailty syndrome and the association between these two syndromes in the elderly population. Systematic review, without restriction of dates, in English, Portuguese and Spanish languages, in the databases PubMed, CINAHL, LILACS and in the SciElo virtual library. The association between both variables was extracted from the studies (Odds Ratio and 95% Confidence Intervals). The review included 19 studies published between 2001 and 2015. The prevalence of falls in the frail elderly population was between 6.7% and 44%; in the pre-frail, between 10.0% and 52.0%, and in the non-frail, between 7.6% and 90.4%. The association between both variables presented a value of OR 1.80 (95% CI 1.51-2.13). There is evidence that falls are associated to the frailty in the elderly. Other factors may influence this association, such as age, sex, data collection instrument of the studies, place where they live and the process of senescence. Analisar a prevalência de quedas e da síndrome da fragilidade e a associação entre essas duas síndromes na população idosa. Revisão sistemática, sem restrição de datas, nos idiomas inglês, português e espanhol, nas bases de dados PubMed, CINAHL, LILACS e na biblioteca virtual SciElo. A associação entre ambas as variáveis foi extraída dos próprios artigos (Odds Ratio e os Intervalos de Confiança de 95%). Foram incluídos na revisão 19 artigos publicados entre 2001 e 2015. A prevalência de queda no idoso frágil esteve entre 6,7% e 44%; nos pré-frágeis, entre 10,0% e 52,0%, e nos não frágeis, entre 7,6% e 90,4%. A associação entre ambas as variáveis apresentou o valor de OR 1,80 (IC 95% 1,51-2,13). Há evidências de que a queda está associada à fragilidade do idoso. Outros fatores podem influenciar essa associação, como idade, sexo, instrumento de coleta de dados dos estudos, local onde vive e o próprio processo de senescência.

Induction of HSP70 promotes DeltaF508 CFTR trafficking.

PubMed

Choo-Kang, L R; Zeitlin, P L

2001-07-01

The DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) is a temperature-sensitive trafficking mutant that is detected as an immature 160-kDa form (band B) in gel electrophoresis. The goal of this study was to test the hypothesis that HSP70, a member of the 70-kDa heat shock protein family, promotes DeltaF508 CFTR processing to the mature 180-kDa form (band C). Both pharmacological and genetic techniques were used to induce HSP70. IB3-1 cells were treated with sodium 4-phenylbutyrate (4PBA) to promote maturation of DeltaF508 CFTR to band C. A dose-dependent increase in band C and total cellular HSP70 was observed. Under these conditions, HSP70-CFTR complexes were increased and 70-kDa heat shock cognate protein-CFTR complexes were decreased. Increased DeltaF508 CFTR maturation was also seen after transfection with an HSP70 expression plasmid and exposure to glutamine, an inducer of HSP70. With immunofluorescence techniques, the increased appearance of CFTR band C correlated with CFTR distribution beyond the perinuclear regions. These data suggest that induction of HSP70 promotes DeltaF508 CFTR maturation and trafficking.

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy.

PubMed

Xie, Jennifer Y; Qu, Chaoling; Patwardhan, Amol; Ossipov, Michael H; Navratilova, Edita; Becerra, Lino; Borsook, David; Porreca, Frank

2014-08-01

Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Potentiation by choline of basal and electrically evoked acetylcholine release, as studied using a novel device which both stimulates and perfuses rat corpus striatum

NASA Technical Reports Server (NTRS)

Farber, S. A.; Kischka, U.; Marshall, D. L.; Wurtman, R. J.

1993-01-01

We examined the release of acetylcholine (ACh) and dopamine (DA) using a novel probe through which striatal neurons could be both superfused and stimulated electrically in both anesthetized and freely moving awake animals. Optimal stimulation parameters for eliciting ACh release from cholinergic neurons differed from those required for eliciting DA release from dopaminergic terminals: at 0.6 ms pulse duration, 20 Hz and 200 microA, ACh release increased to 357 +/- 30% (P < 0.01) of baseline and was blocked by the addition of tetrodotoxin (TTX). Pulse durations of 2.0 ms or greater were required to increase DA release. Unlike ACh release, DA release showed no frequency dependence above 5 Hz. The maximal evoked releases of ACh and DA were 556 +/- 94% (P < 0.01) and 254 +/- 38% (P < 0.05) of baseline, respectively. Peripheral administration of choline (Ch) chloride (30-120 mg/kg) to anesthetized animals caused dose-related (r = 0.994, P < 0.01) increases in ACh release; basal release rose from 117 +/- 7% to 141 +/- 5% of initial baseline levels (P < 0.05) and electrically evoked ACh release rose from 386 +/- 38% to 600 +/- 34% (P < 0.01) in rats given 120 mg/kg. However, Ch failed to affect basal or evoked DA release although neostigmine (10 microM) significantly elevated basal DA release (from 36.7 fmol/10 min to 71.5 fmol/10 min; P < 0.05). In awake animals, Ch (120 mg/kg) also elevated both basal (from 106 +/- 7% to 154 +/- 17%; P < 0.05) and electrically evoked (from 146 +/- 13 to 262 +/- 16%; P < 0.01) ACh release.(ABSTRACT TRUNCATED AT 250 WORDS).

Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent.

PubMed

Sutera, Flavia Maria; Giannola, Libero Italo; Murgia, Denise; De Caro, Viviana

2017-12-01

The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) - a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules. Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool. DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter. Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Humoral and cell-mediated immune responses elicited by poly (DL-lactide) adjuvanted filarial antigen molecules.

PubMed

Saini, Vinay; Verma, Atul Kumar; Kushwaha, Vikas; Joseph, Sujith Kurian; Murthy, P Kalpna; Kohli, Dharmveer

2014-05-01

In our recent studies, Brugia malayi molecules have shown interesting immune-stimulating and immune-suppressive properties. Among these, F6 a pro-inflammatory (54-68 kDa) SDS-PAGE resolved fraction of the parasite when administered with Freund's complete/incomplete adjuvant in animals, elicited both Th1 and Th2 type immune responses and protects the host from filarial parasite. The present study was aimed at developing biodegradable microspheres for filarial antigenic protein molecules and to investigate the immunoadjuvanticity of microspheres (Ms)-loaded F6 molecules. Poly-lactide microspheres (DL-PLA-Ms) were prepared using double emulsification and solvent evaporation method; and studied their size, shape, antigen adsorption efficiency, in-process stability, and antigen release profiles. F6 and B. malayi adult worm (BmA: ∼ 17 to 180 kDa) protein molecules adsorbed on the Ms were administered in a single shot into Swiss mice, subcutaneously, and investigated their immunoadjuvant effect and compared with one/two doses-schedule of plain F6/BmA. Immunization with F6/BmA-loaded DL-PLA-Ms resulted in upregulation of cellular proliferation, IFN- γ, TNF-α and NO release from host's cells stimulated with F6/BmA or LPS/Con A, IgG, IgG1 and IgG2a levels. These responses were well comparable with the responses produced by two doses of plain BmA/F6. In conclusion, a single dose of DL-PLA-Ms-F6 induced predominantly Th1 immune responses and well comparable with two doses of plain F6. This is the first ever report on potential of DL-PLA-Ms as adjuvant for filarial immunogen.

Realistic dosimetry for studies on biological responses to X-rays and γ-rays

PubMed Central

Shahmohammadi Beni, Mehrdad; Krstic, Dragana; Nikezic, Dragoslav

2017-01-01

ABSTRACT A calibration coefficient R (= DA/DE) for photons was employed to characterize the photon dose in radiobiological experiments, where DA was the actual dose delivered to cells and DE was the dose recorded by an ionization chamber. R was determined using the Monte Carlo N-Particle version 5 (MCNP-5) code. Photons with (i) discrete energies, and (ii) continuous-energy distributions under different beam conditioning were considered. The four studied monoenergetic photons had energies E = 0.01, 0.1, 1 and 2 MeV. Photons with E = 0.01 MeV gave R values significantly different from unity, while those with E > 0.1 MeV gave R ≈ 1. Moreover, R decreased monotonically with increasing thickness of water medium above the cells for E = 0.01, 1 or 2 MeV due to energy loss of photons in the medium. For E = 0.1 MeV, the monotonic pattern no longer existed due to the dose delivered to the cells by electrons created through the photoelectric effect close to the medium–cell boundary. The continuous-energy distributions from the X-Rad 320 Biological Irradiator (voltage = 150 kV) were also studied under three different beam conditions: (a) F0: no filter used, (b) F1: using a 2 mm-thick Al filter, and (c) F2: using a filter made of (1.5 mm Al + 0.25 mm Cu + 0.75 mm Sn), giving mean output photon energies of 47.4, 57.3 and 102 keV, respectively. R varied from ~1.04 to ~1.28 for F0, from ~1.13 to ~1.21 for F1, and was very close to unity for F2. PMID:28444359

Evaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma.

PubMed

Karagianis, G; Hill, J S; Stylli, S S; Kaye, A H; Varadaxis, N J; Reiss, J A; Phillips, D R

1996-02-01

A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.

A recombinant 63-kDa form of Bacillus anthracis protective antigen produced in the yeast Saccharomyces cerevisiae provides protection in rabbit and primate inhalational challenge models of anthrax infection.

PubMed

Hepler, Robert W; Kelly, Rosemarie; McNeely, Tessie B; Fan, Hongxia; Losada, Maria C; George, Hugh A; Woods, Andrea; Cope, Leslie D; Bansal, Alka; Cook, James C; Zang, Gina; Cohen, Steven L; Wei, Xiaorong; Keller, Paul M; Leffel, Elizabeth; Joyce, Joseph G; Pitt, Louise; Schultz, Loren D; Jansen, Kathrin U; Kurtz, Myra

2006-03-06

Infection by Bacillus anthracis is preventable by prophylactic vaccination with several naturally derived and recombinant vaccine preparations. Existing data suggests that protection is mediated by antibodies directed against the protective antigen (PA) component of the anthrax toxin complex. PA is an 83-kDa protein cleaved in vivo to yield a biologically active 63-kDa protein. In an effort to evaluate the potential of yeast as an expression system for the production of recombinant PA, and to determine if the yeast-purified rPA63 can protect from a lethal inhalational challenge, the sequence of the 63-kDa form of PA was codon-optimized and expressed in the yeast Saccharomyces cerevisiae. Highly purified rPA63 isolated from Saccharomyces under denaturing conditions demonstrated reduced biological activity in a macrophage-killing assay compared to non-denatured rPA83 purified from Escherichia coli. Rabbits and non-human primates (NHP) immunized with rPA63 and later challenged with a lethal dose of B. anthracis spores were generally protected from infection. These results indicate that epitopes present in the 63-kDa from of PA can protect rabbits and non-human primates from a lethal spore challenge, and further suggest that a fully functional rPA63 is not required in order to provide these epitopes.

The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

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

Walters, Jennifer L., E-mail: Jennifer.l.walters@wmich.edu; Lansdell, Theresa A., E-mail: lansdel1@msu.edu; Lookingland, Keith J., E-mail: lookingl@msu.edu

This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC).more » At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. - Highlights: • Male rats received gestational and chronic exposure to ATZ (10 mg/kg and 100 μg/kg). • ATZ altered locomotor activity and impaired motor coordination. • ATZ lowered striatal DA and DOPAC concentrations. • ATZ produced a potential anxiogenic effect. • ATZ did not impair performance in learning and memory assessments.« less

Fast-scan cyclic voltammetry reveals that L-Dopa produces regionally selective, bimodal influences on striatal dopamine kinetics in vivo

PubMed Central

Harun, R; Munoz, M; Grassi, C; Hare, K; Brough, E; Torres, GE; Grace, AA; Wagner, AK

2016-01-01

Parkinson’s disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. Levodopa (L-Dopa) was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-Dopa to augment striatal DA production are well known, little is actually known about how L-Dopa alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-Dopa administration (100mg/kg carbidopa/250mg/kg L-Dopa) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We demonstrate that L-Dopa enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR, a finding that may be related to high-dose L-Dopa effects. In both regions, L-Dopa progressively attenuated reuptake kinetics through a decrease in Vmax and an increase in Km. This finding is consistent with recent clinical studies suggesting that L-Dopa chronically down-regulates the DA transporter (DAT), which may relate to the common development of L-Dopa induced dyskinesias (LID) in PD subjects. PMID:26611352

Generation of oxyradicals (O2. and H2O2), mitochondrial activity and induction of apoptosis of PBMC of Cyprinus carpio carpio treated in vivo with halomethanes and with recombinant HSP60 kDa and with LPS of Klebsiella pneumoniae.

PubMed

Uraga-Tovar, D Italibi; Domínguez-López, M Lilia; Madera-Sandoval, Ruth L; Nájera-Martínez, Minerva; García-Latorre, Ethel; Vega-López, Armando

2014-10-01

Halomethanes (HM) can be immunotoxic in mammals; however, in the fish immune system HM effects are unknown. In the current study, we evaluated the mitochondrial activity (MA) by MTT, induction of apoptosis by SubG0 technique and quantified serum ROS concentration (O2. and H2O2) and ROS production in PBMC of Cyprinus carpio carpio treated i.p. with CH2Cl2, CHCl3 and BrCHCl2 (0.004-40.0 mg/kg) for 96 h. Positive controls were recombinant heat shock protein of 60 kDa (rHSP60 kDa) of Klebsiella pneumoniae and its LPS. In addition, for in vitro PBMC cultures, two culture media and two sources of sera were tested. Both positive controls increased the MA more than 4-fold as well as the production of O2. (26-fold) and H2O2 (5-fold) compared to their controls. HM induced different effects on MA, ROS production and an induction of apoptosis, depending on the chlorination patterns and the dose; however, a systemic damage prevails. To fish treated with CH2Cl2, the apoptosis was related with serum ROS concentration and with MA. In contrast, in fish dosed with CHCl3 relationships were not found, deducing a systemic damage. However, in fish treated with BrCHCl2, serum O2. concentration and in vitro ROS generation performed by PBMC were involved in the induction of apoptosis of these cells but not with MA suggesting also immunotoxic effects. The current study demonstrated that HMs are immunomodulators increasing an acute inflammatory response and that rHSP60kDA of K. pneumoniae and its LPS are appropriate antigens to assess the immune response of C. c. carpio.

SU-E-T-84: Comparison of Three Different Systems for Patient-Specific Quality Assurance: Cranial Stereotactic Radiosurgery Using VMAT with Multiple Non Coplanar Arcs

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

Fusella, M; Fiandra, C; Giglioli, F

2014-06-01

Purpose: Patient-specific quality assurance in volumetric modulated arc therapy (VMAT) brain stereotactic radiosurgery raises specific issues on dosimetric procedures, mainly represented by the small radiation fields associated with the lack of lateral electronic equilibrium, the need of small detectors and the high dose delivered. The purpose of the study is to compare three different dosimeters for pre-treatment QA. Methods: Nineteen patients (affected by neurinomas, brain metastases, and by meningiomas) were treated with VMAT plans computed on a Monte Carlo based TPS. Gafchromic films inside a slab phantom (GF), 3-D cylindrical phantom with two orthogonal diodes array (DA), and 3-D cylindricalmore » phantom with a single rotating ionization chambers array (ICA), have been evaluated. The dosimeters are, respectively, characterized by a spatial resolution of: 0.4 (in our method), 5 and 2.5 mm. For GF we used a double channel method for calibration and reading protocol; for DA and ICA we used the 3-D dose distributions reconstructed by the two software sold with the dosimeters. With the need of a common system for analyze different measuring approaches, we used an in-house software that analyze a single coronal plane in the middle of the phantoms and Gamma values (2% / 2 mm and 3% / 3 mm) were computed for all patients and dosimeters. Results: The percentage of points with gamma values less than one was: 95.7% for GF, 96.8% for DA and 95% for ICA, using 3%/3mm criteria, and 90.1% for GF, 92.4% for DA and 92% for ICA, using 2% / 2mm gamma criteria. Tstudent test p-values obtained by comparing the three datasets were not statistically significant for both gamma criteria. Conclusion: Gamma index analysis is not affected by different spatial resolution of the three dosimeters.« less

Effects of AT1 receptor antagonism on kainate-induced seizures and concomitant changes in hippocampal extracellular noradrenaline, serotonin, and dopamine levels in Wistar-Kyoto and spontaneously hypertensive rats.

PubMed

Tchekalarova, Jana; Loyens, Ellen; Smolders, Ilse

2015-05-01

In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs. Copyright © 2015 Elsevier Inc. All rights reserved.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

PubMed

Palmatier, Matthew I; Kellicut, Marissa R; Brianna Sheppard, A; Brown, Russell W; Robinson, Donita L

2014-11-01

Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by nicotine and they implicate dopaminergic systems both in conditioned approach as well as the incentive-promoting effects of nicotine. Copyright © 2014 Elsevier Inc. All rights reserved.

Cloning of habutobin cDNA and antithrombotic activity of recombinant protein

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

Sunagawa, Masanori; Nakamura, Mariko; Kosugi, Tadayoshi

2007-11-03

The habutobin cDNA was cloned from total RNA extracted from venom glands of Trimeresurus flavoviridis (the habu snake). The conceptual translation of 1539 bp of habutobin cDNA consists of 236 amino acids and its molecular weight is 25.7 kDa. Histidine (His)-tagged recombinant habutobin fusion protein, pET-r-habutobin and AcNPV-r-habutobin, was purified by bacterial system and baculoviral system, respectively. After refolding pET-r-habutobin, there were two protein bands at about 32 kDa and 65 kDa, indicating that habutobin might be produced as a monomer protein and processed to form two concatenated protein. Purified AcNPV-r-habutobin dose-dependently increased fibrin forming activity and inhibited collagen-induced aggregationmore » of rabbit washed platelets. Thus, AcNPV-r-habutobin produced by baculoviral system is very useful for study on structure-function relationship, which is necessary for developing an antithrombotic drug from habutobin.« less

Interactions of green coffee bean phenolics with wheat bread matrix in a model of simulated in vitro digestion.

PubMed

Świeca, Michał; Gawlik-Dziki, Urszula; Sęczyk, Łukasz; Dziki, Dariusz; Sikora, Małgorzata

2018-08-30

Interactions of phenolics from green coffee bean flour (GCS) with the matrix of wheat bread have been studied employing direct (electrophoretic and chromatographic techniques) and indirect tests (nutrient digestibility). According to the chromatograms of digests, the antiradical activity of enriched bread was exhibited by free phenolics. An increase the area of chromatograms and some additional peaks observed for enriched bread may confirm some interactions of proteins with phenolics. The electrophoretic profile of these extracts showed that the band corresponding to a protein with molecular mass of 38 kDA had much higher intensity in enriched bread. Electrophoretic analysis of pellets remaining after digestion revealed GCS dose-dependent differences in bands corresponding to proteins with molecular masses of 52 kDa and 23 kDa. The relative digestibility of both starch and proteins was slightly decreased by addition of GCS; however, these changes did not exceed 10%, which justifies the use of this functional material. Copyright © 2018 Elsevier Ltd. All rights reserved.

Production and characterization of a PEGylated derivative of recombinant human deoxyribonuclease I for cystic fibrosis therapy.

PubMed

Guichard, Marie-Julie; Patil, Harshad P; Koussoroplis, Salome Juliette; Wattiez, Ruddy; Leal, Teresinha; Vanbever, Rita

2017-05-30

Recombinant human deoxyribonuclease I (rhDNase) is the mucolytic agent most widely used for the treatment of respiratory disease in cystic fibrosis. However, rhDNase is rapidly cleared from the lungs which implies a high dosing frequency and limited patient adherence. The aim of this study was to produce a long-acting PEGylated derivative of rhDNase presenting a preserved enzymatic activity. Site-specific PEGylation on the N-terminal (N-ter) leucine residue of rhDNase was achieved by reductive alkylation at acidic pH using linear 20kDa, linear 30kDa or two-arm 40kDa polyethylene glycol (PEG) propionaldehydes. Yields of mono-PEGylated products ranged between 45% and 61%. Conjugation to PEG fully preserved the secondary structure and the in vitro enzymatic activity of the native protein. These properties offer interesting perspectives for in vivo inhalation studies of the PEGylated enzyme. Copyright © 2017 Elsevier B.V. All rights reserved.

Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia.

PubMed

Kita, Hitoshi; Kita, Takako

2011-07-13

The motor cortex (MC) sends massive projections to the basal ganglia. Motor disabilities in patients and animal models of Parkinson's disease (PD) may be caused by dopamine (DA)-depleted basal ganglia that abnormally process the information originating from MC. To study how DA depletion alters signal transfer in the basal ganglia, MC stimulation-induced (MC-induced) unitary responses were recorded from the basal ganglia of control and 6-hydroxydopamine-treated hemi-parkinsonian rats anesthetized with isoflurane. This report describes new findings about how DA depletion alters MC-induced responses. MC stimulation evokes an excitation in normally quiescent striatal (Str) neurons projecting to the globus pallidus external segment (GPe). After DA-depletion, the spontaneous firing of Str-GPe neurons increases, and MC stimulation evokes a shorter latency excitation followed by a long-lasting inhibition that was invisible under normal conditions. The increased firing activity and the newly exposed long inhibition generate tonic inhibition and a disfacilitation in GPe. The disfacilitation in GPe is then amplified in basal ganglia circuitry and generates a powerful long inhibition in the basal ganglia output nucleus, the globus pallidus internal segment. Intra-Str injections of a behaviorally effective dose of DA precursor l-3,4-dihydroxyphenylalanine effectively reversed these changes. These newly observed mechanisms also support the generation of pauses and burst activity commonly observed in the basal ganglia of parkinsonian subjects. These results suggest that the generation of abnormal response sequences in the basal ganglia contributes to the development of motor disabilities in PD and that intra-Str DA supplements effectively suppress abnormal signal transfer.

Partial dopaminergic denervation-induced impairment in stimulus discrimination acquisition in parkinsonian rats: a model for early Parkinson's disease.

PubMed

Eagle, Andrew L; Olumolade, Oluyemi O; Otani, Hajime

2015-03-01

Parkinson's disease (PD) produces progressive nigrostriatal dopamine (DA) denervation resulting in cognitive and motor impairment. However, it is unknown whether cognitive impairments, such as instrumental learning deficits, are associated with the early stage PD-induced mild DA denervation. The current study sought to model early PD-induced instrumental learning impairments by assessing the effects of low dose (5.5μg), bilateral 6OHDA-induced striatal DA denervation on acquisition of instrumental stimulus discrimination in rats. 6OHDA (n=20) or sham (n=10) lesioned rats were tested for stimulus discrimination acquisition either 1 or 2 weeks post surgical lesion. Stimulus discrimination acquisition across 10 daily sessions was used to assess discriminative accuracy, or a probability measure of the shift toward reinforced responding under one stimulus condition (Sd) away from extinction, when reinforcement was withheld, under another (S(d) phase). Striatal DA denervation was assayed by tyrosine hydroxylase (TH) staining intensity. Results indicated that 6OHDA lesions produced significant loss of dorsal striatal TH staining intensity and marked impairment in discrimination acquisition, without inducing akinetic motor deficits. Rather 6OHDA-induced impairment was associated with perseveration during extinction (S(Δ) phase). These findings suggest that partial, bilateral striatal DA denervation produces instrumental learning deficits, prior to the onset of gross motor impairment, and suggest that the current model is useful for investigating mild nigrostriatal DA denervation associated with early stage clinical PD. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Acetylcholine from the mesopontine tegmental nuclei differentially affects methamphetamine induced locomotor activity and neurotransmitter levels in the mesolimbic pathway

PubMed Central

Dobbs, Lauren K.; Mark, Gregory P.

2012-01-01

Methamphetamine (MA) increases dopamine (DA) levels within the mesolimbic pathway and acetylcholine (ACh), a neurotransmitter known to increase DA cell firing and release and mediate reinforcement, within the ventral tegmental area (VTA). The laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei provide cholinergic input to the VTA; however, the contribution of LDT- and PPT-derived ACh to MA-induced DA and ACh levels and locomotor activation remains unknown. The first experiment examined the role of LDT-derived ACh in MA locomotor activation by reversibly inhibiting these neurons with bilateral intra-LDT microinjections of the M2 receptor agonist oxotremorine (OXO). Male C57BL/6 J mice were given a bilateral 0.1 µl OXO (0, 1, or 10 nM/side) microinjection immediately prior to IP saline or MA (2 mg/kg). The highest OXO concentration significantly inhibited both saline-and MA-primed locomotor activity. In a second set of experiments we characterized the individual contributions of ACh originating in the LDT or pedunculopontine tegmental nucleus (PPT) to MA-induced levels of ACh and DA by administering intra-LDT or PPT OXO and performing in vivo microdialysis in the VTA and NAc. Intra-LDT OXO dose-dependently attenuated the MA-induced increase in ACh within the VTA but had no effect on DA in NAc. Intra-PPT OXO had no effect on ACh or DA levels within the VTA or NAc, respectively. We conclude that LDT, but not PPT, ACh is important in locomotor behavior and the cholinergic, but not dopaminergic, response to systemic MA. PMID:21945297

Blockade of nicotine sensitization by methanol extracts of Glycyrrhizae radix mediated via antagonism of accumbal oxidative stress.

PubMed

Zhao, Zheng Lin; Kim, Sang Chan; Liu, Hong Feng; Wu, Yi Yan; Li, Li Bo; Wang, Yu Hua; Jiao, Yu; Fan, Yu; Lee, Chul Won; Lee, Bong Hyeo; Cho, Il Je; Yang, Chae Ha; Zhao, Rong Jie

2017-11-16

We previously reported that a methanol extract of Glycyrrhizae radix (MEGR) blocked methamphetamine-induced locomotor sensitization and conditioned place preference in rats. In the present study, the effects of MEGR on repeated nicotine-induced locomotor sensitization and enhanced extracellular dopamine (DA) release in the nucleus accumbens (Nacc) were evaluated. Male Sprague-Dawley rats received repeated administrations of nicotine (0.4 mg/kg, subcutaneous) or saline twice a day for 7 d and were challenged with nicotine 4 d after the last daily dosing. During the 4-d withdrawal period, the rats were treated once a day with MEGR (60 or 180 mg/kg/d). Extracellular DA levels were measured by in vivo microdialysis, the malondialdehyde levels and the activities of superoxide dismutase and catalase in the Nacc were biochemically evaluated, and the expression of antioxidant proteins was confirmed by Western blot assays. All data were assessed with analysis of variance tests followed by post-hoc comparison tests and p values <0.05 were considered statistically significant. The expression of repeated nicotine-induced locomotor sensitization was dose-dependently attenuated by MEGR, and 180 mg/kg/d MEGR significantly inhibited augmented accumbal DA release induced by a direct local challenge of nicotine. Moreover, 180 mg/kg/d MEGR reversed increases in malondialdehyde production, decreases in superoxide dismutase and catalase activities, and the reduced expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1 in the nicotine-sensitized Nacc. These results suggest that MEGR inhibited nicotine-induced locomotion and dopaminergic sensitization via antioxidant action.

Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

PubMed

Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

2018-05-18

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Long-term exposure to a ‘safe’ dose of bisphenol A reduced protein acetylation in adult rat testes

NASA Astrophysics Data System (ADS)

Chen, Zhuo; Zuo, Xuezhi; He, Dongliang; Ding, Shibin; Xu, Fangyi; Yang, Huiqin; Jin, Xin; Fan, Ying; Ying, Li; Tian, Chong; Ying, Chenjiang

2017-01-01

Bisphenol A (BPA), a typical environmental endocrine-disrupting chemical, induces epigenetic inheritance. Whether histone acetylation plays a role in these effects of BPA is largely unknown. Here, we investigated histone acetylation in male rats after long-term exposure to a ‘safe’ dose of BPA. Twenty adult male rats received either BPA (50 μg/kg·bw/day) or a vehicle diet for 35 weeks. Decreased protein lysine-acetylation levels at approximately ~17 kDa and ~25 kDa, as well as decreased histone acetylation of H3K9, H3K27 and H4K12, were detected by Western blot analysis of testes from the treated rats compared with controls. Additionally, increased protein expression of deacetylase Sirt1 and reduced binding of Sirt1, together with increased binding of estrogen receptor β (ERβ) to caveolin-1 (Cav-1), a structural protein component of caveolar membranes, were detected in treated rats compared with controls. Moreover, decreased acetylation of Cav-1 was observed in the treated rats for the first time. Our study showed that long-term exposure to a ‘safe’ dose of BPA reduces histone acetylation in the male reproductive system, which may be related to the phenotypic paternal-to-offspring transmission observed in our previous study. The evidence also suggested that these epigenetic effects may be meditated by Sirt1 via competition with ERβ for binding to Cav-1.

Long-term exposure to a ‘safe’ dose of bisphenol A reduced protein acetylation in adult rat testes

PubMed Central

Chen, Zhuo; Zuo, Xuezhi; He, Dongliang; Ding, Shibin; Xu, Fangyi; Yang, Huiqin; Jin, Xin; Fan, Ying; Ying, Li; Tian, Chong; Ying, Chenjiang

2017-01-01

Bisphenol A (BPA), a typical environmental endocrine-disrupting chemical, induces epigenetic inheritance. Whether histone acetylation plays a role in these effects of BPA is largely unknown. Here, we investigated histone acetylation in male rats after long-term exposure to a ‘safe’ dose of BPA. Twenty adult male rats received either BPA (50 μg/kg·bw/day) or a vehicle diet for 35 weeks. Decreased protein lysine-acetylation levels at approximately ~17 kDa and ~25 kDa, as well as decreased histone acetylation of H3K9, H3K27 and H4K12, were detected by Western blot analysis of testes from the treated rats compared with controls. Additionally, increased protein expression of deacetylase Sirt1 and reduced binding of Sirt1, together with increased binding of estrogen receptor β (ERβ) to caveolin-1 (Cav-1), a structural protein component of caveolar membranes, were detected in treated rats compared with controls. Moreover, decreased acetylation of Cav-1 was observed in the treated rats for the first time. Our study showed that long-term exposure to a ‘safe’ dose of BPA reduces histone acetylation in the male reproductive system, which may be related to the phenotypic paternal-to-offspring transmission observed in our previous study. The evidence also suggested that these epigenetic effects may be meditated by Sirt1 via competition with ERβ for binding to Cav-1. PMID:28067316

Using pharmacoeconomic modelling to determine value-based pricing for new pharmaceuticals in malaysia.

PubMed

Dranitsaris, George; Truter, Ilse; Lubbe, Martie S; Sriramanakoppa, Nitin N; Mendonca, Vivian M; Mahagaonkar, Sangameshwar B

2011-10-01

Decision analysis (DA) is commonly used to perform economic evaluations of new pharmaceuticals. Using multiples of Malaysia's per capita 2010 gross domestic product (GDP) as the threshold for economic value as suggested by the World Health Organization (WHO), DA was used to estimate a price per dose for bevacizumab, a drug that provides a 1.4-month survival benefit in patients with metastatic colorectal cancer (mCRC). A decision model was developed to simulate progression-free and overall survival in mCRC patients receiving chemotherapy with and without bevacizumab. Costs for chemotherapy and management of side effects were obtained from public and private hospitals in Malaysia. Utility estimates, measured as quality-adjusted life years (QALYs), were determined by interviewing 24 oncology nurses using the time trade-off technique. The price per dose was then estimated using a target threshold of US$44 400 per QALY gained, which is 3 times the Malaysian per capita GDP. A cost-effective price for bevacizumab could not be determined because the survival benefit provided was insufficient According to the WHO criteria, if the drug was able to improve survival from 1.4 to 3 or 6 months, the price per dose would be $567 and $1258, respectively. The use of decision modelling for estimating drug pricing is a powerful technique to ensure value for money. Such information is of value to drug manufacturers and formulary committees because it facilitates negotiations for value-based pricing in a given jurisdiction.

Effects of ultrafine diesel exhaust particles on oxidative stress generation and dopamine metabolism in PC-12 cells.

PubMed

Kim, Yong-Dae; Lantz-McPeak, Susan M; Ali, Syed F; Kleinman, Michael T; Choi, Young-Sook; Kim, Heon

2014-05-01

A major constituent of urban air pollution is diesel exhaust, a complex mixture of gases, chemicals, and particles. Recent evidence suggests that exposure to air pollution can increase the risk of a fatal stroke, cause cerebrovascular damage, and induce neuroinflammation and oxidative stress that may trigger neurodegenerative diseases, such as Parkinson's disease. The specific aim of this study was to determine whether ultrafine diesel exhaust particles (DEPs), the particle component of exhaust from diesel engines, can induce oxidative stress and effect dopamine metabolism in PC-12 cells. After 24 h exposure to DEPs of 200 nm or smaller, cell viability, ROS and nitric oxide (NO(2)) generation, and levels of dopamine (DA) and its metabolites, (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)), were evaluated. Results indicated cell viability was not significantly changed by DEP exposure. However, ROS showed dramatic dose-dependent changes after DEP exposure (2.4 fold increase compared to control at 200 μg/mL). NO(2) levels were also dose-dependently increased after DEP exposure. Although not in a dose-dependent manner, upon DEP exposure, intracellular DA levels were increased while DOPAC and HVA levels decreased when compared to control. Results suggest that ultrafine DEPs lead to dopamine accumulation in the cytoplasm of PC-12 cells, possibly contributing to ROS formation. Further studies are warranted to elucidate this mechanism. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

A randomized, multi-center, open-label, phase III study of once-per-cycle DA-3031, a pegylated G-CSF, in comparison with daily filgrastim in patients receiving TAC chemotherapy for breast cancer.

PubMed

Park, K H; Lee, S; Park, J H; Kang, S Y; Kim, H Y; Park, I H; Park, Y H; Im, Y H; Lee, H J; Park, S; Lee, S I; Jung, K H; Kim, Y S; Seo, Jae Hong

2017-02-01

This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy for breast cancer in terms of the duration of severe neutropenia (DSN). Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 μg/m 2 /day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle. The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = -0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm 3 and 161.75/mm 3 for the filgrastim and DA-3031 groups, respectively; P = 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively; P = 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug. DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.

A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting

PubMed Central

Ghosh, Sukhen C.; Rodriguez, Melissa; Carmon, Kendra S.; Voss, Julie; Wilganowski, Nathaniel L.; Schonbrunn, Agnes

2017-01-01

Fluorescence-guided surgery is an emerging imaging technique that can enhance the ability of surgeons to detect tumors when compared with visual observation. To facilitate characterization, fluorescently labeled probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. In this study, we selected the somatostatin receptor imaging agent DOTATOC as the foundation for developing a dual-labeled analog. We hypothesized that a customized dual-labeling approach with a multimodality chelation (MMC) scaffold would minimize steric effects of dye conjugation and retain agonist properties. Methods: An MMC conjugate (MMC-TOC) was synthesized on solid-phase and compared with an analog prepared using conventional methods (DA-TOC). Both analogs were conjugated to IRDye 800 using copper-free click chemistry. The resulting compounds, MMC(IR800)-TOC and DA(IR800)-TOC, were labeled with Cu and 64Cu and tested in vitro in somatostatin receptor subtype 2–overexpressing HEK-293 cells to assess agonist properties, and in AR42J rat pancreatic cancer cells to determine receptor binding characteristics. Multimodality imaging was performed in AR42J xenografts. Results: Cu-MMC(IR800)-TOC demonstrated higher potency for cyclic adenosine monophosphate inhibition (half maximal effective concentration [EC50]: 0.21 ± 0.18 vs. 1.38 ± 0.54 nM) and receptor internalization (EC50: 41.9 ± 29.8 vs. 455 ± 299 nM) than Cu-DA(IR800)-TOC. Radioactive uptake studies showed that blocking with octreotide caused a dose-dependent reduction in 64Cu-MMC(IR800)-TOC uptake whereas 64Cu-DA(IR800)-TOC was not affected. In vivo studies revealed higher tumor uptake for 64Cu-MMC(IR800)-TOC than 64Cu-DA(IR800)-TOC (5.2 ± 0.2 vs. 3.6 ± 0.4 percentage injected dose per gram). In vivo blocking studies with octreotide reduced tumor uptake of 64Cu-MMC(IR800)-TOC by 66%. Excretion of 64Cu-MMC(IR800)-TOC was primarily through the liver and spleen whereas 64Cu-DA(IR800)-TOC was cleared through the kidneys. Ex vivo analysis at 24 h confirmed PET/CT data by showing near-infrared fluorescence signal in tumors and a tumor-to-muscle ratio of 5.3 ± 0.8 as determined by γ-counting. Conclusion: The findings demonstrate that drug design affected receptor pharmacology and suggest that the MMC scaffold is a useful tool for the development of dual-labeled imaging agents. PMID:28572490

Immunostimulative Activity of Low Molecular Weight Chitosans in RAW264.7 Macrophages

PubMed Central

Wu, Ning; Wen, Zheng-Shun; Xiang, Xing-Wei; Huang, Yan-Na; Gao, Yang; Qu, You-Le

2015-01-01

Chitosan and its derivatives such as low molecular weight chitosans (LMWCs) have been reported to exert many biological activities, such as antioxidant and antitumor effects. However, complex and molecular weight dependent effects of chitosan remain controversial and the mechanisms that mediate these complex effects are still poorly defined. This study was carried out to investigate the immunostimulative effect of different molecular weight chitosan in RAW264.7 macrophages. Our data suggested that two LMWCs (molecular weight of 3 kDa and 50 kDa) both possessed immunostimulative activity, which was dependent on dose and, at the higher doses, also on the molecular weight. LMWCs could significantly enhance the the pinocytic activity, and induce the production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon-γ (IFN-γ), nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in a molecular weight and concentration-dependent manner. LMWCs were further showed to promote the expression of the genes including iNOS, TNF-α. Taken together, our findings suggested that LMWCs elicited significantly immunomodulatory response through up-regulating mRNA expression of proinflammatory cytokines and activated RAW264.7 macrophage in a molecular weight- and concentration-dependent manner. PMID:26437419

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

PubMed

Lim, Chae-Seok; Hoang, Elizabeth T; Viar, Kenneth E; Stornetta, Ruth L; Scott, Michael M; Zhu, J Julius

2014-02-01

Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1.

PubMed

Petrella, Antonello; D'Acunto, Cosimo Walter; Rodriquez, Manuela; Festa, Michela; Tosco, Alessandra; Bruno, Ines; Terracciano, Stefania; Taddei, Maurizio; Paloma, Luigi Gomez; Parente, Luca

2008-03-01

FR235222, a novel histone deacetylase inhibitor (HDACi), at 50nM caused accumulation of acetylated histone H4, inhibition of cell proliferation and G1 cycle arrest accompanied by increase of p21 and down-regulation of cyclin E in human promyelocytic leukaemia U937 cells. The compound was also able to increase the protein and mRNA levels of annexin A1 (ANXA1) without effects on apoptosis. Similar effects were observed in human chronic myelogenous leukaemia K562 cells and human T cell leukaemia Jurkat cells. Cycle arrest and ANXA1 expression, without significant effects on apoptosis, were also induced by different HDACi like suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). FR235222 at 0.5 microM stimulated apoptosis of all leukaemia cell lines associated to an increased expression of the full-length (37kDa) protein and the appearance of a 33kDa N-terminal cleavage product in both cytosol and membrane. These results suggest that ANXA1 expression may mediate cycle arrest induced by low doses FR235222, whereas apoptosis induced by high doses FR235222 is associated to ANXA1 processing.

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects.

PubMed

Azmy, Mariama S; Menze, Esther T; El-Naga, Reem N; Tadros, Mariane G

2018-01-11

All current treatments of Parkinson's disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40 μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40 μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.

T48. ANTIPSYCHOTIC EFFICACY OF EVENAMIDE (NW-3509) IS DUE TO MODULATION OF GLUTAMATERGIC DYSREGULATION

PubMed Central

Anand, Ravi; Forrest, Emma C; Hartman, Richard D; Graham, Stephen M; Faravelli, Laura

2018-01-01

Abstract Background Over 70% of schizophrenic patients discontinue treatment with first (F)- or second-generation antipsychotics (SGA) due to dissatisfaction with their therapeutic effects; median time to discontinuation ranges from 3–7 months (1). Switching to another antipsychotic, except clozapine, did not yield better results (2). These results indicate it is essential to modulate mechanisms other than dopaminergic (DA)/serotoninergic (5-HT) systems to improve symptoms of schizophrenia (SCZ). Increasingly, NMDA receptor (NMDAr) hypofunction (3) and hippocampal hyperactivity (4) are implicated in the dysregulation of mesolimbic DA and glutamate (Glu) neurons, leading to increasing synaptic activity of Glu in the PFC (5). Augmenting the effects of current antipsychotics with Glu release inhibitors may improve symptoms of psychosis in patients with SCZ. Evenamide does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with >130 different targets involved in CNS activity, except for sodium channels, leading to modulation of Glu release. Evenamide shows efficacy in animal models of SCZ as monotherapy and as an add-on to FGA or SGA, irrespective of whether impairment was spontaneous, or induced by amphetamine, NMDAr antagonists or stress. Methods In a pilot, proof of mechanism, randomized, double-blind, placebo-controlled, parallel group, 4-week trial, evenamide (n=50; 15–25 mg bid) or placebo (n=39) was added to patients with SCZ worsening on their current antipsychotic doses of risperidone (RIS; ≥2 mg/day) or aripiprazole (ARI; ≥10 mg/day), in 2 sites in the US (n=61) and 3 in India (n=28). Results 89 patients with SCZ (mean baseline PANSS total: 62.9 ± 7.4; CGI-S: 3.5 ± 0.5), experiencing break-through psychotic symptoms on previously effective and stable doses of RIS (mean dose: 4.2 ± 2.0 mg/day; n=70) or ARI (mean dose: 19.7 ± 7.0 mg/day; n=19) were randomized (1.3:1 ratio) to treatment with evenamide or placebo. Analyses demonstrated the addition of evenamide to RIS or ARI was associated with statistically significant efficacy, based on the PANSS Positive Symptoms sub-scale (mean change, responders), and CGI-C responder rates. The study treatments were very well tolerated; 2 patients on evenamide discontinued treatment due to AEs (atrial fibrillation and seizure). The most common AEs (evenamide vs placebo [%]), were somnolence (16 vs 12.8%), insomnia (10 vs 6%) and headache (6 vs 0%). Discussion Addition of evenamide in patients worsening on SGAs modulating DA/5-HT significantly improved positive symptoms and CGI. No AEs such as EPS, endocrine, or sexual side effects, or weight gain were noted. These data indicate that evenamide’s Glu antagonism, demonstrated in preclinical experiments, is of value in patients worsening on current antipsychotics. Evenamide, as monotherapy or add-on, has reversed ketamine- and PCP-induced worsening of PPI. The results in the pilot clinical trial demonstrated an absence of side effects common with DA/5-HT blockers, and a rapid onset of action mediated by evenamide targeting altered Glu transmission in patients in whom SGA treatment had lost its efficacy. Efficacy of evenamide as add-on to antipsychotics would revolutionize development of novel antipsychotics targeting aberrant firing and Glu transmission in SCZ. Potentially pivotal studies with evenamide are in planning to demonstrate that the addition of evenamide, a Glu release inhibitor, augments antipsychotic efficacy in patients worsening on current antipsychotics, and in patients with treatment-resistant SCZ not responding/worsening on clozapine.

Alpha6-Containing Nicotinic Acetylcholine Receptors Mediate Nicotine-Induced Structural Plasticity in Mouse and Human iPSC-Derived Dopaminergic Neurons.

PubMed

Collo, Ginetta; Cavalleri, Laura; Zoli, Michele; Maskos, Uwe; Ratti, Emiliangelo; Merlo Pich, Emilio

2018-01-01

Midbrain dopamine (DA) neurons are considered a critical substrate for the reinforcing and sensitizing effects of nicotine and tobacco dependence. While the role of the α4 and β2 subunit containing nicotinic acetylcholine receptors (α4β2 ∗ nAChRs) in mediating nicotine effects on DA release and DA neuron activity has been widely explored, less information is available on their role in the morphological adaptation of the DA system to nicotine, eventually leading to dysfunctional behaviors observed in nicotine dependence. In particular, no information is available on the role of α6 ∗ nAChRs in nicotine-induced structural plasticity in rodents and no direct evidence exists regarding the occurrence of structural plasticity in human DA neurons exposed to nicotine. To approach this problem, we used two parallel in vitro systems, mouse primary DA neuron cultures from E12.5 embryos and human DA neurons differentiated from induced pluripotent stem cells (iPSCs) of healthy donors, identified using TH + immunoreactivity. In both systems, nicotine 1-10 μM produced a dose-dependent increase of maximal dendrite length, number of primary dendrites, and soma size when measured after 3 days in culture. These effects were blocked by pretreatments with the α6 ∗ nAChR antagonists α-conotoxin MII and α-conotoxin PIA, as well as by the α4β2nAChR antagonist dihydro-β-erythroidine (DHβE) in both mouse and human DA neurons. Nicotine was also ineffective when the primary DA neurons were obtained from null mutant mice for either the α6 subunit or both the α4 and α6 subunits of nAChR. When pregnant mice were exposed to nicotine from gestational day 15, structural plasticity was also observed in the midbrain DA neurons of postnatal day 1 offspring only in wild-type mice and not in both null mutant mice. This study confirmed the critical role of α4α6 ∗ nAChRs in mediating nicotine-induced structural plasticity in both mouse and human DA neurons, supporting the translational relevance of neurons differentiated from human iPSCs for pharmacological studies.

Effect of piracetam, a nootropic agent, on rat brain monoamines and prostaglandins.

PubMed

Bhattacharya, S K; Upadhyay, S N; Jaiswal, A K; Bhattacharya, S

1989-03-01

Piracetam is the prototype of a new class of psychotropic drugs, the nootropic agents, which are claimed to selectively improve the higher telencephalic integrative activities. The effect of piracetam on rat brain monoamines and prostaglandins (PGs) was assessed so as to garner information on its mode of action. Two doses of the drug were used, a lower dose (20 mg/kg ip) and a higher dose (100 mg/kg, ip), the latter being known to exert a facilitatory effect on learning and memory. Piracetam produced a dose-related effect on rat brain serotonin (5HT) and noradrenaline (NA), with the lower dose inducing a decrease in 5HT levels and an increase in NA concentrations. The higher dose of piracetam produced the opposite effect. Dopamine (DA) levels were not significantly affected. The lower dose of the drug attenuated 5HT turnover and augmented that of NA, whereas the higher dose of piracetam produced the reverse effects, in clorgyline treated rats. The lower dose of piracetam produced a slight and statistically insignificant increase in rat brain PGE2 and PGF2 alpha. However, the higher dose of the drug produced marked increase in the levels of both the PGs. The observed biochemical effects may provide a basis for the nootropic effect of piracetam. However, they may also be due to the GA-BA-mimetic action of the drug, particularly those observed with the lower dose of piracetam.

Activation of the EGFR/p38/JNK Pathway by Mitochondrial-Derived Hydrogen Peroxide Contributes To Oxygen-induced Contraction Of Ductus Arteriosus

PubMed Central

Hong, Zhigang; Cabrera, Jésus A; Mahapatra, Saswati; Kutty, Shelby; Weir, E. Kenneth; Archer, Stephen L.

2014-01-01

Oxygen-induced contraction of the ductus arteriosus (DA) involves a mitochondrial oxygen-sensor, which signals pO2 in the DA smooth muscle cell (DASMC) by increasing production of diffusible hydrogen peroxide (H2O2). H2O2 stimulates vasoconstriction by regulating ion channels and rho kinase, leading to calcium influx and calcium sensitization. Because epidermal growth factor receptor (EGFR) signaling is also redox regulated and participates in oxygen sensing and vasoconstriction in other systems, we explored the role of the EGFR and its signaling cascade (p38 and JNK) in DA contraction. Experiments were performed in DA rings isolated from full-term New Zealand White rabbits and human DASMC. In human DASMCs increasing pO2 from hypoxia to normoxia (40 to 100 mmHg) significantly increased cytosolic calcium, p<0.01. This normoxic rise in intracellular calcium was mimicked by EGF and inhibited by EGFR siRNA. In DA rings, EGF caused contraction whilst the specific EGFR inhibitor (AG1478) and the tyrosine kinase inhibitors (genistein or tyrphostin A23) selectively attenuated oxygen-induced contraction (p <0.01). Conversely, orthovanadate, a tyrosine phosphatase inhibitor known to activate EGFR signaling, caused dose-dependent contraction of hypoxic DA and superimposed increases in oxygen caused minimal additional contraction. Ansomycin, an activator of EGFR’s downstream kinases, p38 and JNK, caused DA contraction; conversely, oxygen-induced DA contraction was blocked by inhibitors of p38 MAPK (SB203580) or JNK (JNK inhibitor II). O2-induced phosphorylation of EGFR occurred within 5-minutes of increasing pO2 and was inhibited by mitochondrial-targeted overexpression of catalase. AG1478 prevented the oxygen-induced p38 and JNK phosphorylation. In conclusion, O2-induced EGFR transactivation initiates p38/JNK-mediated increases in cytosolic calcium and contributes to DA contraction. The EGFR/p38/JNK pathway is regulated by mitochondrial redox signaling and is a promising therapeutic target for modulation of the patent ductus arteriosus. PMID:24906456

Therapeutic Effect of a Novel Oxazolidinone, DA-7867, in BALB/c Mice Infected with Nocardia brasiliensis

PubMed Central

Vera-Cabrera, Lucio; Daw-Garza, Alejandra; Said-Fernández, Salvador; Lozano-Garza, Hector Gerardo; de Torres, Noemi Waksman; Rocha, Norma Cavazos; Ocampo-Candiani, Jorge; Choi, Sung-Hak; Welsh, Oliverio

2008-01-01

Background Mycetoma is a chronic infectious disease of tropical and subtropical countries. It is produced by true fungi and actinobacteria. In México, Nocardia brasiliensis is the main causative agent of mycetoma, producing about 86% of the cases; the gold standard for the therapy of mycetoma by N. brasiliensis is the use of sulfonamides which give a 70% cure rate. The addition of amikacin to this regime increases to 95% the cure rate; however, the patients have to be monitored for creatinine clearance and audiometry studies because of the potential development of side effects. Because of that it is important to search for new active compounds. In the present work, we evaluated the in vivo effect of DA-7867, an experimental oxazolidinone, on the development of experimental mycetomas by N. brasiliensis in BALB/c mice. Methodology/Principal Findings In order to determine the optimal dose utilized to apply to the animals, we first determined by HPLC the plasma levels using several concentrations of the compounds. Based on these results, we used 10 and 25 mg/kg subcutaneously every 24 hr; DA-7867 was also supplied in the drinking water at a calculated dose of 25 mg/kg. As a control we utilized linezolid at 25 mg/kg, a compound active in murine and human infections, three times a day. The mice were infected in the right footpad with a young culture of N. brasiliensis HUJEG-1, and one week later we started the application of the antimicrobials for six more weeks. After that we compared the development of lesions in the groups injected with saline solution or with the antimicrobials; the results were analyzed by the variance ANOVA test. DA-7867 was able to reduce the production of lesions at 25 mg/kg, when given either subcutaneously or in the drinking water. Conclusions/Significance The experimental oxazolidinone DA-7867 is active in vivo against N. brasiliensis, which opens the possibility of using this drug once it is accepted for human application. Since oxazolidinones seem to be active against a wide spectrum of actinobacteria, it is possible they could be used in human cases of mycetoma by other actinomycetales, such as Streptomyces somaliensis, highly prevalent in Sudan, or Actinomadura madurae and A. pelletieri, which are commonly observed in Africa and India. PMID:18820738

Changes in the brain biogenic monoamines of rats, induced by piracetam and aniracetam.

PubMed

Petkov, V D; Grahovska, T; Petkov, V V; Konstantinova, E; Stancheva, S

1984-01-01

Single oral dose of 600 mg/kg weight piracetam, respectively 50 mg/kg aniracetam, causes essential changes in the level and turnover of dopamine (DA) and serotonin (5-HT) in some rat cerebral structures. When the animals were killed one hour after the administration of the drugs, piracetam significantly increased the DA level in the cerebral cortex and in the striatum, as well as the 5-HT level in the cortex, reducing the 5-HT level in the striatum, brain stem and hypothalamus. At the same time, under the effect of piracetam the DA turnover was accelerated in the cortex and hypothalamus and delayed in the striatum, the noradrenaline turnover was accelerated in the brain stem, the 5-HT turnover was accelerated in the cortex and delayed in the striatum, stem and hypothalamus. Under the effect of aniracetam the DA level was reduced in the striatum and hypothalamus; the 5-HT level was also decreased in the hypothalamus and increased in the cortex and striatum. Aniracetam delayed the DA turnover in the striatum and the 5-HT turnover in the hypothalamus, accelerating the 5-HT turnover in the cortex, striatum and stem. The results obtained show that the changes induced in the cerebral biogenic monoamines participate in the mechanism of action of piracetam and aniracetam, whereby it seems that the analogies and differences in their effects on the cerebral biogenic monoamines play a definite role for the observed analogies and differences in the behavioural effects of these two "nootropic" compounds.

Extended Access Cocaine Self-Administration Results in Tolerance to the Dopamine-Elevating and Locomotor-Stimulating Effects of Cocaine

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Jones, Sara R.

2013-01-01

Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self-administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Further, we report reductions in cocaine-induced uptake inhibition as measured by fast scan cyclic voltammetry, and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (Ki) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. Additionally, cocaine-induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts. PMID:24102293

Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire.

PubMed

Ferreira, Tiago; Ou, Yimiao; Li, Sally; Giniger, Edward; van Meyel, Donald J

2014-02-01

The architectures of dendritic trees are crucial for the wiring and function of neuronal circuits because they determine coverage of receptive territories, as well as the nature and strength of sensory or synaptic inputs. Here, we describe a cell-intrinsic pathway sculpting dendritic arborization (da) neurons in Drosophila that requires Longitudinals Lacking (Lola), a BTB/POZ transcription factor, and its control of the F-actin cytoskeleton through Spire (Spir), an actin nucleation protein. Loss of Lola from da neurons reduced the overall length of dendritic arbors, increased the expression of Spir, and produced inappropriate F-actin-rich dendrites at positions too near the cell soma. Selective removal of Lola from only class IV da neurons decreased the evasive responses of larvae to nociception. The increased Spir expression contributed to the abnormal F-actin-rich dendrites and the decreased nocifensive responses because both were suppressed by reduced dose of Spir. Thus, an important role of Lola is to limit expression of Spir to appropriate levels within da neurons. We found Spir to be expressed in dendritic arbors and to be important for their development. Removal of Spir from class IV da neurons reduced F-actin levels and total branch number, shifted the position of greatest branch density away from the cell soma, and compromised nocifensive behavior. We conclude that the Lola-Spir pathway is crucial for the spatial arrangement of branches within dendritic trees and for neural circuit function because it provides balanced control of the F-actin cytoskeleton.

The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory.

PubMed

Dodds, Chris M; Clark, Luke; Dove, Anja; Regenthal, Ralf; Baumann, Frank; Bullmore, Ed; Robbins, Trevor W; Müller, Ulrich

2009-11-01

Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear. The present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory. Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation. Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex. These results support models of dopamine function that posit a 'gating' function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.

Effets tardifs d'une irradiation corporelle totale sur le métabolisme intraneuronal de la dopamine et de la sérotonine

NASA Astrophysics Data System (ADS)

Joubert, C.; Jacquet, N.; Lambert, F.; Martin, S.; Martin, C.

1998-04-01

Whole-body irradiation leads to delayed cognitive dysfunction which could result from perturbations of neurotransmission, specially the dopaminergic and the serotoninergic one. The aim of this study was to determine the concentrations of dopamine (DA), serotonin (5-HT) and their metabolites in three cerebral areas of rats, one month after (neutron-gamma) irradiation at 3.38Gy. An increase of DA, 5-HT, and their catabolites was observed. These effects are weak but observed in older rats. Au cours des mois suivant une irradiation corporell totale peuvent se manifester des troubles comportementaux qui pourraient être la conséquence d'altérations de la neuraotransmission, plus particulièrement de la transmission dopaminergique ou sérotoninergique. Nous avons recherché les variations des taux de dopamine (DA), de sérotonine (5-HT) et de leurs métabolites dans 3structures cérébrales 1 mois après une irradiation (neutron-gamma) à la dose de 3,38Gy. Les résultats préliminaires mettent en évidence une augmentation des taux de DA, de 5-HT et de leurs catabolites ; ces effets sont plus discrets mais similaires à ceux observés chez des animaux plus âgés.

Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates.

PubMed

Huang, Shih-Li; Jao, Chia-Ling; Ho, Kit-Pan; Hsu, Kuo-Chiang

2012-05-01

The in vitro DPP-IV inhibitory activity of isolated peptides from of tuna cooking juice hydrolyzed by Protease XXIII (PR) and orientase (OR) was determined. The results showed that the peptide fractions with the molecular weight over 1,422 Da possessed the greatest DPP-IV inhibitory activity. The amino acid sequences of the three peptides isolated from PR and OR hydrolysates were identified by MALDI-TOF/TOF MS/MS, and they were Pro-Gly-Val-Gly-Gly-Pro-Leu-Gly-Pro-Ile-Gly-Pro-Cys-Tyr-Glu (1412.7 Da), Cys-Ala-Tyr-Gln-Trp-Gln-Arg-Pro-Val-Asp-Arg-Ile-Arg (1690.8 Da) and Pro-Ala-Cys-Gly-Gly-Phe-Try-Ile-Ser-Gly-Arg-Pro-Gly (1304.6 Da), while they showed the dose-dependent inhibition effect of DPP-IV with IC(50) values of 116.1, 78.0 and 96.4 μM, respectively. In vitro simulated gastrointestinal digestion retained or even improved the DPP-IV inhibitory activities of the three peptides. The results suggest that tuna cooking juice would be a good precursor of DPP-IV inhibitor, and the DPP-IV inhibitory peptides can successfully passed through the digestive tract. Copyright © 2012 Elsevier Inc. All rights reserved.

Characterisation of gas and particle emissions from wildfires =

NASA Astrophysics Data System (ADS)

Vicente, Ana Margarida Proenca

Os incendios florestais sao uma importante fonte de emissao de compostos gasosos e de aerossois. Em Portugal, onde a maioria dos incendios ocorre no norte e centro do pais, os incendios destroem todos os anos milhares de hectares, com importantes perdas em termos economicos, de vidas humanas e qualidade ambiental. As emissoes podem alterar consideravelmente a quimica da atmosfera, degradar a qualidade do ar e alterar o clima. Contudo, a informacao sobre as carateristicas das emissoes dos incendios florestais nos paises do Mediterrâneo e limitada. Tanto a nivel nacional como internacional, existe um interesse crescente na elaboracao de inventarios de emissoes e de regulamentos sobre as emissoes de carbono para a atmosfera. Do ponto de vista atmosferico da monitorizacao atmosferica, os incendios sao considerados um desafio, dada a sua variabilidade temporal e espacial, sendo de esperar um aumento da sua frequencia, dimensao e severidade, e tambem porque as estimativas de emissoes dependem das carateristicas dos biocombustiveis e da fase de combustao. O objetivo deste estudo foi quantificar e caraterizar as emissoes de gases e aerossois de alguns dos mais representativos incendios florestais que ocorreram no centro de Portugal nos veroes de 2009 e de 2010. Efetuou-se a colheita de amostras de gases e de duas fracoes de particulas (PM2.5 e PM2.5-10) nas plumas de fumo em sacos Tedlar e em filtros de quartzo acoplados a um amostrador de elevado volume, respetivamente. Os hidrocarbonetos totais (THC) e oxidos de carbono (CO e CO2) nas amostras gasosas foram analisados em instrumentos automaticos de ionizacao de chama e detetores nao dispersivos de infravermelhos, respetivamente. Para algumas amostras, foram tambem quantificados alguns compostos de carbonilo apos reamostragem do gas dos sacos Tedlar em cartuchos de silica gel revestidos com 2,4-dinitrofenilhidrazina (DNPH), seguida de analise por cromatografia liquida de alta resolucao. Nas particulas, analisou-se o carbono orgânico e elementar (tecnica termo-optica), ioes soluveis em agua (cromatografia ionica) e elementos (espectrometria de massa com plasma acoplado por inducao ou analise instrumental por ativacao com neutroes). A especiacao orgânica foi obtida por cromatografia gasosa acoplada a espectrometria de massa apos extracao com recurso a varios solventes e separacao dos extratos orgânicos em diversas classes de diferentes polaridades atraves do fracionamento com silica gel. Tendo em conta que a estimativa das emissoes dos incendios florestais requer um conhecimento de fatores de emissao apropriados para cada biocombustivel, a base de dados abrangente obtida neste estudo e potencialmente util para atualizar os inventarios de emissoes. Tem vindo a ser observado que a fase de combustao latente sem chama, a qual pode ocorrer simultaneamente com a fase de chama e durar varias horas ou dias, pode contribuir para uma quantidade consideravel de poluentes atmosfericos, pelo que os fatores de emissao correspondentes devem ser considerados no calculo das emissoes globais de incendios florestais. Devido a falta de informacao detalhada sobre perfis quimicos de emissao, a base de dados obtida neste estudo pode tambem ser util para a aplicacao de modelos no recetor no sul da Europa. (Abstract shortened by ProQuest.).

Uma Comparação entre Técnicas de Propagação de Erros em Astrofísica: Monte Carlo x Bootstrap

NASA Astrophysics Data System (ADS)

Zabot, Alexandre; Baptista, Raymundo

2005-07-01

Neste trabalho é feito um estudo comparativo entre dois algoritmos numéricos usados para propagação de erros em dados experimentais. Um deles é conhecido por Método de Monte carlo e o outro por Método de Bootstrap. Recentemente, Dhullon & Watson argüiram que a aplicação do método de Monte Carlo introduz ruído nos dados, e propuseram então a utilização do Bootstrap como alternativa capaz de produzir resultados superiores. O objetivo deste trabalho é testar a validade dessa afirmação. As duas técnicas foram aplicadas a três problemas diferentes: o ajsute de modelos de emissão LTE simples e atmosfera estelar a espectros estelares observados e o ajuste de curvas de luz de eclipses de Variáveis Cataclísmicas para a detemrinação da distribuição radial de brilho dos seus discos de acréscimo. Os métodos foram testados quanto à sua robusteza, ou seja, a capacidade de prover resultados coerentes enre si. Além disso, as soluções dos métodos foram comparadas. Os resultados indicam que não existe evidência de superioridade de um métodos em relação ao outro.

INHIBITION OF TESTICULAR STEROIDOGENESIS BY THE XENOESTROGEN BISPHENOL A IS ASSOCIATED WITH REDUCED PITUITARY LH SECRETION AND DECREASED STEROIDOGENIC ENZYME GENE EXPRESSION IN RAT LEYDIG CELLS

EPA Science Inventory

Exposure of humans to bisphenol A (BPA), a monomer in polycarbonate plastics and constituent of resins used in food packaging and denistry, is significant. In this report, exposure of rats to 2.4 ug/kg/day (a dose that approximates BPA levels in the environment) from postnatal da...

[Effect of Corydalis yanhusuo and L-THP on Gastrointestinal Dopamine System in Morphine-Dependent Rats].

PubMed

Xu, Jing-yu; Bai, Wei-feng; Qiu, Cheng-kai; Tu, Ping; Yu, Shou-yang; Luo, Su-yuan

2015-12-01

To investigate the protective mechanism of Corydalis yanhuso and L-THP in morphine-dependent gastrointestinal injury rats. 180 male rats were randomly divided into nine groups, 20 rats for each group: saline group (N), model group (M), NS treatment group and three different dosage of Corydalis yanhusuo and L-THP groups (low dose group,middle dose group and high dose group). The rat CPP (conditioned place preference) model was established by injecting the rats with an increasing dosage of morphine, all groups received CPP training in a black compartments and white ones (drug-paired compartment) for ten days. At 48 h after the final training, the performance of CPP models were assessed to make sure all models were exported correctly. Then the treatment groups were administered with different concentration of Corydalis yanhuso (0.5, 1 and 2 g/kg) and L-THP (0.94, 1.88 and 3.76 mg/kg) for six days. All rats were immediately killed after finish the last CPP test. For each group, ten rats were killed to detect the contents of DA in the stomach and duodenum through the fluorescence spectrophotometer. The expression levels of D2 receptor( D2R) in different tissues (gastric cardia, gastric body, pylorus and duodenum) were checked by Western-blot in the other rats. In the NS treatment group, the time when rats stay in the white ones were significantly decreased compared with the Corydalis yanhusuo treated groups (1 and 2 g/kg) and L-THP treated groups (1.88 and 3.76 mg/kg) (P < 0.01), the high expression of DA contents in the stomach and duodenum were significantly decreased (P < 0.01). However the protein level of D2R were notably lower in gastric cardia, gastric body, pylorus and duodenum (P < 0.01). Injuries of the gastrointestinal tract followed lower DA contents and an abnormal increase of D2R in the stomach and duodenum of rats, which induced by morphine-dependent could be reversed by treatment with Corydalis yanhusuo and L-THP. This is one of mechanism underlying the protective effects of gastrointestinal tract in morphine-dependent rats.

Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida).

PubMed

Linck, Viviane M; Ganzella, Marcelo; Herrmann, Ana P; Okunji, Christopher O; Souza, Diogo O; Antonelli, Marta C; Elisabetsky, Elaine

2015-01-15

Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field. Copyright © 2014 Elsevier GmbH. All rights reserved.

Differential glutamate AMPA-receptor plasticity in subpopulations of VTA neurons in the presence or absence of residual cocaine: Implications for the development of addiction

PubMed Central

Lane, D.A.; Reed, B.; Kreek, M.J.; Pickel, V.M.

2011-01-01

Cocaine-induced plasticity of mesocorticolimbic dopamine (DA) neurons, originating in the ventral tegmental area (VTA), persists in the absence of cocaine and may contribute to both drug-craving and relapse. Glutamate AMPA receptors (AMPARs) in these neurons are implicated in this plasticity. However, there is no ultrastructural evidence that the absence of cocaine following repeated administrations affects the critical surface/synaptic availability of AMPAR GluR1 subunits in either DA or non-DA, putative GABAergic neurons within the VTA. To assess this, we used electron microscopic immunolabeling in the VTA of adult male mice sacrificed at 30 minutes or 72 hours after receiving the final of six (15 mg/kg) cocaine injections, a dosing paradigm that resulted in development of locomotor sensitization. At each time point, both cocaine- and saline-injected mice showed AMPAR GluR1 immunogold labeling in somatodendritic profiles, many of which contained immunoperoxidase labeling for the DA-synthesizing enzyme, tyrosine hydroxylase (TH). At 30 minutes after the last injection, when cocaine was systemically present, only the non-TH labeled dendrites showed a significant increase in the synaptic/plasmalemmal density of GluR1 immunogold particles. At 72 hours, when systemic cocaine was depleted, synaptic GluR1 labeling was greatly enhanced in TH-containing dendrites throughout the VTA and in non-TH dendrites of the limbic-associated paranigral VTA. Our results demonstrate that systemic cocaine produces GluR1 trafficking specifically in non-DA neurons of the VTA, which may subsequently contribute to the abstinent-induced enhancement of AMPA receptor synaptic transmission in mesocorticolimbic DA neurons leading to heightened drug seeking behavior. PMID:21215761

In vivo gastric residence and gastroprotective effect of floating gastroretentive tablet of DA-9601, an extract of Artemisia asiatica, in beagle dogs

PubMed Central

Kim, Jeong Soo; Cha, Kwang Ho; Kang, Seung Yeob; Won, Donghan; Jang, Sun Woo; Son, Miwon; Son, Moon Ho; Choi, Ho Jung; Lee, Young Won; Kang, Myung Joo

2016-01-01

Objective DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601. Method In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days. Results Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm3) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy. Conclusion Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance. PMID:27354765

Relationship between molecular weight, monosaccharide composition and immunobiologic activity of Astragalus polysaccharides.

PubMed

Jiang, Yiping; Qi, Xiaohui; Gao, Kai; Liu, Wenjun; Li, Na; Cheng, Ningbo; Ding, Gang; Huang, Wenzhe; Wang, Zhenzhong; Xiao, Wei

2016-10-01

Four Astragalus polysaccharides (APS1-APS4) were isolated from the water extract of Radix Astragali and purified through ethanol precipitation with 20 %, 40 %, 60 % and 80 % ethanol, respectively. The total sugar content was measured by sulfuric acid-phenol method. Their molecular weight was determined using high performance gel permeation chromatography (HPGPC) and their monosaccharide composition was analyzed by reversed-phase high performance liquid chromatography (HPLC) after pre-column derivatization. Then the immunobiologic activity of APS was evaluated by the experiment of spleen lymphocytes proliferation in vitro. The data suggested that precipitation by different concentration of ethanol will obtain different molecular weight APS, the higher concentration of ethanol the smaller molecular weight for APS. The molecular weights of four APS were 257.7 kDa, 40.1 kDa, 15.3 kDa and 3.2 kDa. Monosaccharide composition analysis indicated that APS1 consisted of glucose only, and APS2 all consisted of arabinose. APS3 consisted of rhamnose, glucose, galactose and arabinose and APS4 consisted of galactose and arabinose, in a molar ratio of 1:10.76:6.55:12 and 3.02:1. The result of immunobiologic activity assay showed that both APS2 and APS3 can effectively stimulate normal spleen lymphocyte proliferation in vitro. Apart from this, the effect of APS2 also showed dose dependent tendency from 6.25 μg/mL to 800 μg/mL. The result of this research indicated that Astragalus polysaccharides, which consist of arabinose and their molecular weight between 15.2 kDa to 40.1 kDa, neither too high nor too low, had significant immune activity.

Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice.

PubMed

Shen, Hui; Harvey, Brandon K; Chiang, Yung-Hsiao; Pick, Chaim G; Wang, Yun

2011-01-12

We previously demonstrated that high doses of methamphetamine (MA) exacerbate damage induced by severe brain trauma. The purpose of the present study was to examine if MA, at low dosage, affected abnormalities in locomotor activity and dopamine turnover in a mouse model of mild traumatic brain injury (mTBI). Adult male CD1 mice were treated with MA (5 mg/kgi.p.) or vehicle 30-min prior to mTBI, conducted by dropping a 30 g metal weight onto the temporal skull, anterior the right ear. At 15 min after mTBI, animals were put into locomotor activity chambers for up to 72 h. During the first 3 h, mTBI alone, compared with vehicle control, did not alter total distance travelled. Treatment with MA significantly increased locomotor activity in the control animals during the first 3 h; mTBI reduced MA-induced hyperactivity. In contrast, at 2 and 3 days after injury, mTBI or MA alone reduced locomotor activity. Co-treatment with MA and mTBI further reduced this activity, suggesting a differential and temporal behavioral interaction between MA and mTBI during acute and subacute phases after injury. Dopamine and DOPAC levels in striatal tissue were analyzed using HPLC-ECD. At 1h after mTBI or injection, DA was not altered but DOPAC level and DOPAC/DA turnover ratios were significantly reduced. Co-treatment with MA further reduced the DOPAC/DA ratio. At 36 h after injury, mTBI increased tissue DA levels, but reduced DOPAC levels and DOPAC/DA ratios. Co-treatment with MA further reduced DOPAC/DA ratios in striatum. In conclusion, our data suggest that low dosage of MA worsens the suppression of locomotor responses and striatal dopamine turnover after mTBI. Published by Elsevier B.V.

In vivo gastric residence and gastroprotective effect of floating gastroretentive tablet of DA-9601, an extract of Artemisia asiatica, in beagle dogs.

PubMed

Kim, Jeong Soo; Cha, Kwang Ho; Kang, Seung Yeob; Won, Donghan; Jang, Sun Woo; Son, Miwon; Son, Moon Ho; Choi, Ho Jung; Lee, Young Won; Kang, Myung Joo

2016-01-01

DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601. In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days. Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm(3)) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy. Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance.

Prepuberal intranasal dopamine treatment in an animal model of ADHD ameliorates deficient spatial attention, working memory, amino acid transmitters and synaptic markers in prefrontal cortex, ventral and dorsal striatum.

PubMed

Ruocco, L A; Treno, C; Gironi Carnevale, U A; Arra, C; Mattern, C; Huston, J P; de Souza Silva, M A; Nikolaus, S; Scorziello, A; Nieddu, M; Boatto, G; Illiano, P; Pagano, C; Tino, A; Sadile, A G

2014-09-01

Intranasal application of dopamine (IN-DA) has been shown to increase motor activity and to release DA in the ventral (VS) and dorsal striatum (DS) of rats. The aim of the present study was to assess the effects of IN-DA treatment on parameters of DA and excitatory amino acid (EAA) function in prepuberal rats of the Naples high-excitability (NHE) line, an animal model for attention-deficit hyperactivity disorder (ADHD) and normal random bred (NRB) controls. NHE and NRB rats were daily administered IN-DA (0.075, 0.15, 0.30 mg/kg) or vehicle for 15 days from postnatal days 28-42 and subsequently tested in the Làt maze and in the Eight-arm radial Olton maze. Soluble and membrane-trapped L-glutamate (L-Glu) and L-aspartate (L-Asp) levels as well as NMDAR1 subunit protein levels were determined after sacrifice in IN-DA- and vehicle-treated NHE and NRB rats in prefrontal cortex (PFc), DS and VS. Moreover, DA transporter (DAT) protein and tyrosine hydroxylase (TH) levels were assessed in PFc, DS, VS and mesencephalon (MES) and in ventral tegmental area (VTA) and substantia nigra, respectively. In NHE rats, IN-DA (0.30 mg/kg) decreased horizontal activity and increased nonselective attention relative to vehicle, whereas the lower dose (0.15 mg/kg) increased selective spatial attention. In NHE rats, basal levels of soluble EAAs were reduced in PFc and DS relative to NRB controls, while membrane-trapped EAAs were elevated in VS. Moreover, basal NMDAR1 subunit protein levels were increased in PFc, DS and VS relative to NRB controls. In addition, DAT protein levels were elevated in PFc and VS relative to NRB controls. IN-DA led to a number of changes of EAA, NMDAR1 subunit protein, TH and DAT protein levels in PFc, DS, VS, MES and VTA, in both NHE and NRB rats with significant differences between lines. Our findings indicate that the NHE rat model of ADHD may be characterized by (1) prefrontal and striatal DAT hyperfunction, indicative of DA hyperactivty, and (2) prefrontal and striatal NMDA receptor hyperfunction indicative of net EAA hyperactivty. IN-DA had ameliorative effects on activity level, attention, and working memory, which are likely to be associated with DA action at inhibitory D2 autoreceptors, leading to a reduction in striatal DA hyperactivity and, possibly, DA action on striatal EAA levels, resulting in a decrease of striatal EAA hyperfunction (with persistence of prefrontal EAA hyperfunction). Previous studies on IN-DA treatment in rodents have indicated antidepressant, anxiolytic and anti-parkinsonian effects in relation to enhanced central DAergic activity. Our present results strengthen the prospects of potential therapeutic applications of intranasal  DA by indicating an enhancement of selective attention and working memory in a deficit model.

Assessment of central dopaminergic function using plasma-free homovanillic acid after debrisoquin administration.

PubMed

Riddle, M A; Leckman, J F; Cohen, D J; Anderson, M; Ort, S I; Caruso, K A; Shaywitz, B A

1986-01-01

Central dopaminergic (DA) function in children and adults was assessed by monitoring plasma-free levels of the dopamine metabolite homovanillic acid (pHVA) before and after a single oral dose and chronic oral administration of debrisoquin. Debrisoquin inhibits peripheral metabolism of dopamine to HVA and does not cross the blood-brain barrier. By reducing peripheral formation of HVA through the use of debrisoquin, the remaining HVA in plasma more accurately reflects central DA activity. Debrisoquin administration resulted in marked reductions of pHVA in each of 12 patients studied. Eleven of the 12 subjects tolerated debrisoquin without physical or behavioral side effects. The debrisoquin administration method appears to be a safe and potentially valid technique for evaluating aspects of central dopaminergic function in children and adults.

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients.

PubMed

Stocchi, Fabrizio; Borgohain, Rupam; Onofrj, Marco; Schapira, Anthony H V; Bhatt, Mohit; Lucini, Valentina; Giuliani, Rodolfo; Anand, Ravi

2012-01-01

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation. Copyright © 2011 Movement Disorder Society.

Suppression of proliferation and neurite extension of human neuroblastoma SH-SY5Y cells on immobilized Psathyrella velutina lectin.

PubMed

Kitamura, Noriaki; Ikekita, Masahiko; Hayakawa, Satoru; Funahashi, Hisayuki; Furukawa, Kiyoshi

2004-02-01

Glycoproteins from mammalian brain tissues contain unique N-linked oligosaccharides terminating with beta-N-acetylglucosamine residues. Lectin blot analysis of membrane glycoprotein samples from human neuroblastoma SH-SY5Y cells showed that several protein bands bind to Psathylera velutina lectin (PVL), which interacts with beta-N-acetylglucosamine-terminating oligosaccharides. No lectin positive bands were detected by digestion with jack bean beta-N-acetyl-hexosaminidase or N-glycanase before incubation with the lectin, indicating that the cells contain beta-N-acetylglucosamine-terminating N-linked oligosaccharides. When cells were cultured in dishes with different concentrations of PVL, the cell proliferation was inhibited in a dose-dependent manner. Similarly, the neurite extension, which was stimulated with nerve growth factor, was also inhibited in a manner dependent on the lectin dose. Cell proliferation and neurite extension were recovered by the addition of 10 mM N-acetylglucosamine into the medium. Immunoblot analysis of the activation of mitogen-activated protein (MAP) kinases and protein kinase C revealed that phosphorylation of 42-kDa and 44-kDa MAP kinases and 80-kDa protein kinase C are inhibited when SH-SY5Y cells are cultured in PVL-coated dishes, but are restored by the addition of the haptenic sugar into the medium, indicating that MAP kinase and protein kinase C pathways are inhibited by interaction with immobilized PVL. These results indicate that beta-N-acetylglucosamine-terminating N-linked oligosaccharides expressed on neural cells can induce intracellular signals upon binding to extracellular receptors, and are important for growth regulation of neural cells. Copyright 2003 Wiley-Liss, Inc.

Venom from Opisthacanthus elatus scorpion of Colombia, could be more hemolytic and less neurotoxic than thought.

PubMed

Estrada-Gómez, Sebastián; Vargas Muñoz, Leidy Johana; Saldarriaga-Córdoba, Mónica; Quintana Castillo, Juan Carlos

2016-01-01

We report the first biochemical, biological, pharmacological and partial proteomic characterization studies of the Opisthancanthus elatus venom (Gervais, 1844) from Colombia. The Reverse Phase High-Performance Liquid Chromatography venom profile showed 28 main well-defined peaks, most eluting between 20 and 45min (18-30% of acetonitrile, respectively). High-resolution mass analysis indicates the presence of 106 components ranging from 806.59742Da to 16849.4139Da. O. elatus venom showed hemolytic activity and hydrolyzed the specific substrate BapNa suggesting the presence of proteins with serine-protease activity. Collected RP-HPLC fractions eluting at 52.6, 55.5, 55.8, 56.2, and 63.9min (PLA2 region between 33 and 40% of acetonitrile), showed hemolytic activity and hydrolyzed the synthetic substrate 4-nitro-3-octanoyloxy-benzoic acid, indicating the presence of compounds with phospholipases A2 activity. These RP-HPLC fractions, showed molecular masses values up to 13978.19546Da, corroborating the possible presence of the mentioned enzymes. Tryptic digestion and MS/MS analysis showed the presence of a phospholipase like fragment, similar to on described in other Opisthacanthus genus studies. No coagulant activity was observed. No larvicidal or antimicrobial activity was observed at concentrations evaluated. Lethal and toxic activity is expected at doses above 100mg/kg, no neurotoxic effects were detected at lower doses. In conclusion, O. elatus exhibits a venom with a predominant phospholipase A2 activity than thought; mammal's neurotoxic activity is expected above the 100mg/kg, which is very high compared to the venom from other neurotoxic scorpions. Copyright © 2015 Elsevier B.V. All rights reserved.

Ocular tissue distribution and pharmacokinetic study of a small 13kDa domain antibody after intravitreal, subconjuctival and eye drop administration in rabbits.

PubMed

Gough, Gerald; Szapacs, Matthew; Shah, Tejash; Clements, Peter; Struble, Craig; Wilson, Robert

2018-02-01

Domain antibodies (dAb's) comprise the smallest functional unit of human IgG and can be targeted to a range of different soluble cytokine and receptor targets in the eye. In particular their small size may offer advantage for ocular tissue penetration and distribution. To investigate this we used a 13kDa tool molecule to undertake a preliminary short term ocular tissue distribution and pharmacokinetic study in the rabbit eye. The dAb was administered by the intravitreal or subconjunctival route or, as topical eye drops for up to five days and dAb concentrations measured in vitreous, aqueous, conjunctiva, choroid-RPE, retina, iris, sclera, and ciliary body. The observed elimination half-live of the dAb (~3 days) in vitreous showed a similar elimination rate to that of a much larger (∼50kDa) Fab fragment whilst the half-life following subconjunctival administration was ∼24 h and, after eye drop dosing the dAb was detectable in aqueous and conjunctiva. These preliminary data show that the intravitreal half-life of dAb's are similar to much larger antibody fragments, offering the potential to deliver significantly more drug to target on a molar basis with a single intravitreal injection potentially enabling dosing frequencies of once a month or less. Subconjunctival injection may provide short duration therapeutic levels of dAb to the anterior and posterior chamber whilst topical eye drop delivery of dAbs may be useful in front-of-eye disease. These data indicate that small domain antibodies may have utility in ophthalmology. Further studies are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Long-term outcome of macroprolactinomas.

PubMed

Képénékian, Lori; Cebula, Hélène; Castinetti, Frédéric; Graillon, Thomas; Brue, Thierry; Goichot, Bernard

2016-12-01

Management of macroprolactinomas has dramatically changed in recent decades, from surgical to medical treatment as first-line therapy, with the development of dopamine agonists (DA). But few data exist on the long-term outcome of these patients. Retrospective descriptive multicenter study of patients with macroprolactinoma followed for at least 5 years between 1973 and 2008 at the University Hospitals of Strasbourg and Marseille. Forty-eight patients were included with 27 men, hypopituitarism in 33.3% of all patients and mean serum prolactin (PRL) level at diagnosis 2218.2±4154.7μg/L. Among the patients, 58.3% received medical treatment, 25% had additional surgery and 12.5% surgery and radiotherapy. The mean follow-up duration was 196±100 months. At the end of follow-up, 10 patients (20.8%) were cured (i.e. normal PRL level and normal imaging, no symptoms and withdrawal of DA≥1 year), 33 (68.8%) were controlled (i.e. normal PRL level, normal or abnormal imaging, no symptoms, DA in progress) and 5 (10.4%) were uncontrolled. Uncontrolled patients had significant higher baseline PRL level (P=0.0412) and cabergoline cumulative dose (P=0.0065) compared to the controlled group. There was no increase in frequency of hypopituitarism. Clinically significant valvular heart disease was found in 2 patients but screening was not systematic. Macroprolactinoma is currently most often a chronic disease controlled with DA. However, uncertainty about the adverse effects associated with high cumulative doses and the lack of data on the prognosis at very long-term should incite to revisit current strategies, including the role of surgery combined to medical treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effort-Related Motivational Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Animal Models of the Motivational Symptoms of Depression

PubMed Central

Nunes, Eric J.; Randall, Patrick A.; Hart, Evan E.; Freeland, Charlotte; Yohn, Samantha E.; Baqi, Younis; Müller, Christa E.; López-Cruz, Laura; Correa, Mercè

2013-01-01

Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders. PMID:24305809

Purification, structural characterization and anticancer activity of the novel polysaccharides from Rhynchosia minima root.

PubMed

Jia, Xuejing; Zhang, Chao; Qiu, Jianfeng; Wang, Lili; Bao, Jiaolin; Wang, Kai; Zhang, Yulin; Chen, Meiwan; Wan, Jianbo; Su, Huanxing; Han, Jianping; He, Chengwei

2015-11-05

Three novel acidic polysaccharides termed PRM1, PRM3 and PRM5 were purified from Rhynchosia minima root using DEAE-52 cellulose and sephadex G-150 column chromatography. Their structures were characterized by ultraviolet (UV) and Fourier transform infrared (FTIR) spectrometry, gel permeation chromatography (GPC), gas chromatography-mass spectrometry (GC-MS), and differential scanning colorimeter (DSC) analysis. The uronic acid contents of PRM1, PRM3 and PRM5 were 30.7%, 12.7% and 47.7%, respectively. PRM1 (143.2 kDa), PRM3 (105.3 kDa) and PRM5 (162.1 kDa) were heteropolysaccharides because they were composed of arabinose, mannose, glucose and galactose. Their enthalpy values were 201.0, 111.0 and 206.8 J/g, respectively. PRM3 and PRM1 exhibited strong in vitro anticancer activity against lung cancer A549 and liver cancer HepG2 cells in a dose-dependent manner. These findings suggested that PRM1 and PRM3 could be potentially developed as natural anticancer agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells

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

Not Available

The effects of bacterial lipopolysaccharide (endotoxin) on the fibrinolytic activity of bovine pulmonary artery endothelial cells were examined. Endotoxin suppressed the net fibrinolytic activity of cell extracts and conditioned media in a dose-dependent manner. The effects of endotoxin required at least 6 h for expression. Cell extracts and conditioned media contained a 44-kDa urokinase-like plasminogen activator. Media also contained multiple plasminogen activators with molecular masses of 65-75 and 80-100 kDa. Plasminogen activators in extracts and media were unchanged by treatment of cells with endotoxin. Diisopropyl fluorophosphate (DFP)-abolished fibrinolytic activity of extracts and conditioned media. DFP-treated samples from endotoxin-treated but notmore » untreated cells inhibited urokinase and tissue plasminogen activator, but not plasmin. Inhibitory activity was lost by incubation at pH 3 or heating to 56/sup 0/C for 10 min. These treatments did not affect inhibitory activity of fetal bovine serum. Incubation of /sup 125/I-urokinase with DFP-treated medium from endotoxin-treated cells produced an inactive complex with an apparent molecular mass of 80-85 kDa.« less

Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations.

PubMed

Wang, Xiuyan; Yan, Husheng

2017-09-01

Methotrexate as a model drug with poor aqueous solubility was adsorbed into porous polymeric adsorbents, which was used as oral sustained release formulations. In vitro release assay in simulated gastrointestinal fluids showed that the methotrexate-loaded adsorbents showed distinct sustained release performance. The release rate increased with increase in pore size of the adsorbents. In vivo pharmacokinetic study showed that the maximal plasma methotrexate concentrations after oral administration of free methotrexate and methotrexate-loaded DA201-H (a commercial porous polymeric adsorbent) to rats occurred at 40min and 5h post-dose, respectively; and the plasma concentrations decreased to 22% after 5h for free methotrexate and 44% after 24h for methotrexate-loaded DA201-H, respectively. The load of methotrexate into the porous polymeric adsorbents not only resulted in obvious sustained release, but also enhanced the oral bioavailability of methotrexate. The areas under the curve, AUC 0-24 and AUC 0-inf , for methotrexate-loaded DA201-H increased 3.3 and 7.7 times, respectively, compared to those for free methotrexate. Copyright © 2017 Elsevier B.V. All rights reserved.

Self‐expanding stent effects on radiation dosimetry in esophageal cancer

PubMed Central

Francis, Samual R.; Wang, Brian; Williams, Greg V.; Cox, Kristen; Adler, Douglas G.; Shrieve, Dennis C.; Salter, Bill J.

2013-01-01

It is the purpose of this study to evaluate how self‐expanding stents (SESs) affect esophageal cancer radiation planning target volumes (PTVs) and dose delivered to surrounding organs at risk (OARs). Ten patients were evaluated, for whom a SES was placed before radiation. A computed tomography (CT) scan obtained before stent placement was fused to the post‐stent CT simulation scan. Three methods were used to represent pre‐stent PTVs: 1) image fusion (IF), 2) volume approximation (VA), and 3) diameter approximation (DA). PTVs and OARs were contoured per RTOG 1010 protocol using Eclipse Treatment Planning software. Post‐stent dosimetry for each patient was compared to approximated pre‐stent dosimetry. For each of the three pre‐stent approximations (IF, VA, and DA), the mean lung and liver doses and the estimated percentages of lung volumes receiving 5 Gy, 10 Gy, 20 Gy, and 30 Gy, and heart volumes receiving 40 Gy were significantly lower (p‐values <0.02) than those estimated in the post‐stent treatment plans. The lung V5, lung V10, and heart V40 constraints were achieved more often using our pre‐stent approximations. Esophageal SES placement increases the dose delivered to the lungs, heart, and liver. This may have clinical importance, especially when the dose‐volume constraints are near the recommended thresholds, as was the case for lung V5, lung V10, and heart V40. While stents have established benefits for treating patients with significant dysphagia, physicians considering stent placement and radiation therapy must realize the effects stents can have on the dosimetry. PACS number: 87.55.dk PMID:23835387

Using Pharmacoeconomic Modelling to Determine Value-Based Pricing for New Pharmaceuticals in Malaysia

PubMed Central

Dranitsaris, George; Truter, Ilse; Lubbe, Martie S; Sriramanakoppa, Nitin N; Mendonca, Vivian M; Mahagaonkar, Sangameshwar B

2011-01-01

Background: Decision analysis (DA) is commonly used to perform economic evaluations of new pharmaceuticals. Using multiples of Malaysia’s per capita 2010 gross domestic product (GDP) as the threshold for economic value as suggested by the World Health Organization (WHO), DA was used to estimate a price per dose for bevacizumab, a drug that provides a 1.4-month survival benefit in patients with metastatic colorectal cancer (mCRC). Methods: A decision model was developed to simulate progression-free and overall survival in mCRC patients receiving chemotherapy with and without bevacizumab. Costs for chemotherapy and management of side effects were obtained from public and private hospitals in Malaysia. Utility estimates, measured as quality-adjusted life years (QALYs), were determined by interviewing 24 oncology nurses using the time trade-off technique. The price per dose was then estimated using a target threshold of US$44 400 per QALY gained, which is 3 times the Malaysian per capita GDP. Results: A cost-effective price for bevacizumab could not be determined because the survival benefit provided was insufficient According to the WHO criteria, if the drug was able to improve survival from 1.4 to 3 or 6 months, the price per dose would be $567 and $1258, respectively. Conclusion: The use of decision modelling for estimating drug pricing is a powerful technique to ensure value for money. Such information is of value to drug manufacturers and formulary committees because it facilitates negotiations for value-based pricing in a given jurisdiction. PMID:22589671

Evaluation of the trade-offs encountered in planning and treating locally advanced head and neck cancer: intensity-modulated radiation therapy vs dual-arc volumetric-modulated arc therapy

PubMed Central

Oliver, M; McConnell, D; Romani, M; McAllister, A; Pearce, A; Andronowski, A; Wang, X; Leszczynski, K

2012-01-01

Objective The primary purpose of this study was to assess the practical trade-offs between intensity-modulated radiation therapy (IMRT) and dual-arc volumetric-modulated arc therapy (DA-VMAT) for locally advanced head and neck cancer (HNC). Methods For 15 locally advanced HNC data sets, nine-field step-and-shoot IMRT plans and two full-rotation DA-VMAT treatment plans were created in the Pinnacle3 v. 9.0 (Philips Medical Systems, Fitchburg, WI) treatment planning environment and then delivered on a Clinac iX (Varian Medical Systems, Palo Alto, CA) to a cylindrical detector array. The treatment planning goals were organised into four groups based on their importance: (1) spinal cord, brainstem, optical structures; (2) planning target volumes; (3) parotids, mandible, larynx and brachial plexus; and (4) normal tissues. Results Compared with IMRT, DA-VMAT plans were of equal plan quality (p>0.05 for each group), able to be delivered in a shorter time (3.1 min vs 8.3 min, p<0.0001), delivered fewer monitor units (on average 28% fewer, p<0.0001) and produced similar delivery accuracy (p>0.05 at γ2%/2mm and γ3%/3mm). However, the VMAT plans took more planning time (28.9 min vs 7.7 min per cycle, p<0.0001) and required more data for a three-dimensional dose (20 times more, p<0.0001). Conclusions Nine-field step-and-shoot IMRT and DA-VMAT are both capable of meeting the majority of planning goals for locally advanced HNC. The main trade-offs between the techniques are shorter treatment time for DA-VMAT but longer planning time and the additional resources required for implementation of a new technology. Based on this study, our clinic has incorporated DA-VMAT for locally advanced HNC. Advances in knowledge DA-VMAT is a suitable alternative to IMRT for locally advanced HNC. PMID:22806619

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

PubMed Central

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

2016-01-01

Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here, menthol alone exerts several neurobiological changes. We are among the first to show that menthol, by itself, increases the number of nicotinic acetylcholine receptors (nAChRs) in the mouse brain. It does so at a dose that matches nicotine in its ability to increase nAChR number. At this same dose, menthol also alters midbrain dopamine neuron function and prevents nicotine reward-related behavior. Together, our data show that menthol is more than an “inert” flavor additive and is able to change the function of midbrain dopamine neurons that are part of the mesolimbic reward pathway. PMID:26961950

Addition of 20-kDa PEG to Insulin Lispro Alters Absorption and Decreases Clearance in Animals.

PubMed

Knadler, Mary Pat; Nguyen, Tri-Hung; Campanale, Kristina; De Veer, Michael J; Beals, John M; Li, Shun; Hansen, Ryan; Siesky, Angela; Michael, M Dodson; Porter, Christopher J H

2016-12-01

Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep. BIL is insulin lispro modified with 20-kDa linear PEG at lysine B28 increasing the hydrodynamic size to 4-fold larger than insulin lispro. Pharmacokinetics of BIL and insulin lispro after IV administration were compared in 5/6-nephrectomized and sham rats. BIL was administered IV or SC into the interdigital space of the hind leg, and peripheral lymph and/or serum samples were collected from both LDC and non-LDC sheep to determine pharmacokinetics and absorption route of BIL. The clearance of BIL was similar in 5/6-nephrectomized and sham rats, while the clearance of insulin lispro was 3.3-fold slower in 5/6-nephrectomized rats than in the sham rats. In non-LDC sheep, the terminal half-life after SC was about twice as long vs IV suggesting flip-flop pharmacokinetics. In LDC sheep, bioavailability decreased to <2%; most of the dose was absorbed via the lymphatic system, with 88% ± 19% of the dose collected in the lymph after SC administration. This work demonstrates that increasing the hydrodynamic size of insulin lispro through PEGylation can impact both absorption and clearance to prolong drug action.

Attenuated migration by green tea extract (-)-epigallocatechin gallate (EGCG): involvement of 67 kDa laminin receptor internalization in macrophagic cells.

PubMed

Ren, Xuezhi; Guo, Xingzhi; Chen, Li; Guo, Minxia; Peng, Ning; Li, Rui

2014-08-01

Excessive activation of the microglia in the brain is involved in the development of several neurodegenerative diseases. Previous studies have indicated that (-)-epigallocatechin gallate (EGCG), a major active constituent of green tea, exhibits potent suppressive effects on the activation of microglia. As the 67 kDa laminin receptor (67LR) is a key element in cellular activation and migration, we investigated the effect of EGCG on cell migration and 67LR in lipopolysaccharide (LPS)-activated macrophagic RAW264.7 cells. The presence of EGCG (1-25 μM) markedly attenuated LPS-induced cell migration in a dose-dependent manner. However, the total amount of 67LR protein in the RAW264.7 cells was unaffected by EGCG, as revealed by Western blot analysis. In addition, confocal immunofluorescence microscopy indicated that EGCG caused a marked membrane translocation of 67LR from the membrane surface towards the cytoplasm. Cell-surface biotinylation analysis confirmed that EGCG induced a significant internalization of 67LR by 24-68% in a dose-dependent manner. This study helps to explain the pharmacological action of EGCG on 67LR, suggesting its potential use in the treatment of diseases associated with macrophage/microglia activation, such as neurodegenerative diseases and cancer.

Identification of a major 50-kDa molecular weight human B-cell growth factor with Tac antigen-inducing activity on B cells.

PubMed

Kawano, M; Matsushima, K; Oppenheim, J J

1987-08-01

A bioassay was developed using human small B cells adherent to anti-human IgM (anti-mu)-coated wells. These B cells were stimulated to proliferate by culture supernatants of concanavalin A (Con A)-activated human peripheral blood lymphocytes (Con A Sup) even in the presence of high concentrations of anti-mu coated on assay wells. Human B-cell growth factor (BCGF) activities were partially purified from Con A Sup. Preparative chromatography (Sephacryl S-200 and isoelectrofocusing) yielded a major peak of BCGF activity for B cells adherent to anti-mu-coated wells with a molecular weight of 50,000 (50 kDa) and a pI 7.6. The 50-kDa BCGF was further purified by sequential chromatography using DEAE-Sephacel, CM-Sepharose, Sephacryl S-200, CM-high performance liquid chromatography (HPLC), and hydroxyapatite (HA)-HPLC. The HA-HPLC-purified 50-kDa BCGF was free of interleukin-1 (IL-1), interleukin-2 (IL-2), and interferon activities, but could support growth of BCL1 cells, similar to BCGF-II. Neither IL-1 nor interferon-gamma had any growth-stimulating effect in our B-cell proliferation assay with or without BCGF in Iscove's synthetic assay medium. BCGF-induced proliferation of B cells adherent to anti-mu-coated wells could be markedly augmented by the simultaneous or sequential addition of recombinant human IL-2 (rIL-2). When cultured for 3 days with 50-kDa BCGF, about 40% of B cells adherent to anti-mu-coated wells expressed Tac antigen, and monoclonal anti-Tac antibody inhibited rIL-2 enhancement of proliferation of 50-kDa BCGF-preactivated B cells. In addition, 50-kDa BCGF could induce Tac antigen on an Epstein-Barr virus-transformed B-cell line (ORSON) in the presence of a suboptimal dose of phorbol myristate acetate (PMA) and also on a natural killer-like cell line (YT cells). We have therefore identified a major 50-kDa BCGF activity with Tac antigen-inducing activity that also has a synergistic effect with IL-2 on normal B-cell proliferation.

Peripheral Administration of Ethanol Results in a Correlated Increase in Dopamine and Serotonin Within the Posterior Ventral Tegmental Area

PubMed Central

Deehan, Gerald A.; Knight, Christopher P.; Waeiss, R. Aaron; Engleman, Eric A.; Toalston, Jamie E.; McBride, William J.; Hauser, Sheketha R.; Rodd, Zachary A.

2016-01-01

Aims Two critical neurotransmitter systems regulating ethanol (EtOH) reward are serotonin (5-HT) and dopamine (DA). Within the posterior ventral tegmental area (pVTA), 5-HT receptors have been shown to regulate DA neuronal activity. Increased pVTA neuronal activity has been linked to drug reinforcement. The current experiment sought to determine the effect of EtOH on 5-HT and DA levels within the pVTA. Methods Wistar rats were implanted with cannula aimed at the pVTA. Neurochemical levels were determined using standard microdialysis procedures with concentric probes. Rats were randomly assigned to one of the five groups (n = 41; 7–9 per group) that were treated with 0–3.0 g/kg EtOH (intraperitoneally). Results Ethanol produced increased extracellular DA levels in the pVTA that resembled an inverted U-shape dose–response curve with peak levels (~200% of baseline) at the 2.25 g/kg dose. The increase in DA levels was observed for an extended period of time (~100 minutes). The effects of EtOH on extracellular 5-HT levels in the pVTA also resembled an inverted U-shape dose–response curve. However, increased 5-HT levels were only observed during the initial post-injection sample. The increases in extracellular DA and 5-HT levels were significantly correlated. Conclusion The data indicate intraperitoneal EtOH administration stimulated the release of both 5-HT and DA within the pVTA, the levels of which were significantly correlated. Overall, the current findings suggest that the ability of EtOH to stimulate DA activity within the mesolimbic system may be modulated by increases in 5-HT release within the pVTA. Short summary Two critical neurotransmitter systems regulating ethanol reward are serotonin and dopamine. The current experiment determined that intraperitoneal ethanol administration increased serotonin and dopamine levels within the pVTA (levels were significantly correlated). The current findings suggest the ability of EtOH to stimulate serotonin and dopamine activity within the mesolimbic system. PMID:27307055

Quantification of transient increase of the blood–brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles

PubMed Central

Shi, Lingyan; Palacio-Mancheno, Paolo; Badami, Joseph; Shin, Da Wi; Zeng, Min; Cardoso, Luis; Tu, Raymond; Fu, Bingmei M

2014-01-01

Radioimmunotherapy using a radiolabeled monoclonal antibody that targets tumor cells has been shown to be efficient for the treatment of many malignant cancers, with reduced side effects. However, the blood–brain barrier (BBB) inhibits the transport of intravenous antibodies to tumors in the brain. Recent studies have demonstrated that focused ultrasound (FUS) combined with microbubbles (MBs) is a promising method to transiently disrupt the BBB for the drug delivery to the central nervous system. To find the optimal FUS and MBs that can induce reversible increase in the BBB permeability, we employed minimally invasive multiphoton microscopy to quantify the BBB permeability to dextran-155 kDa with similar molecular weight to an antibody by applying different doses of FUS in the presence of MBs with an optimal size and concentration. The cerebral microcirculation was observed through a section of frontoparietal bone thinned with a micro-grinder. About 5 minutes after applying the FUS on the thinned skull in the presence of MBs for 1 minute, TRITC (tetramethylrhodamine isothiocyanate)-dextran-155 kDa in 1% bovine serum albumin in mammalian Ringer’s solution was injected into the cerebral circulation via the ipsilateral carotid artery by a syringe pump. Simultaneously, the temporal images were collected from the brain parenchyma ~100–200 μm below the pia mater. Permeability was determined from the rate of tissue solute accumulation around individual microvessels. After several trials, we found the optimal dose of FUS. At the optimal dose, permeability increased by ~14-fold after 5 minutes post-FUS, and permeability returned to the control level after 25 minutes. FUS without MBs or MBs injected without FUS did not change the permeability. Our method provides an accurate in vivo assessment for the transient BBB permeability change under the treatment of FUS. The optimal FUS dose found for the reversible BBB permeability increase without BBB disruption is reliable and can be applied to future clinical trials. PMID:25258533

Detecção inesperada de efeitos de lentes fracas em grupos de galáxias pouco luminosos em raios-X

NASA Astrophysics Data System (ADS)

Carrasco, R.; Mendes de Oliveira, C.; Sodré, L., Jr.; Lima Neto, G. B.; Cypriano, E. S.; Lengruber, L. L.; Cuevas, H.; Ramirez, A.

2003-08-01

Obtivemos, como parte do programa de verificação científica do GMOS Sul, imagens profundas de três grupos de galáxias: G97 e G102 (z~0,4) e G124 (z = 0,17). Esses alvos foram selecionados a partir do catálogo de fontes extensas de Vikhlinin (1998), por terem luminosidades em raios X menores que 3´1043 ergs s-1, valor cerca de uma ou duas ordens de grandeza inferior ao de aglomerados de galáxias. O objetivo primário dessas observações é o estudo da evolução de galáxias em grupos. Grupos são ambientes menos densos que aglomerados, contêm a grande maioria das galáxias do Universo mas que, até o momento, foram estudados detalhadamente apenas no Universo local (z~0). Com esses dados efetuamos uma análise estatística da distorção na forma das galáxias de fundo (lentes gravitacionais fracas) como forma de inferir o conteúdo e a distribuição de massa nesses grupos apesar de que, em princípio, esse efeito não deveria ser detectado uma vez que os critérios de seleção adotados previlegiam sistemas de baixa massa. De fato, para G124 obtivemos apenas um limite superior para sua massa que é compatível com sua luminosidade em raios X. De modo contrário e surpreendente, os objetos G102 e G097, aparentam ter massas que resultariam em dispersões de velocidade maiores que 1000 km s-1, muito maiores do que se espera para grupos de galáxias. Com efeito, para G097 obtivemos, a partir de dados do satélite XMM, uma estimativa para a temperatura do gás intragrupo de kT = 2,6 keV, que é tipica de sistemas com dispersões de velocidade de ~ 600 km s-1, bem característica de grupos. Essas contradições aparentes entre lentes fracas e raios X podem ser explicadas de dois modos: i) a massa obtida por lentes estaria sobreestimada devido à superposição de estruturas massivas ao longo da linha de visada ou ii) a temperatura do gás do meio intra-grupo reflete o potencial gravitacional de estruturas menores que estariam se fundindo para formar uma estrutura maior.

Prior Methamphetamine Self-Administration Attenuates the Dopaminergic Deficits Caused by a Subsequent Methamphetamine Exposure

PubMed Central

McFadden, Lisa M.; Vieira-Brock, Paula L.; Hanson, Glen R.; Fleckenstein, Annette E.

2015-01-01

Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose “binge” METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures. PMID:25645392

Distinguishing dose, focus, and blur for lithography characterization and control

NASA Astrophysics Data System (ADS)

Ausschnitt, Christopher P.; Brunner, Timothy A.

2007-03-01

We derive a physical model to describe the dependence of pattern dimensions on dose, defocus and blur. The coefficients of our model are constants of a given lithographic process. Model inversion applied to dimensional measurements then determines effective dose, defocus and blur for wafers patterned with the same process. In practice, our approach entails the measurement of proximate grating targets of differing dose and focus sensitivity. In our embodiment, the measured attribute of one target is exclusively sensitive to dose, whereas the measured attributes of a second target are distinctly sensitive to defocus and blur. On step-and-scan exposure tools, z-blur is varied in a controlled manner by adjusting the across slit tilt of the image plane. The effects of z-blur and x,y-blur are shown to be equivalent. Furthermore, the exposure slit width is shown to determine the tilt response of the grating attributes. Thus, the response of the measured attributes can be characterized by a conventional focus-exposure matrix (FEM), over which the exposure tool settings are intentionally changed. The model coefficients are determined by a fit to the measured FEM response. The model then fully defines the response for wafers processed under "fixed" dose, focus and blur conditions. Model inversion applied to measurements from the same targets on all such wafers enables the simultaneous determination of effective dose and focus/tilt (DaFT) at each measurement site.

Intraspecific Variation of Centruroides Edwardsii Venom from Two Regions of Colombia

PubMed Central

Estrada-Gómez, Sebastián; Cupitra, Nelson Ivan; Arango, Walter Murillo; Vargas Muñoz, Leidy Johana

2014-01-01

We report the first description studies, partial characterization, and intraspecific difference of Centruroides edwardsii, Gervais 1843, venom. C. edwardsii from two Colombian regions (Antioquia and Tolima) were evaluated. Both venoms showed hemolytic activity, possibly dependent of enzymatic active phospholipases, and neither coagulant nor proteolytic activities were observed. Venom electrophoretic profile showed significant differences between C. edwardsii venom from both regions. A high concentration of proteins with molecular masses between 31 kDa and 97.4 kDa, and an important concentration close or below 14.4 kDa were detected. RP-HPLC retention times between 38.2 min and 42.1 min, showed bands close to 14.4 kDa, which may correspond to phospholipases. RP-HPLC venom profile showed a well conserved region in both venoms between 7 and 17 min, after this, significant differences were detected. From Tolima region venom, 50 well-defined peaks were detected, while in the Antioquia region venom, 55 well-defined peaks were detected. Larvicidal activity was only detected in the C. edwardsii venom from Antioquia. No antimicrobial activity was observed using complete venom or RP-HPLC collected fractions of both venoms. Lethally activity (carried out on female albino swiss mice) was detected at doses over 19.2 mg/kg of crude venom. Toxic effects included distress, excitability, eye irritation and secretions, hyperventilation, ataxia, paralysis, and salivation. PMID:25025710

Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent regionally selective, bimodal effects on striatal dopamine kinetics in vivo.

PubMed

Harun, R; Hare, K M; Brough, M E; Munoz, M J; Grassi, C M; Torres, G E; Grace, A A; Wagner, A K

2015-11-27

Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. Levodopa (L-DOPA) was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50mg/kg carbidopa + 0, 100, and 250mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax. These findings have important implications on understanding the pharmacodynamics of L-DOPA, which can be informative for understand its therapeutic effects and also common side effects like L-DOPA induced dyskinesias (LID). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of zinc supplementation on fatigue and quality of life in patients with colorectal cancer.

PubMed

Ribeiro, Sofia Miranda de Figueiredo; Braga, Camila Bitu Moreno; Peria, Fernanda Maris; Martinez, Edson Zangiacomi; Rocha, José Joaquim Ribeiro da; Cunha, Selma Freire Carvalho

2017-01-01

To investigate the effects of oral zinc supplementation on fatigue intensity and quality of life of patients during chemotherapy for colorectal cancer. A prospective, randomized, double-blinded, placebo-controlled study was conducted with 24 patients on chemotherapy for colorectal adenocarcinoma in a tertiary care public hospital. The study patients received zinc capsules 35mg (Zinc Group, n=10) or placebo (Placebo Group, n=14) orally, twice daily (70mg/day), for 16 weeks, from the immediate postoperative period to the fourth chemotherapy cycle. Approximately 45 days after surgical resection of the tumor, all patients received a chemotherapeutic regimen. Before each of the four cycles of chemotherapy, the Functional Assessment of Chronic Illness Therapy-Fatigue scale was completed. We used a linear mixed model for longitudinal data for statistical analysis. The scores of quality of life and fatigue questionnaires were similar between the groups during the chemotherapy cycles. The Placebo Group presented worsening of quality of life and increased fatigue between the first and fourth cycles of chemotherapy, but there were no changes in the scores of quality of life or fatigue in the Zinc Group. Zinc supplementation prevented fatigue and maintained quality of life of patients with colorectal cancer on chemotherapy. Investigar os efeitos da suplementação oral de zinco sobre a intensidade da fadiga e a qualidade de vida de pacientes durante a quimioterapia para neoplasia colorretal. Estudo prospectivo, randomizado, controlado e duplo-cego conduzido em um hospital universitário público terciário, com 24 pacientes em regime quimioterápico para adenocarcinoma colorretal. Os pacientes receberam cápsulas de zinco 35mg (Grupo Zinco, n=10) ou placebo (Grupo Placebo, n=14) por via oral, duas vezes ao dia (70mg/dia), durante 16 semanas, desde o período pós-operatório imediato até o quarto ciclo de quimioterapia. Todos os pacientes receberam quimioterapia por aproximadamente 45 dias após a ressecção cirúrgica do tumor. A escala Functional Assessment of Chronic Illness Therapy-Fatigue foi preenchida antes de cada um dos quatro ciclos de quimioterapia. Utilizou-se o modelo de regressão linear misto para dados longitudinais para análise estatística. Os escores de qualidade de vida e de fadiga foram semelhantes entre os grupos de estudo durante os ciclos de quimioterapia. O Grupo Placebo apresentou piora da qualidade de vida e da fadiga entre o primeiro e o quarto ciclos de quimioterapia, mas não houve mudança nos escores de qualidade de vida e fadiga no Grupo Zinco. A suplementação com zinco previne a fadiga e preserva a qualidade de vida de pacientes em quimioterapia para neoplasia colorretal.

78 FR 32413 - Oklahoma; Amendment No. 1 to Notice of a Major Disaster Declaration

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-30

... adjustments. Further, under this pilot program, FEMA shall obtain any applicable private insurance payments... Services; 97.034, Disaster Unemployment Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048...

76 FR 34243 - Alabama; Amendment No. 14 to Notice of a Major Disaster Declaration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-13

.... Further, under this pilot program, FEMA shall obtain any applicable private insurance payments for debris..., Disaster Unemployment Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing...

76 FR 34243 - Mississippi; Amendment No. 4 to Notice of a Major Disaster Declaration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-13

..., FEMA shall obtain any applicable private insurance payments for debris removal to reimburse Federal... Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to...

Structural, thermal, functional, antioxidant & antimicrobial properties of β-d-glucan extracted from baker's yeast (Saccharomyces cereviseae)-Effect of γ-irradiation.

PubMed

Khan, Asma Ashraf; Gani, Adil; Masoodi, F A; Amin, Furheen; Wani, Idrees Ahmed; Khanday, Firdous Ahmad; Gani, Asir

2016-04-20

This study was carried out to evaluate the effect of γ-irradiation (0, 5, 10, 20, 30 & 50kGy) on the structural, functional, antioxidant and antimicrobial properties of yeast β-d-glucan. The samples were characterized by ATR-FTIR, gel permeation chromatography (GPC) and the thermal properties were studied using DSC. There was a decrease in the average molecular weight of β-d-glucan as the irradiation dose increased. The functional properties of irradiated yeast β-d-glucan were largely influenced by the action of gamma radiation like swelling power and viscosity decreases with increase in the irradiation dose while as fat binding capacity, emulsifying properties, foaming properties and bile acid binding capacity shows an increasing trend. All the antioxidant properties carried out using six different assays increased significantly (p≤0.05) in a dose dependent manner. The antibacterial activity of yeast β-d-glucan also showed an increasing trend with increase in the irradiation dose from 5 to 50kDa. Copyright © 2016 Elsevier Ltd. All rights reserved.

Application of multi-enzymatic hydrolysis for improving the efficiency of the biogas production in solid waste fermentation process in Ostróda WWTP

NASA Astrophysics Data System (ADS)

Lipiński, Kamil; Umiejewska, Katarzyna

2017-11-01

Biomass fermentation is one of the important sources of renewable energy in EU. Application of multi-enzymatic hydrolysis process enables a significant increase in efficiency of biogas production. The main goal of the paper is to present the results of the pilot scale research performed in WWTP in óstroda. The fixed combination of three enzymes was continiously introduced: amylase, lipase and protease. Research aimed at verifying the impact of enzyme dose on sludge digestion process and on the amount of biogas produced. Statistical analysis of the research results allows to determine the influence of dosing the enzymes in mesophilic digestion on the biogas production.

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

PubMed

Broderick, Patricia A; Ho, Helen; Wat, Karyn; Murthy, Vivek

2008-07-04

Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE ® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/ voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE ® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc); dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) and Ltryptophan (L-TP) are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a) is an antihypertensive and cocaine and caffeine produce hypertension and (b) acts at 5-HT 2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a) the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b) ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in NAc and open-field behaviors and (c) ketanserin inhibits 5-HT release in NAc and open-field behaviors produced by caffeine, but, surprisingly, acts to increase DA release in NAc. Importantly, the latter effect may be a possible adverse effect of the moderate dose of caffeine in hypertensive patients. Thus, an antihypertensive medication is shown here to play a role in inhibiting brain reward possibly via antihypertensive mechanisms at DA and 5-HT receptor subtypes within DA motor neurons. An explanatory note for the results obtained, is the role likely played by the G Protein Receptor Complex (GPRC) family of proteins. Empirical evidence shows that GPRC dimers, heteromers and heterotrimers may cause cross-talk between distinct signalling cascade pathways in the actions of cocaine and caffeine. Ligand-directed functional selectivity, particularly for ketanserin, in addition to GPRCs, may also cause differential responses. The results promise new therapeutic strategies for drug addiction, brain reward and cardiovascular medicine.

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

PubMed Central

Broderick, Patricia A.; Ho, Helen; Wat, Karyn; Murthy, Vivek

2008-01-01

Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc); dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) and L-tryptophan (L-TP) are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a) is an antihypertensive and cocaine and caffeine produce hypertension and (b) acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a) the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b) ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in NAc and open-field behaviors and (c) ketanserin inhibits 5-HT release in NAc and open-field behaviors produced by caffeine, but, surprisingly, acts to increase DA release in NAc. Importantly, the latter effect may be a possible adverse effect of the moderate dose of caffeine in hypertensive patients. Thus, an antihypertensive medication is shown here to play a role in inhibiting brain reward possibly via antihypertensive mechanisms at DA and 5-HT receptor subtypes within DA motor neurons. An explanatory note for the results obtained, is the role likely played by the G Protein Receptor Complex (GPRC) family of proteins. Empirical evidence shows that GPRC dimers, heteromers and heterotrimers may cause cross-talk between distinct signalling cascade pathways in the actions of cocaine and caffeine. Ligand-directed functional selectivity, particularly for ketanserin, in addition to GPRCs, may also cause differential responses. The results promise new therapeutic strategies for drug addiction, brain reward and cardiovascular medicine. PMID:27879921

Influence of Angiotensin-Converting-Enzyme Gene Polymorphism on Echocardiographic Data of Patients with Ischemic Heart Failure.

PubMed

Duque, Gustavo Salgado; Silva, Dayse Aparecida da; Albuquerque, Felipe Neves de; Schneider, Roberta Siuffo; Gimenez, Alinne; Pozzan, Roberto; Rocha, Ricardo Mourilhe; Albuquerque, Denilson Campos de

2016-11-01

Association between angiotensin-converting-enzyme (ACE) gene polymorphisms and different clinical and echocardiographic outcomes has been described in patients with heart failure (HF) and coronary artery disease. Studying the genetic profile of the local population with both diseases is necessary to assess the occurrence of that association. To assess the frequency of ACE gene polymorphisms in patients with ischemic HF in a Rio de Janeiro population, as well as its association with echocardiographic findings. Genetic assessment of I/D ACE polymorphism in association with clinical, laboratory and echocardiographic analysis of 99 patients. The allele frequency was: 53 I alleles, and 145 D alleles. Genotype frequencies were: 49.5% DD; 47.48% DI; 3.02% II. Drug treatment was optimized: 98% on beta-blockers, and 84.8% on ACE inhibitors or angiotensin-receptor blocker. Echocardiographic findings: difference between left ventricular diastolic diameters (ΔLVDD) during follow-up: 2.98±8.94 (DD) vs. 0.68±8.12 (DI) vs. -11.0±7.00 (II), p=0.018; worsening during follow-up of the LV systolic diameter (LVSD): 65.3% DD vs. 19.0% DI vs. 0.0% II, p=0.01; of the LV diastolic diameter (LVDD): 65.3% DD vs. 46.8% DI vs. 0.0% II, p=0.03; and of the LV ejection fraction (LVEF): 67.3% DD vs. 40.4% DI vs. 33.3% II, p=0.024. Correlated with D allele: ΔLVEF, ΔLVSD, ΔLVDD. More DD genotype patients had worsening of the LVEF, LVSD and LVDD, followed by DI genotype patients, while II genotype patients had the best outcome. The same pattern was observed for ΔLVDD. Associação entre polimorfismos genéticos da enzima conversora da angiotensina (ECA) e diferentes evoluções clínicas e ecocardiográficas foi descrita em pacientes com insuficiência cardíaca (IC) e coronariopatia. O estudo do perfil genético da população local com as duas doenças torna-se necessário para verificar a ocorrência dessa associação. Avaliar a frequência dos polimorfismos genéticos da ECA em pacientes com IC de etiologia isquêmica de uma população do Rio de Janeiro e sua associação com achados ecocardiográficos. Avaliação genética do polimorfismo I/D da ECA associada a análise de dados clínicos, laboratoriais e ecocardiográficos de 99 pacientes. Foram encontrados 53 alelos I, 145 alelos D, quanto aos genótipos da ECA: 49,5% DD, 47,48% DI, 3,02% II. O tratamento medicamentoso foi otimizado com 98% usando betabloqueadores e 84,8%, IECA ou bloqueador do receptor de angiotensina. Achados ecocardiográficos: diferença entre os diâmetros diastólicos do ventrículo esquerdo (ΔVED): 2,98±8,94 (DD) vs. 0,68±8,12 (DI) vs. -11,0±7,00 (II), p=0,018; piora evolutiva do diâmetro sistólico do VE (VES): 65,3 % DD vs. 19,0 % DI vs. 0,0 % II, p=0,01; do diâmetro diastólico do VE (VED): 65,3 % DD vs. 46,8 % DI vs. 0,0 % II, p=0,03; e da fração de ejeção do VE (FEVE): 67,3 % DD vs. 40,4 % DI vs. 33,3 % II, p=0,024. Correlação com alelo D: ΔFEVE, ΔVES, ΔVED. Foram identificados mais pacientes com piora evolutiva da FEVE e dos diâmetros cavitários do VE no genótipo DD, seguido do DI, sendo o II o de melhor evolução. O mesmo padrão foi observado na ΔVED.

76 FR 44026 - Mississippi; Amendment No. 5 to Notice of a Major Disaster Declaration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-22

... obtain any applicable private insurance payments for debris removal to reimburse Federal costs to the... Counseling; 97.033, Disaster Legal Services; 97.034, Disaster Unemployment Assistance (DUA); 97.046, Fire...

20 CFR 625.7 - Disaster Unemployment Assistance: Duration.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Disaster Unemployment Assistance: Duration... DISASTER UNEMPLOYMENT ASSISTANCE § 625.7 Disaster Unemployment Assistance: Duration. DUA shall be payable... unemployment which begin during a Disaster Assistance Period. ...

20 CFR 625.7 - Disaster Unemployment Assistance: Duration.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Disaster Unemployment Assistance: Duration... DISASTER UNEMPLOYMENT ASSISTANCE § 625.7 Disaster Unemployment Assistance: Duration. DUA shall be payable... unemployment which begin during a Disaster Assistance Period. ...

20 CFR 625.7 - Disaster Unemployment Assistance: Duration.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Disaster Unemployment Assistance: Duration... DISASTER UNEMPLOYMENT ASSISTANCE § 625.7 Disaster Unemployment Assistance: Duration. DUA shall be payable... unemployment which begin during a Disaster Assistance Period. ...

20 CFR 625.7 - Disaster Unemployment Assistance: Duration.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Disaster Unemployment Assistance: Duration... DISASTER UNEMPLOYMENT ASSISTANCE § 625.7 Disaster Unemployment Assistance: Duration. DUA shall be payable... unemployment which begin during a Disaster Assistance Period. ...

20 CFR 625.7 - Disaster Unemployment Assistance: Duration.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Disaster Unemployment Assistance: Duration... DISASTER UNEMPLOYMENT ASSISTANCE § 625.7 Disaster Unemployment Assistance: Duration. DUA shall be payable... unemployment which begin during a Disaster Assistance Period. ...

Contrasting effects of increased and decreased dopamine transmission on latent inhibition in ovariectomized rats and their modulation by 17beta-estradiol: an animal model of menopausal psychosis?

PubMed

Arad, Michal; Weiner, Ina

2010-06-01

Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis-inducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17beta-Estradiol (50, 150 microg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17beta-estradiol and clozapine were effective only at high doses (150 microg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17beta-estradiol (50 microg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17beta-estradiol exerts antipsychotic activity.

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

Comparison of Thermal and Non-Thermal Processing of Swine Feed and the Use of Selected Feed Additives on Inactivation of Porcine Epidemic Diarrhea Virus (PEDV).

PubMed

Trudeau, Michaela P; Verma, Harsha; Sampedro, Fernando; Urriola, Pedro E; Shurson, Gerald C; McKelvey, Jessica; Pillai, Suresh D; Goyal, Sagar M

2016-01-01

Infection with porcine epidemic diarrhea virus (PEDV) causes diarrhea, vomiting, and high mortality in suckling pigs. Contaminated feed has been suggested as a vehicle of transmission for PEDV. The objective of this study was to compare thermal and electron beam processing, and the inclusion of feed additives on the inactivation of PEDV in feed. Feed samples were spiked with PEDV and then heated to 120-145°C for up to 30 min or irradiated at 0-50 kGy. Another set of feed samples spiked with PEDV and mixed with Ultracid P (Nutriad), Activate DA (Novus International), KEM-GEST (Kemin Agrifood), Acid Booster (Agri-Nutrition), sugar or salt was incubated at room temperature (~25°C) for up to 21 days. At the end of incubation, the virus titers were determined by inoculation of Vero-81 cells and the virus inactivation kinetics were modeled using the Weibull distribution model. The Weibull kinetic parameter delta represented the time or eBeam dose required to reduce virus concentration by 1 log. For thermal processing, delta values ranged from 16.52 min at 120°C to 1.30 min at 145°C. For eBeam processing, a target dose of 50 kGy reduced PEDV concentration by 3 log. All additives tested were effective in reducing the survival of PEDV when compared with the control sample (delta = 17.23 days). Activate DA (0.81) and KEM-GEST (3.28) produced the fastest inactivation. In conclusion, heating swine feed at temperatures over 130°C or eBeam processing of feed with a dose over 50 kGy are effective processing steps to reduce PEDV survival. Additionally, the inclusion of selected additives can decrease PEDV survivability.

Dopaminergic dysfunction in abstinent dexamphetamine users: results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge.

PubMed

Schouw, M L J; De Ruiter, M B; Kaag, A M; van den Brink, W; Lindauer, R J L; Reneman, L

2013-06-01

Dopamine (DA) is involved in systems governing motor actions, motivational processes and cognitive functions. Preclinical studies have shown that even relatively low doses of d-amphetamine (dAMPH) (equivalent to doses used in clinical Practice) can lead to DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005). Therefore, we investigated the DAergic function in eight male recreational users of dAMPH and eight male healthy controls using functional magnetic resonance imaging (fMRI). We compared brain activation between both groups during a monetary incentive delay task (Knutson et al., 2001) with and without an oral methylphenidate (MPH) challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1.5 h after receiving an oral dose of 35 mg MPH (approximately 0.5 mg/kg) when peak MPH binding was assumed. When anticipating reward, dAMPH users showed lower striatal activation in comparison to control subjects. In addition, MPH induced a reduction in the striatal activation during reward anticipation in healthy controls, whereas no such effect was observed in dAMPH users. The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A novel PKB/Akt inhibitor, MK-2206, effectively inhibits insulin-stimulated glucose metabolism and protein synthesis in isolated rat skeletal muscle.

PubMed

Lai, Yu-Chiang; Liu, Yang; Jacobs, Roxane; Rider, Mark H

2012-10-01

PKB (protein kinase B), also known as Akt, is a key component of insulin signalling. Defects in PKB activation lead to insulin resistance and metabolic disorders, whereas PKB overactivation has been linked to tumour growth. Small-molecule PKB inhibitors have thus been developed for cancer treatment, but also represent useful tools to probe the roles of PKB in insulin action. In the present study, we examined the acute effects of two allosteric PKB inhibitors, MK-2206 and Akti 1/2 (Akti) on PKB signalling in incubated rat soleus muscles. We also assessed the effects of the compounds on insulin-stimulated glucose uptake, glycogen and protein synthesis. MK-2206 dose-dependently inhibited insulin-stimulated PKB phosphorylation, PKBβ activity and phosphorylation of PKB downstream targets (including glycogen synthase kinase-3α/β, proline-rich Akt substrate of 40 kDa and Akt substrate of 160 kDa). Insulin-stimulated glucose uptake, glycogen synthesis and glycogen synthase activity were also decreased by MK-2206 in a dose-dependent manner. Incubation with high doses of MK-2206 (10 μM) inhibited insulin-induced p70 ribosomal protein S6 kinase and 4E-BP1 (eukaryotic initiation factor 4E-binding protein-1) phosphorylation associated with increased eEF2 (eukaryotic elongation factor 2) phosphorylation. In contrast, Akti only modestly inhibited insulin-induced PKB and mTOR (mammalian target of rapamycin) signalling, with little or no effect on glucose uptake and protein synthesis. MK-2206, rather than Akti, would thus be the tool of choice for studying the role of PKB in insulin action in skeletal muscle. The results point to a key role for PKB in mediating insulin-stimulated glucose uptake, glycogen synthesis and protein synthesis in skeletal muscle.

Nursing diagnosis in older adults with chronic kidney disease on hemodialysis.

PubMed

Debone, Mayara Cristina; Pedruncci, Elisângela da Silva Nunes; Candido, Maristela do Carmo Peterossi; Marques, Sueli; Kusumota, Luciana

2017-01-01

To identify the main nursing diagnoses (NSs) in older adult patients under hemodialysis treatment. Exploratory research using case studies in data collection performed by interview and physical examination of older adults, in the first semester of 2016. Were included twenty-eight older adults undergoing chronic hemodialysis treatment who met the selection criteria. The analysis followed two steps (RISNER, 1990): Phase I - Data analysis and synthesis; and Phase II - Establishment of nursing diagnoses using the taxonomy of NANDA-I (2015). The total of NSs was 110, averaging 3.9 per patient. It was listed seven different NSs, and both the Risk of infection and the Volume of excessive liquids appeared on all patients (28; 100%), and risk of electrolyte imbalance, in 26 (96.8%) older adults, being considered as main NSs. Such results can help systematize the care of older people who are undergoing hemodialysis treatment. Identificar os principais diagnósticos de enfermagem (DEs) em pacientes idosos em tratamento hemodialítico. Pesquisa exploratória utilizando estudos de casos na coleta de dados realizada por entrevista e exame físico dos idosos, no primeiro semestre de 2016. Foram incluídos 28 idosos em tratamento crônico por hemodiálise que atenderam aos critérios de seleção. A análise seguiu duas etapas (RISNER, 1990): Fase I - Análise e síntese dos dados; e Fase II - Estabelecimento dos diagnósticos de enfermagem utilizando a taxonomia da NANDA-I (2015). O total de DEs foi de 110, com média de 3,9 por paciente. Foram elencados sete DEs diferentes, sendo que tanto o Risco de infecção quanto o Volume de líquidos excessivo apareceram em todos os pacientes (28; 100%), e Risco de desequilíbrio eletrolítico, em 26 (96,8%) idosos, sendo considerados como principais DEs. Tais resultados podem colaborar na sistematização da assistência do idoso em tratamento hemodialítico.

Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor.

PubMed

Podurgiel, Samantha; Collins-Praino, Lyndsey E; Yohn, Samantha; Randall, Patrick A; Roach, Arthur; Lobianco, Christophe; Salamone, John D

2013-04-01

Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. Copyright © 2013 Elsevier Inc. All rights reserved.

Changes caused by haloperidol are blocked by music in Wistar rat.

PubMed

Tasset, Inmaculada; Quero, Ismael; García-Mayórgaz, Ángel D; del Río, Manuel Causse; Túnez, Isaac; Montilla, Pedro

2012-06-01

This study sought to evaluate the effect of classical music, using Mozart's sonata for two pianos (K. 448), on changes in dopamine (DA) levels in the striatal nucleus (SN), prefrontal cortex (PFC) and mesencephalon, and on prolactin (PRL) and corticosterone secretion in adult male Wistar rats. Rats were divided into four groups: (1) control, (2) haloperidol treatment (single dose of 2 mg/kg s.c.), (3) music (two 2-h sessions per day) and (4) haloperidol plus music. Rats were sacrificed 2 h after haloperidol injection. Music prompted a fall in plasma PRL and corticosterone levels in healthy rats (P < 0.05) and prevented the increase in levels triggered by haloperidol (P < 0.001). Moreover, exposure to music was associated with a significant increase in DA levels in all groups, with the increase being particularly marked in PFC and SN (P < 0.001). Haloperidol is a recognised D2 receptor antagonist, and these findings suggest that music, by contrast, enhances DA activity and turnover in the brain. The results obtained here bear out reports that music triggers a reduction in systolic pressure and an increase in mesencephalon dopamine levels in human and rats treated with ecstasy, through a calmodulin-dependent system.

Haloperidol response and plasma catecholamines and their metabolites.

PubMed

Green, A I; Alam, M Y; Boshes, R A; Waternaux, C; Pappalardo, K M; Fitzgibbon, M E; Tsuang, M T; Schildkraut, J J

1993-06-01

Eleven acutely psychotic patients with schizophrenia or schizoaffective disorder underwent a 5-7 day drug-washout period (with lorazepam allowed) prior to participating in a 6-week controlled dose haloperidol trial. Patients were evaluated longitudinally with clinical ratings and with plasma measures of the catecholamines dopamine (pDA) and norepinephrine (pNE) and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG). All patients exhibited clinical improvement with haloperidol; the decrease in their Brief Psychiatric Rating Scale (BPRS) scores ranged from 32 to 89%. Measures of pHVA increased within the first week of treatment and returned to baseline by week 5. The pattern of change of pDA resembled that of pHVA. The pattern of change of pNE and pMHPG revealed a decrease over the course of treatment. The early increase and the subsequent decrease in pHVA were strongly correlated with improvement in positive symptoms on the BPRS. These data are consistent with previous reports on the change in pHVA and pMHPG during clinical response to haloperidol. The data on change of pDA and pNE further describe the nature of the biochemical response to this drug.

76 FR 34244 - Missouri; Amendment No. 5 to Notice of a Major Disaster Declaration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-13

... August 7, 2011. FEMA and the State of Missouri shall pursue any applicable private insurance payments for... (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to Individuals and...

Gene-by-environment interactions that disrupt mitochondrial homeostasis cause neurodegeneration in C. elegans Parkinson's models.

PubMed

Kim, Hanna; Perentis, Rylee J; Caldwell, Guy A; Caldwell, Kim A

2018-05-10

Parkinson's disease (PD) is a complex multifactorial disorder where environmental factors interact with genetic susceptibility. Accumulating evidence suggests that mitochondria have a central role in the progression of neurodegeneration in sporadic and/or genetic forms of PD. We previously reported that exposure to a secondary metabolite from the soil bacterium, Streptomyces venezuelae, results in age- and dose-dependent dopaminergic (DA) neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. Initial characterization of this environmental factor indicated that neurodegeneration occurs through a combination of oxidative stress, mitochondrial complex I impairment, and proteostatic disruption. Here we present extended evidence to elucidate the interaction between this bacterial metabolite and mitochondrial dysfunction in the development of DA neurodegeneration. We demonstrate that it causes a time-dependent increase in mitochondrial fragmentation through concomitant changes in the gene expression of mitochondrial fission and fusion components. In particular, the outer mitochondrial membrane fission and fusion genes, drp-1 (a dynamin-related GTPase) and fzo-1 (a mitofusin homolog), are up- and down-regulated, respectively. Additionally, eat-3, an inner mitochondrial membrane fusion component, an OPA1 homolog, is also down regulated. These changes are associated with a metabolite-induced decline in mitochondrial membrane potential and enhanced DA neurodegeneration that is dependent on PINK-1 function. Genetic analysis also indicates an association between the cell death pathway and drp-1 following S. ven exposure. Metabolite-induced neurotoxicity can be suppressed by DA-neuron-specific RNAi knockdown of eat-3. AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) ameliorated metabolite- or PINK-1-induced neurotoxicity; however, it enhanced neurotoxicity under normal conditions. These studies underscore the critical role of mitochondrial dynamics in DA neurodegeneration. Moreover, given the largely undefined environmental components of PD etiology, these results highlight a response to an environmental factor that defines distinct mechanisms underlying a potential contributor to the progressive DA neurodegeneration observed in PD.

Investigating Bacterial Sources of Toxicity as an Environmental Contributor to Dopaminergic Neurodegeneration

PubMed Central

Caldwell, Kim A.; Tucci, Michelle L.; Armagost, Jafa; Hodges, Tyler W.; Chen, Jue; Memon, Shermeen B.; Blalock, Jeana E.; DeLeon, Susan M.; Findlay, Robert H.; Ruan, Qingmin; Webber, Philip J.; Standaert, David G.; Olson, Julie B.; Caldwell, Guy A.

2009-01-01

Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD. PMID:19806188

Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats.

PubMed

Chai, Hann-Juang; Kiew, Lik-Voon; Chin, Yunni; Norazit, Anwar; Mohd Noor, Suzita; Lo, Yoke-Lin; Looi, Chung-Yeng; Lau, Yeh-Siang; Lim, Tuck-Meng; Wong, Won-Fen; Abdullah, Nor Azizan; Abdul Sattar, Munavvar Zubaid; Johns, Edward J; Chik, Zamri; Chung, Lip-Yong

2017-01-01

Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. 3 H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3 H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.

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

Avkshtol, V; Tanny, S; Reddy, K

Purpose: Stereotactic radiation therapy (SRT) provides an excellent alternative to embolization and surgical excision for the management of appropriately selected cerebral arteriovenous malformations (AVMs). The currently accepted standard for delineating AVMs is planar digital subtraction angiography (DSA). DSA can be used to acquire a 3D data set that preserves osseous structures (3D-DA) at the time of the angiography for SRT planning. Magnetic resonance imaging (MRI) provides an alternative noninvasive method of visualizing the AVM nidus with comparable spatial resolution. We utilized 3D-DA and T1 post-contrast MRI data to evaluate the differences in SRT target volumes. Methods: Four patients underwent 3D-DAmore » and high-resolution MRI. 3D T1 post-contrast images were obtained in all three reconstruction planes. A planning CT was fused with MRI and 3D-DA data sets. The AVMs were contoured utilizing one of the image sets at a time. Target volume, centroid, and maximum and minimum dimensions were analyzed for each patient. Results: Targets delineated using post-contrast MRI demonstrated a larger mean volume. AVMs >2 cc were found to have a larger difference between MRI and 3D-DA volumes. Larger AVMs also demonstrated a smaller relative uncertainty in contour centroid position (1 mm). AVM targets <2 cc had smaller absolute differences in volume, but larger differences in contour centroid position (2.5 mm). MRI targets demonstrated a more irregular shape compared to 3D-DA targets. Conclusions: Our preliminary data supports the use of MRI alone to delineate AVM targets >2 cc. The greater centroid stability for AVMs >2 cc ensures accurate target localization during image fusion. The larger MRI target volumes did not result in prohibitively greater volumes of normal brain tissue receiving the prescription dose. The larger centroid instability for AVMs <2 cc precludes the use of MRI alone for target delineation. We recommend incorporating a 3D-DA for these patients.« less

Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats

PubMed Central

Chai, Hann-Juang; Kiew, Lik-Voon; Chin, Yunni; Norazit, Anwar; Mohd Noor, Suzita; Lo, Yoke-Lin; Looi, Chung-Yeng; Lau, Yeh-Siang; Lim, Tuck-Meng; Wong, Won-Fen; Abdullah, Nor Azizan; Abdul Sattar, Munavvar Zubaid; Johns, Edward J; Chik, Zamri; Chung, Lip-Yong

2017-01-01

Background and purpose Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. Experimental approach 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). Results In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. Conclusion/Implications The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier. PMID:28144140

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats.

PubMed

Noworyta-Sokołowska, Karolina; Kamińska, Katarzyna; Kreiner, Grzegorz; Rogóż, Zofia; Gołembiowska, Krystyna

2016-11-01

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, 'foxy') is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.

Time- and dose-related effects of a gonadotropin-releasing hormone agonist and dopamine antagonist on reproduction in the Northern leopard frog (Lithobates pipiens).

PubMed

Vu, Maria; Weiler, Bradley; Trudeau, Vance L

2017-12-01

Gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone release to control ovulation and spermiation in vertebrates. Dopamine (DA) has a clear inhibitory role in the control of reproduction in numerous teleosts, and emerging evidence suggests that similar mechanisms may exist in amphibians. The interactions between GnRH and DA on spawning success and pituitary gene expression in the Northern leopard frog (Lithobates pipiens) were therefore investigated. Frogs were injected during the natural breeding season with a GnRH agonist [GnRH-A; (Des-Gly 10 , D-Ala 6 , Pro-NHEt 9 )-LHRH; 0.1μg/g and 0.4μg/g] alone and in combination with the dopamine receptor D2 antagonist metoclopramide (MET; 5μg/g and 10μg/g). Injected animals were allowed to breed in outdoor mesocosms. Time to amplexus and oviposition were assessed, and egg mass release, incidences of amplexus, egg mass weight, total egg numbers and fertilization rates were measured. To examine gene expression, female pituitaries were sampled at 12, 24 and 36h following injection of GnRH-A (0.4μg/g) alone and in combination with MET (10μg/g). The mRNA levels of the genes lhb, fshb, gpha, drd2 and gnrhr1 were measured using quantitative real-time PCR. Data were analyzed by a two-way ANOVA. Both GnRH-A doses increased amplexus, oviposition and fertilization alone. Co-injection of MET with GnRH-A did not further enhance spawning success. Injection of GnRH-A alone time-dependently increased expression of lhb, fshb, gpha and gnrhr1. The major effect of MET alone was to decrease expression of drd2. Importantly, the stimulatory effects of GnRH-A on lhb, gpha and gnrhr1 were potentiated by the co-injection of MET at 36h. At this time, expression of fshb was increased only in animals injected with both GnRH-A and MET. Spawning success was primarily driven by the actions of GnRH-A. The hypothesized inhibitory action of DA was supported by pituitary gene expression analysis. The results from this study provide a fundamental framework for future time- and dose-response investigations to improve current spawning methods in amphibians. Copyright © 2017. Published by Elsevier Inc.

Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine.

PubMed

Sotnikova, Tatyana D; Budygin, Evgeny A; Jones, Sara R; Dykstra, Linda A; Caron, Marc G; Gainetdinov, Raul R

2004-10-01

Beta-phenylethylamine (beta-PEA) is an endogenous amine that is found in trace amounts in the brain. It is believed that the locomotor-stimulating action of beta-PEA, much like amphetamine, depends on its ability to increase extracellular dopamine (DA) concentrations owing to reversal of the direction of dopamine transporter (DAT)-mediated DA transport. beta-PEA can also bind directly to the recently identified G protein-coupled receptors, but the physiological significance of this interaction is unclear. To assess the mechanism by which beta-PEA mediates its effects, we compared the neurochemical and behavioral effects of this amine in wild type (WT), heterozygous and 'null' DAT mutant mice. In microdialysis studies, beta-PEA, administered either systemically or locally via intrastriatal infusion, produced a pronounced outflow of striatal DA in WT mice whereas no increase was detected in mice lacking the DAT (DAT-KO mice). Similarly, in fast-scan voltammetry studies beta-PEA did not alter DA release and clearance rate in striatal slices from DAT-KO mice. In behavioral studies beta-PEA produced a robust but transient increase in locomotor activity in WT and heterozygous mice. In DAT-KO mice, whose locomotor activity and stereotypy are increased in a novel environment, beta-PEA (10-100 mg/kg) exerted a potent inhibitory action. At high doses, beta-PEA induced stereotypies in WT and heterozygous mice; some manifestations of stereotypy were also observed in the DAT-KO mice. These data demonstrate that the DAT is required for the striatal DA-releasing and hyperlocomotor actions of beta-PEA. The inhibitory action on hyperactivity and certain stereotypies induced by beta-PEA in DAT-KO mice indicate that targets other than the DAT are responsible for these effects.

Positron emission tomography (PET) imaging of nicotine-induced dopamine release in squirrel monkeys using [18F]Fallypride.

PubMed

Naylor, Jennifer E; Hiranita, Takato; Matazel, Katelin S; Zhang, Xuan; Paule, Merle G; Goodwin, Amy K

2017-10-01

Nicotine, the principal psychoactive tobacco constituent, is thought to produce its reinforcing effects via actions within the mesolimbic dopamine (DA) system. The objective of the current study was to examine the effect of nicotine on DA D 2 /D 3 receptor availability in the nonhuman primate brain with the use of the radioligand [ 18 F]fallypride and positron emission tomography (PET). Ten adult male squirrel monkeys were used in the current study. Each subject underwent two PET scans, one with an injection (IV) of saline and subsequently one with an injection of nicotine (0.032mg/kg). The DA D 2 /D 3 antagonist, [ 18 F]fallypride, was delivered IV at the beginning of each scan, and nicotine or saline was delivered at 45min into the scan. Regions of interest (ROI) were drawn on specific brain regions and these were used to quantify standard uptake values (SUVs). The SUV is defined as the average concentration of radioactivity in the ROI x body weight/injected dose. Using the cerebellum as a reference region, SUV ratios (SUV ROI /SUV cerebellum ) were calculated to compare saline and nicotine effects in each ROI. Two-way repeated ANOVA revealed a significant decrease of SUV ratios in both striatal and extrastriatal regions following an injection of nicotine during the PET scans. Like other drugs of abuse, these results indicate that nicotine administration may produce DA release, as suggested by the decrease in [ 18 F]fallypride signal in striatal regions. These findings from a nonhuman primate model provide further evidence that the mesolimbic DA system is affected by the use of products that contain nicotine. Published by Elsevier B.V.

Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure.

PubMed

McFadden, Lisa M; Vieira-Brock, Paula L; Hanson, Glen R; Fleckenstein, Annette E

2015-06-01

Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose "binge" METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of progesterone administered after MPTP on dopaminergic neurons of male mice.

PubMed

Litim, Nadhir; Morissette, Marc; Di Paolo, Thérèse

2017-05-01

Progesterone neuroprotection of striatal dopamine (DA) in male mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was previously reported when administered before MPTP or an hour after. A dose of MPTP to induce a partial lesion was used to model early stages or prodromal Parkinson. We hypothesized that brain DA can be restored by progesterone administered early (24 h) or later (5 days) after MPTP. Male mice received 4 injections of MPTP (8 mg/kg) and progesterone (8 mg/kg) once daily for 5 days started 24 h or 5 days after MPTP. The lesion decreased striatal DA and its metabolites but not serotonin contents. MPTP mice treated with progesterone starting 24 h but not 5 days after MPTP had higher striatal DA and its metabolites content than vehicle-treated MPTP mice. Striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding decreased in lesioned mice and were corrected with progesterone treatment starting 24 h but not 5 days after MPTP. Striatal glial fibrillary acidic protein (GFAP) levels, a marker of activated astrocytes, were elevated by the MPTP lesion and were corrected with progesterone treatment starting 24 h after MPTP. Striatal brain derived neurotrophic factor (BDNF) levels were decreased by the MPTP lesion and were prevented by progesterone treatments whereas no change of Akt, GSK3β, ERK1 and 2 and their phosphorylated forms were observed. Thus, progesterone administered after MPTP in mice protected dopaminergic neurons through modulation of neuroinflammation and BDNF. In humans, progesterone could possibly be used as a disease-modifying drug in prodromal Parkinson. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala.

PubMed

Larkin, Joshua D; Jenni, Nicole L; Floresco, Stan B

2016-01-01

Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown. We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task. Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 μg) or D2 (eticlopride, 0.1-1 μg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 μg) and D2 (quinpirole, 1-10 μg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice. BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior. These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.

Radiobiological Impact of Planning Techniques for Prostate Cancer in Terms of Tumor Control Probability and Normal Tissue Complication Probability

PubMed Central

Rana, S; Cheng, CY

2014-01-01

Background: The radiobiological models describe the effects of the radiation treatment on cancer and healthy cells, and the radiobiological effects are generally characterized by the tumor control probability (TCP) and normal tissue complication probability (NTCP). Aim: The purpose of this study was to assess the radiobiological impact of RapidArc planning techniques for prostate cancer in terms of TCP and normal NTCP. Subjects and Methods: A computed tomography data set of ten cases involving low-risk prostate cancer was selected for this retrospective study. For each case, two RapidArc plans were created in Eclipse treatment planning system. The double arc (DA) plan was created using two full arcs and the single arc (SA) plan was created using one full arc. All treatment plans were calculated with anisotropic analytical algorithm. Radiobiological modeling response evaluation was performed by calculating Niemierko's equivalent uniform dose (EUD)-based Tumor TCP and NTCP values. Results: For prostate tumor, the average EUD in the SA plans was slightly higher than in the DA plans (78.10 Gy vs. 77.77 Gy; P = 0.01), but the average TCP was comparable (98.3% vs. 98.3%; P = 0.01). In comparison to the DA plans, the SA plans produced higher average EUD to bladder (40.71 Gy vs. 40.46 Gy; P = 0.03) and femoral heads (10.39 Gy vs. 9.40 Gy; P = 0.03), whereas both techniques produced NTCP well below 0.1% for bladder (P = 0.14) and femoral heads (P = 0.26). In contrast, the SA plans produced higher average NTCP compared to the DA plans (2.2% vs. 1.9%; P = 0.01). Furthermore, the EUD to rectum was slightly higher in the SA plans (62.88 Gy vs. 62.22 Gy; P = 0.01). Conclusion: The SA and DA techniques produced similar TCP for low-risk prostate cancer. The NTCP for femoral heads and bladder was comparable in the SA and DA plans; however, the SA technique resulted in higher NTCP for rectum in comparison with the DA technique. PMID:24761232

Stabilization of Tetanus Toxoid Encapsulated in PLGA Microspheres

PubMed Central

Jiang, Wenlei; Schwendeman, Steven P.

2014-01-01

Delivery of vaccine antigens from controlled-release poly(lactic/glycolic acid) (PLGA) microspheres is a novel approach to reduce the number of antigen doses required for protection against infection. A major impediment to developing single-shot vaccines is encapsulated antigen instability during months of exposure to physiological conditions. For example, efforts to control neonatal tetanus in developing countries with a single-dose TT vaccine have been plagued by poor stability of the 150 kDa formaldehyde-detoxified protein antigen, tetanus toxoid (TT) in PLGA microspheres. We examined the denatured states of PLGA-encapsulated TT, revealing two primary TT instability mechanisms: 1) protein aggregation mediated by formaldehyde and 2) acid-induced protein unfolding and epitope damage. Further, we systemically identified excipients which can efficiently inhibit TT aggregation and retain TT antigenicity under simulated deleterious conditions, i.e., elevated temperature and humidity. By employing these novel additives in the PLGA system, we report the slow and continuous release of high doses of TT for one month with retained antigen stability during bioerosion of PLGA. PMID:18710256

Geraniol attenuates α-synuclein expression and neuromuscular impairment through increase dopamine content in MPTP intoxicated mice by dose dependent manner.

PubMed

Rekha, Karamkolly R; Selvakumar, Govindasamy P; Santha, Karunanithi; Inmozhi Sivakamasundari, Ramu

2013-11-01

Parkinson's disease (PD) is characterized by progressive loss of dopamine (DA) neurons in the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein (α-Syn) aggregates. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in C57BL/6 mice. In the present study, we investigated the effect of geraniol (GE) against α-Syn aggregation on MPTP induced mouse model of PD in dose dependant manner. When pretreatment of GE improved neuromuscular impairment, TH expressions and decreases α-Syn expressions in MPTP intoxicated PD mice by dose dependent manner. In addition, we confirmed that sub-chronic administration of MPTP in mice leads to permanent neuromuscular deficits and depletion of dopamine and its metabolites. Our results suggest that GE is beneficial for the treatment of PD associated with neuromuscular disability and LB aggregation. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

PubMed

Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

1997-01-01

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity.

PubMed

Monnery, Bryn D; Wright, Michael; Cavill, Rachel; Hoogenboom, Richard; Shaunak, Sunil; Steinke, Joachim H G; Thanou, Maya

2017-04-15

The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22kDa linear and 25kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly "non-toxic" low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Quercetin inhibits the invasion of murine melanoma B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.

PubMed

Zhang, Xian-Ming; Huang, Shao-Peng; Xu, Qiang

2004-01-01

On the basis of the inhibitory effect of quercetin on the invasion of melanoma B16-BL6 cells previously reported by us, the mechanisms of quercetin-mediated inhibition of invasion were further investigated in the present study. The ability of B16-BL6 cells to invade and migrate was evaluated in terms of the numbers of cells penetrating a reconstituted basement membrane in the Transwell coculture system. The relative levels and activities of matrix metalloproteinase-9 (MMP-9) and MMP-2 were determined by gelatin zymography and quantified using LabWorks 4.0 software. The quercetin-mediated inhibition of invasion was partially blocked by phorbol-12,13-dibutyrate (PDB), a PKC (protein kinase C) activator, and by doxorubicin, a PKC inhibitor. Only the proforms of MMP-9 (92 kDa) and MMP-2 (72 kDa) were detected by gelatin zymography. Quercetin dose-dependently decreased the gelatinolytic activity of pro-MMP-9. Doxorubicin also markedly reversed the quercetin-induced decrease. Quercetin showed a dose-dependent antagonism of increases in gelatinolytic activity of pro-MMP-9 induced by PDB and free fatty acid (another PKC activator). Together with the report that quercetin directly reduces PKC activity, the results reported here suggest that quercetin may inhibit the invasion of B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

PubMed

Weber, Tobias; Bötticher, Benedikt; Arndt, Michaela A E; Mier, Walter; Sauter, Max; Exner, Evelyn; Keller, Armin; Krämer, Susanne; Leotta, Karin; Wischnjow, Artjom; Grosse-Hovest, Ludger; Strumberg, Dirk; Jäger, Dirk; Gröne, Hermann-Josef; Haberkorn, Uwe; Brem, Gottfried; Krauss, Jürgen

2016-10-28

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Structural characterization and evaluation of antioxidant, anticancer and hypoglycemic activity of radiation degraded oat (Avena sativa) β- glucan

NASA Astrophysics Data System (ADS)

Hussain, Peerzada R.; Rather, Sarver A.; Suradkar, Prashant P.

2018-03-01

Oat β-D-glucan after extraction was degraded at doses of 3, 6, 9, 12 and 15 kGy. The average molecular weight decreased to 45 kDa at dose of 15 kGy from an initial value of 200 kDa in native sample. XRD analysis revealed no significant change in diffraction pattern of irradiated samples when compared with control, except a decrease in intensity of x-ray diffraction. The results of the antioxidant activity revealed decrease in EC50 values and corresponding increase in antioxidant activity of radiation degraded oat β-D-glucan. Results of the anticancer studies indicated that cytotoxicity of gamma irradiated oat β-D-glucan in cancer cell lines was highest against colo-205 and MCF7 cancer cells compared to T47D cell and no cytotoxicity was observed in normal cell lines at all concentrations used. Evaluation of hypoglycemic activity showed highest inhibition in α-glucosidase activity compared to α-amylase activity due to gamma irradiation of oat β-D-glucan. Comparison of the EC50 values of known standards and gamma irradiated oat beta-glucan samples indicates that radiation treatment significantly modified the biological activity of the beta-glucan samples. Therefore, it is suggested that gamma irradiation can be used for producing low molecular weight oat β-D-glucan; which can help in modifying the biological activities.

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

PubMed

Pezze, M A; Marshall, H J; Cassaday, H J

2016-08-01

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Effects of heparin and hyperbaric oxygenation on necrosis reduction in an animal model for degloving injuries.

PubMed

Menon, Douglas Neumar; Teixeira, Letícia; Paurosi, Natalha Bristot; Barros, Marcio Eduardo

2017-01-01

to evaluate the efficacy of the treatment with hyperbaric oxygen therapy or with topical and intralesional heparin in an animal model of degloving lesions. we conducted an experimental study with adult, male Wistar rats submitted to degloving of the left hind limb and divided into four groups according to the treatment: Group 1 (control) - without treatment; Group 2 (Heparin) - intralesional application at the time of surgery and topically, in the postoperative period, with heparin spray 10,000IU/mL; Group 3 (hyperbaric oxygenation) - daily sessions of 30 minutes in a hyperbaric chamber with 100% oxygen and 2 ATA pressure; Group 4 (positive control) - administration of a single dose of 45 mg/kg of intraperitoneal allopurinol. On the seventh day, we killed the animals, removed the cutaneous flaps and measured the total and necrotic areas, as well as computed the percentage of necrotic area. the mean percentage of necrosis in the control group was 56.03%; in the positive control group it was 51.36% (p<0.45); in the heparin group, 42.10% (p<0.07); and in the hyperbaric oxygen therapy group, 31.58% (p<0.01) . both hyperbaric oxygen and heparin therapies were effective in reducing the percentage of necrosis in the model studied, although only the hyperbaric oxygenation showed statistical significance. avaliar a eficácia do tratamento com oxigenoterapia hiperbárica ou com heparina tópica e intralesional em modelo animal de desluvamentos. estudo experimental, com ratos adultos machos Wistar, submetidos a desluvamento do membro posterior esquerdo e divididos em quatro grupos, de acordo com o tratamento: Grupo 1 (controle) - sem tratamento; Grupo 2 (Heparina) - aplicação intralesional no momento da cirurgia e tópica, no pós operatório, com spray de heparina 10.000UI/mL; Grupo 3 (oxigenação hiperbárica) - sessões diárias de 30 minutos em câmara hiperbárica com 100% de oxigênio e 2 ATA de pressão; Grupo 4 (controle positivo) - administração de dose única de 45mg/kg de alopurionol intraperitoneal. No sétimo dia os animais foram mortos e os retalhos cutâneos foram retirados e realizadas medidas das áreas total e necrótica, bem como cálculo da porcentagem da área de necrose. a média da porcentagem de necrose do grupo controle foi 56,03%; no grupo controle positivo, 51,36% (p≤0,45); no grupo da heparina, 42,10% (p≤0,07) e no grupo da oxigenoterapia hiperbárica, 31,58% (p≤0,01). tanto a oxigenoterapia hiperbárica quanto a terapia com heparina mostraram-se eficazes na redução do percentual de necrose no modelo estudado, embora neste trabalho apenas a oxigenação hiperbárica tenha demonstrado significância estatística.

Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function

PubMed Central

Vinish, Monika; Elnabawi, Ahmed; Milstein, Jean A.; Burke, Jesse S.; Kallevang, Jonathan K.; Turek, Kevin C.; Lansink, Carien S.; Merchenthaler, Istvan; Bailey, Aileen M.; Kolb, Bryan; Cheer, Joseph F.; Frost, Douglas O.

2018-01-01

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors ; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28–49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients. PMID:23351612

Subchronic steroid administration induces long lasting changes in neurochemical and behavioral response to cocaine in rats.

PubMed

Kailanto, Sanna; Kankaanpää, Aino; Seppälä, Timo

2011-11-01

The abuse of anabolic androgenic steroids (AASs), such as nandrolone, is not only a problem in the world of sports but is associated with the polydrug use of non-athletes. Among other adverse effects, AAS abuse has been associated with long term or even persistent psychiatric problems. We have previously found that nandrolone decanoate treatment could produce prolonged changes in rats' brain reward circuits associated to drug dependence. The aim in this study was to evaluate whether AAS-induced neurochemical and behavioral changes are reversible. The increases in extracellular dopamine (DA) and serotonin (5-HT) concentration, as well as stereotyped behavior and locomotor activity (LMA) evoked by cocaine were attenuated by pretreatment with nandrolone. The recovery period, which was needed for the DA system to return back to the basic level, was fairly long compared to the dosing period of the steroid. In the 5-HT system, the time that system needed to return back to the basal level, was even longer than in the DA system. The attenuation was still seen though there were no detectable traces of nandrolone in the blood samples. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior are all related to reward of stimulant drugs, this study suggests that nandrolone decanoate has significant, long-lasting but reversible effects on the rewarding properties of cocaine. Copyright © 2011 Elsevier Ltd. All rights reserved.

Perinatal methadone exposure affects dopamine, norepinephrine, and serotonin in the weanling rat.

PubMed

Robinson, S E; Maher, J R; Wallace, M J; Kunko, P M

1997-01-01

On gestational day 7 pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. On postnatal day 21, dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites were analyzed. Perinatal methadone exposure disrupted dopaminergic, noradrenergic, and serotonergic activity in a brain region- and gender-specific fashion. The ratio of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) to DA was reduced in the frontal cortex of males exposed to methadone postnatally. No effects of perinatal methadone exposure were observed on DA and DOPAC in the striatum. The ratio of 3-methoxy-4-hydroxyphenylglycol (MOPEG) to NE in the hippocampus was increased significantly in males exposed to methadone prenatally. Striatal and parietal cortical 5-hydroxyindoleacetic acid (5-HIAA), but not its ratio to 5-HT, was increased slightly in rats exposed to methadone postnatally. Although parietal cortical 5-HT, 5-HIAA, and 5-hydroxytryptophan were all affected by perinatal methadone exposure, the ratios of metabolite and precursor to 5-HT were not affected. Effects of methadone exposure appeared to depend upon the developmental stage at which exposure occurred and did not appear to result from the phenomenon of neonatal withdrawal. Changes in activity of these three neurotransmitter systems may contribute to the effect of perinatal methadone on the activity of other neurons, such as cholinergic neurons.

Errors introduced by dose scaling for relative dosimetry

PubMed Central

Watanabe, Yoichi; Hayashi, Naoki

2012-01-01

Some dosimeters require a relationship between detector signal and delivered dose. The relationship (characteristic curve or calibration equation) usually depends on the environment under which the dosimeters are manufactured or stored. To compensate for the difference in radiation response among different batches of dosimeters, the measured dose can be scaled by normalizing the measured dose to a specific dose. Such a procedure, often called “relative dosimetry”, allows us to skip the time‐consuming production of a calibration curve for each irradiation. In this study, the magnitudes of errors due to the dose scaling procedure were evaluated by using the characteristic curves of BANG3 polymer gel dosimeter, radiographic EDR2 films, and GAFCHROMIC EBT2 films. Several sets of calibration data were obtained for each type of dosimeters, and a calibration equation of one set of data was used to estimate doses of the other dosimeters from different batches. The scaled doses were then compared with expected doses, which were obtained by using the true calibration equation specific to each batch. In general, the magnitude of errors increased with increasing deviation of the dose scaling factor from unity. Also, the errors strongly depended on the difference in the shape of the true and reference calibration curves. For example, for the BANG3 polymer gel, of which the characteristic curve can be approximated with a linear equation, the error for a batch requiring a dose scaling factor of 0.87 was larger than the errors for other batches requiring smaller magnitudes of dose scaling, or scaling factors of 0.93 or 1.02. The characteristic curves of EDR2 and EBT2 films required nonlinear equations. With those dosimeters, errors larger than 5% were commonly observed in the dose ranges of below 50% and above 150% of the normalization dose. In conclusion, the dose scaling for relative dosimetry introduces large errors in the measured doses when a large dose scaling is applied, and this procedure should be applied with special care. PACS numbers: 87.56.Da, 06.20.Dk, 06.20.fb PMID:22955658

Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates.

PubMed

Gill, Kathryn E; Pierre, Peter J; Daunais, James; Bennett, Allyson J; Martelle, Susan; Gage, H Donald; Swanson, James M; Nader, Michael A; Porrino, Linda J

2012-11-01

Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹⁸F]fluoroclebopride (DA D2/D3) and [¹⁸F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.

Diamond detector in absorbed dose measurements in high‐energy linear accelerator photon and electron beams

PubMed Central

Binukumar, John Pichy; Amri, Iqbal Al; Davis, Cheriyathmanjiyil Antony

2016-01-01

Diamond detectors (DD) are preferred in small field dosimetry of radiation beams because of small dose profile penumbras, better spatial resolution, and tissue‐equivalent properties. We investigated a commercially available ‘microdiamond’ detector in realizing absorbed dose from first principles. A microdiamond detector, type TM 60019 with tandem electrometer is used to measure absorbed doses in water, nylon, and PMMA phantoms. With sensitive volume 0.004 mm3, radius 1.1 mm, thickness 1×10−3mm, the nominal response is 1 nC/Gy. It is assumed that the diamond detector could collect total electric charge (nC) developed during irradiation at 0 V bias. We found that dose rate effect is less than 0.7% for changing dose rate by 500 MU/min. The reproducibility in obtaining readings with diamond detector is found to be ±0.17% (1 SD) (n=11). The measured absorbed doses for 6 MV and 15 MV photons arrived at using mass energy absorption coefficients and stopping power ratios compared well with Nd, water calibrated ion chamber measured absorbed doses within 3% in water, PMMA, and nylon media. The calibration factor obtained for diamond detector confirmed response variation is due to sensitivity due to difference in manufacturing process. For electron beams, we had to apply ratio of electron densities of water to carbon. Our results qualify diamond dosimeter as a transfer standard, based on long‐term stability and reproducibility. Based on micro‐dimensions, we recommend these detectors for pretreatment dose verifications in small field irradiations like stereotactic treatments with image guidance. PACS number(s): 87.56.Da PMID:27074452

Intraoperative near-infrared fluorescent imaging during robotic operations.

PubMed

Macedo, Antonio Luiz de Vasconcellos; Schraibman, Vladimir

2016-01-01

The intraoperative identification of certain anatomical structures because they are small or visually occult may be challenging. The development of minimally invasive surgery brought additional difficulties to identify these structures due to the lack of complete tactile sensitivity. A number of different forms of intraoperative mapping have been tried. Recently, the near-infrared fluorescence imaging technology with indocyanine green has been added to robotic platforms. In addition, this technology has been tested in several types of operations, and has advantages such as safety, low cost and good results. Disadvantages are linked to contrast distribution in certain clinical scenarios. The intraoperative near-infrared fluorescent imaging is new and promising addition to robotic surgery. Several reports show the utility of this technology in several different procedures. The ideal dose, time and site for dye injection are not well defined. No high quality evidence-based comparative studies and long-term follow-up outcomes have been published so far. Initial results, however, are good and safe. RESUMO A identificação intraoperatória de certas estruturas anatômicas, por seu tamanho ou por elas serem ocultas à visão, pode ser desafiadora. O desenvolvimento da cirurgia minimamente invasiva trouxe dificuldades adicionais, pela falta da sensibilidade tátil completa. Diversas formas de detecção intraoperatória destas estruturas têm sido tentadas. Recentemente, a tecnologia de fluorescência infravermelha com verde de indocianina foi associada às plataformas robóticas. Além disso, essa tecnologia tem sido testada em uma variedade de cirurgias, e suas vantagens parecem estar ligadas a baixo custo, segurança e bons resultados. As desvantagens estão associadas à má distribuição do contraste em determinados cenários. A imagem intraoperatória por fluorescência infravermelha é uma nova e promissora adição à cirurgia robótica. Diversas séries mostram a utilidade da tecnologia em diferentes procedimentos. Dose ideal, local e tempo da injeção do corante ainda não estão bem estabelecidos. Estudos comparativos de alta qualidade epidemiológica baseados em evidência ainda não estão disponíveis. No entanto, os resultados iniciais são bons e seguros.

Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition.

PubMed

Brodnik, Zachary D; Ferris, Mark J; Jones, Sara R; España, Rodrigo A

2017-02-15

The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximately 2% of maximal DAT blockade. Overall, our data indicate that abused doses of cocaine produce a relatively modest degree of DA uptake inhibition, and suggest that the relationship between DAT occupancy and functional blockade of the DAT is more complex than originally posited.

An updated view on the role of dopamine in myopia.

PubMed

Feldkaemper, Marita; Schaeffel, Frank

2013-09-01

A large body of data is available to support the hypothesis that dopamine (DA) is one of the retinal neurotransmitters involved in the signaling cascade that controls eye growth by vision. Initially, reduced retinal DA levels were observed in eyes deprived of sharp vision by either diffusers ("deprivation myopia", DM) or negative lenses ("lens induced myopia", LIM). Simulating high retinal DA levels by intravitreal application of a DA agonist can suppress the development of both DM and LIM. Also more recent studies using knock-out mouse models of DA receptors support the idea of an association between decreased DA levels and DM. There seem to be differences in the magnitude of the effects of DA on DM and LIM, with larger changes in DM but the degrees of image degradation by both treatments need to be matched to support this conclusion. Although a number of studies have shown that the inhibitory effects of dopamine agonists on DM and LIM are mediated through stimulation of the D2-receptor, there is also recent evidence that the balance of D2- and D1-receptor activation is important. Inhibition of D2-receptors can also slow the development of spontaneous myopia in albino guinea pigs. Retinal DA content displays a distinct endogenous diurnal, and partially circadian rhythm. In addition, retinal DA is regulated by a number of visual stimuli like retinal illuminance, spatial frequency content of the image, temporal contrast and, in chicks, by the light input from the pineal organ. A close interaction was found between muscarinergic and dopaminergic systems, and between nitric oxide and dopaminergic pathways, and there is evidence for crosstalk between the different pathways, perhaps multiple binding of the ligands to different receptors. It was shown that DA agonists interact with the immediate early signaling molecule ZENK which triggers the first steps in eye growth regulation. However, since long treatment periods were often needed to induce significant changes in retinal dopamine synthesis and release, the role of dopamine in the early steps is unclear. The wide spatial distribution of dopaminergic amacrine cells in the retina and the observation that changes in dopamine levels can be locally induced by local retinal deprivation is in line with the assumption that dopaminergic mechanisms control both central and peripheral eye growth. The protective effect of outdoor activity on myopia development in children seems to be partly mediated by the stimulatory effect of light on retinal dopamine production and release. However, the dose-response function linking light exposure to dopamine and to the suppression of myopia is not known and requires further studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

SPANXB2 and Prostate Cancer Progression

DTIC Science & Technology

2013-10-01

critical  to  observe  some  important  relation  between  epithelial   and  stromas  which   hold  a  dose/timing-­‐dependent...Bodogai M, et al. (2009) Sperm -derived SPANX-B is a clinically relevant tumor antigen that is expressed in human tumors and readily recognized by...diversification of SPANX-N sperm protein gene structure and expression. PLoS One. 2007 Apr 4;2(4) 3. Barron DA, Rowley DR. (2012) The reactive stroma

[Effect of Corydalis Rhizoma and L-tetrahydropalmatine on dopamine system of hippocampus and striatum in morphine-induced conditioned place preference rats].

PubMed

Yu, Shou-Yang; Bai, Wei-Feng; Tu, Ping; Qiu, Cheng-Kai; Yang, Pei-Run; Luo, Su-Yuan

2016-10-01

To investigate the effects of Corydalis Rhizoma and L-tetrahydropalma-tine (L-THP) on the levels of dopamine neurotransmitter (DA), dopamine transporter (DAT) and the second dopamine receptor (D2R) in learning and memory-related brain areas, hippocampus and striatum, the DA, DAT and D2R were detected in conditioned place preference (CPP) rats suffered from morphine. And comparation the degree of similarity and consistency of the pharmacological effects was also studied. The rats were trained in black compartments and white ones (drug-paired compartment) with the increasing doses of morphine for 10 days (hypodermically injected from 10 mg•kg⁻¹ to 100 mg•kg⁻¹). Models of CPP were validated in those psychological dependence rats after 48 h training. The dopamine contents were detected as soon as the materials of hippocampus and striatum are harvested from rats of NS control group and model group. The DAT and D2R levels are measured by Western blot. The high, medium and low dose group of Corydalis Rhizoma are given Corydalis Rhizoma 2, 1, 0.5 g•kg⁻¹ water extraction liquid respectively (which contains L-THP were 0.274, 0.137 and 0.137 mg respectively), and the high, medium and low dose group of L-THP were given L-THP 3.76, 1.88, 0.94 mg•kg⁻¹ lavage treatment respectively, NS treatment group were lavaged normal saline for 6 days and they were killed after test of CPP, again tested DA levels and expression of DAT and D2R similar to the front of materials. The reduction effects of CPP were observed in the groups of both Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) subjected to medicine for 6 days (P<0.01). Compared with the NS treatment group and the model group, the higher values including in the contents of neurotransmitter dopamine were detected of hippocampus and striatum (P<0.01, P<0.05), the DAT and D2R protein expression of Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) increased in hippocampus and striatum (P<0.01). Learning and memory-related brain regions hippocampus and striatum was another neuroanatomical sites of action in the treatment of mental dependence of fumarate and L-THP, its mechanism was related to lowering its elevated DA neurotransmitter levels, and increasing the expression of DAT and D2R. Corydalis Rhizoma could be play 14-times roles in effect of L-THP. The similar effects were observed on the neurotransmitter dopamine, DAT and D2R in learning and memory-related brain areas, hippocampus and striatum of the morphine- dependent rats. Copyright© by the Chinese Pharmaceutical Association.

Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes

PubMed Central

Kadam, Rajendra S.; Williams, Jason; Tyagi, Puneet; Edelhauser, Henry F.

2013-01-01

Purpose First, to determine the influence of drug lipophilicity (using eight beta-blockers) and molecular weight (using 4 kDa and 40 kDa fluoroscein isothiocyanate [FITC]-dextrans) on suprachoroidal delivery to the posterior segment of the eye by using a rabbit ex vivo eye model. Second, to determine whether drug distribution differs between the dosed and undosed side of the eye following suprachoroidal delivery. Third, to compare the suprachoroidal delivery of sodium fluorescein (NaF) with the intracameral and intravitreal routes by using noninvasive fluorophotometry. Methods Using a small hypodermic 26G needle (3/8”) with a short bevel (250 µm), location of the suprachoroidal injection in an ex vivo New Zealand white rabbit eye model was confirmed with India ink. Ocular tissue distribution of NaF (25 µl of 1.5 µg/ml) at 37 °C was monitored noninvasively using the Fluorotron MasterTM at 0, 1, and 3 h following suprachoroidal, intravitreal, or intracameral injections in ex vivo rabbit eyes. For assessing the influence of lipophilicity and molecular size, 25 µl of a mixture of eight beta-blockers (250 µg/ml each) or FITC-dextran (4 kDa and 40 kDa, 30 mg/ml) was injected into the suprachoroidal space of excised rabbit eyes and incubated at 37 °C. Eyes were incubated for 1 and 3 h, and frozen at the end of incubation. Ocular tissues were isolated in frozen condition. Beta-blocker and FITC-dextran levels in excised ocular tissue were measured by liquid chromatography–tandem mass spectrometry and spectrofluorometry, respectively. Results Histological sections of India ink-injected albino rabbit eye showed the localization of dye as a black line in the suprachoroidal space. Suprachoroidal injection of NaF showed signal localization to the choroid and retina at 1 and 3 h post injection when compared with intravitreal and intracameral injections. Drug delivery to the vitreous after suprachoroidal injection decreased with an increase in solute lipophilicity and molecular weight. With an increase in drug lipophilicity, drug levels in the choroid–retinal pigment epithelium (RPE) and retina generally increased with some exceptions. Beta-blockers and FITC-dextrans were localized more to the dosed side when compared to the opposite side of the sclera, choroid–RPE, retina, and vitreous. These differences were greater for FITC-dextrans as compared to the beta-blockers. Conclusions The suprachoroidal route of injection allows localized delivery to the choroid–RPE and retina for small as well as large molecules. Suprachoroidal drug delivery to the vitreous declines with an increase in drug lipophilicity and molecular weight. Drug delivery differs between the dosed and opposite sides following suprachoroidal injection, at least up to 3 h. PMID:23734089

20 CFR 625.13 - Restrictions on entitlement; disqualification.

Code of Federal Regulations, 2010 CFR

2010-04-01

... DISASTER UNEMPLOYMENT ASSISTANCE § 625.13 Restrictions on entitlement; disqualification. (a) Income reductions. The amount of DUA payable to an individual for a week of unemployment, as computed pursuant to... wages due to illness or disability; (2) A supplemental unemployment benefit pursuant to a collective...

20 CFR 625.10 - Appeal and review.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Appeal and review. 625.10 Section 625.10 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT... Appeals Promptness-Unemployment Compensation” in part 650 of this chapter shall not apply to the DUA...

20 CFR 625.10 - Appeal and review.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Appeal and review. 625.10 Section 625.10 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT... Appeals Promptness-Unemployment Compensation” in part 650 of this chapter shall not apply to the DUA...

20 CFR 625.13 - Restrictions on entitlement; disqualification.

Code of Federal Regulations, 2012 CFR

2012-04-01

... DISASTER UNEMPLOYMENT ASSISTANCE § 625.13 Restrictions on entitlement; disqualification. (a) Income reductions. The amount of DUA payable to an individual for a week of unemployment, as computed pursuant to... wages due to illness or disability; (2) A supplemental unemployment benefit pursuant to a collective...

20 CFR 625.13 - Restrictions on entitlement; disqualification.

Code of Federal Regulations, 2011 CFR

2011-04-01

... DISASTER UNEMPLOYMENT ASSISTANCE § 625.13 Restrictions on entitlement; disqualification. (a) Income reductions. The amount of DUA payable to an individual for a week of unemployment, as computed pursuant to... wages due to illness or disability; (2) A supplemental unemployment benefit pursuant to a collective...

20 CFR 625.13 - Restrictions on entitlement; disqualification.

Code of Federal Regulations, 2014 CFR

2014-04-01

... DISASTER UNEMPLOYMENT ASSISTANCE § 625.13 Restrictions on entitlement; disqualification. (a) Income reductions. The amount of DUA payable to an individual for a week of unemployment, as computed pursuant to... wages due to illness or disability; (2) A supplemental unemployment benefit pursuant to a collective...

20 CFR 625.10 - Appeal and review.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Appeal and review. 625.10 Section 625.10 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT... Appeals Promptness-Unemployment Compensation” in part 650 of this chapter shall not apply to the DUA...

20 CFR 625.10 - Appeal and review.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 3 2013-04-01 2013-04-01 false Appeal and review. 625.10 Section 625.10 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT... Appeals Promptness-Unemployment Compensation” in part 650 of this chapter shall not apply to the DUA...

20 CFR 625.13 - Restrictions on entitlement; disqualification.

Code of Federal Regulations, 2013 CFR

2013-04-01

... DISASTER UNEMPLOYMENT ASSISTANCE § 625.13 Restrictions on entitlement; disqualification. (a) Income reductions. The amount of DUA payable to an individual for a week of unemployment, as computed pursuant to... wages due to illness or disability; (2) A supplemental unemployment benefit pursuant to a collective...

20 CFR 625.10 - Appeal and review.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 3 2014-04-01 2014-04-01 false Appeal and review. 625.10 Section 625.10 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT... Appeals Promptness-Unemployment Compensation” in part 650 of this chapter shall not apply to the DUA...

Cloning and sequencing of a gene encoding a 21-kilodalton outer membrane protein from Bordetella avium and expression of the gene in Salmonella typhimurium.

PubMed Central

Gentry-Weeks, C R; Hultsch, A L; Kelly, S M; Keith, J M; Curtiss, R

1992-01-01

Three gene libraries of Bordetella avium 197 DNA were prepared in Escherichia coli LE392 by using the cosmid vectors pCP13 and pYA2329, a derivative of pCP13 specifying spectinomycin resistance. The cosmid libraries were screened with convalescent-phase anti-B. avium turkey sera and polyclonal rabbit antisera against B. avium 197 outer membrane proteins. One E. coli recombinant clone produced a 56-kDa protein which reacted with convalescent-phase serum from a turkey infected with B. avium 197. In addition, five E. coli recombinant clones were identified which produced B. avium outer membrane proteins with molecular masses of 21, 38, 40, 43, and 48 kDa. At least one of these E. coli clones, which encoded the 21-kDa protein, reacted with both convalescent-phase turkey sera and antibody against B. avium 197 outer membrane proteins. The gene for the 21-kDa outer membrane protein was localized by Tn5seq1 mutagenesis, and the nucleotide sequence was determined by dideoxy sequencing. DNA sequence analysis of the 21-kDa protein revealed an open reading frame of 582 bases that resulted in a predicted protein of 194 amino acids. Comparison of the predicted amino acid sequence of the gene encoding the 21-kDa outer membrane protein with protein sequences in the National Biomedical Research Foundation protein sequence data base indicated significant homology to the OmpA proteins of Shigella dysenteriae, Enterobacter aerogenes, E. coli, and Salmonella typhimurium and to Neisseria gonorrhoeae outer membrane protein III, Haemophilus influenzae protein P6, and Pseudomonas aeruginosa porin protein F. The gene (ompA) encoding the B. avium 21-kDa protein hybridized with 4.1-kb DNA fragments from EcoRI-digested, chromosomal DNA of Bordetella pertussis and Bordetella bronchiseptica and with 6.0- and 3.2-kb DNA fragments from EcoRI-digested, chromosomal DNA of B. avium and B. avium-like DNA, respectively. A 6.75-kb DNA fragment encoding the B. avium 21-kDa protein was subcloned into the Asd+ vector pYA292, and the construct was introduced into the avirulent delta cya delta crp delta asd S. typhimurium chi 3987 for oral immunization of birds. The gene encoding the 21-kDa protein was expressed equivalently in B. avium 197, delta asd E. coli chi 6097, and S. typhimurium chi 3987 and was localized primarily in the cytoplasmic membrane and outer membrane. In preliminary studies on oral inoculation of turkey poults with S. typhimurium chi 3987 expressing the gene encoding the B. avium 21-kDa protein, it was determined that a single dose of the recombinant Salmonella vaccine failed to elicit serum antibodies against the 21-kDa protein and challenge with wild-type B. avium 197 resulted in colonization of the trachea and thymus with B. avium 197. Images PMID:1447140

Evaluation of body posture in nursing students.

PubMed

Andrade, Marília Fernandes; Chaves, Érika de Cássia Lopes; Miguel, Michele Rita Oliveira; Simão, Talita Prado; Nogueira, Denismar Alves; Iunes, Denise Hollanda

2017-08-28

To investigate the body posture of nursing students before and after clinical practice. The study was developed in two stages. Initially the body posture of students of the 2nd, 4th, 6th, and 8th periods were assessed through photogrammetry. All images were analyzed in a random and masked manner with CorporisPro® 3.1.3 software. Three evaluations were performed for each angle and then the mean value was calculated. Two years later, when the 4th period students had developed their clinical internships, their body posture was again evaluated. The total sample consisted of 112 students. Comparison of their posture with the normality pattern showed that all the angles presented significant differences (p< 0.00), except for the angle of the Thales triangle. Reassessment of these students evidenced significant differences in the angles of the acromioclavicular joint (p=0.03), knee flexion (p< 0.00) and in the tibiotarsal angle (p< 0.00). All the students presented alterations when compared to the normality values. The segments that presented significant differences between before and after practice were the acromioclavicular angle, knee flexion, and tibiotarsal angle; the latter two were in the rolling position. Investigar a postura dos estudantes de enfermagem antes e após a prática clínica. O estudo foi desenvolvido em duas etapas, inicialmente com estudantes (2º, 4°, 6° e 8º períodos) tiveram sua postural corporal avaliada por meio da fotogrametria. Todas as imagens foram analisadas, de maneira aleatória e mascarada, por meio do software CorporisPro® 3.1.3. Foram realizadas três avaliações para cada ângulo e calculada a média. Dois anos depois, quando os estudantes do 4º período desenvolveram os estágios clínicos, foram novamente avaliados quanto à postura corporal. A amostra total foi composta por 112 estudantes. Comparando-se os estudantes com o padrão de normalidade, todos os ângulos apresentaram diferença significativa (p< 0,00), com exceção do ângulo triângulo de Tales. Reavaliando os mesmos estudantes, houve diferença significativa nos ângulos da articulação acromioclavicular (p=0,03), da flexão de joelhos (p< 0,00) e no ângulo tibiotársico (p< 0,00). Todos os estudantes apresentaram alterações, comparadas aos valores de normalidade. Os segmentos com diferença significativa, comparando-se antes e após a prática, foram o ângulo acromioclavicular, flexo de joelho e ângulo tibiotársico, sendo os dois últimos na posição de rolamento.

Experiences and coping with the altered body image in digestive stoma patients.

PubMed

Hueso-Montoro, César; Bonill-de-Las-Nieves, Candela; Celdrán-Mañas, Miriam; Hernández-Zambrano, Sandra Milena; Amezcua-Martínez, Manuel; Morales-Asencio, José Miguel

2016-12-08

to describe the coping of stoma patients with the news about the ostomy, as well as to analyze the meaning and the experience of their new bodily reality. qualitative phenomenological study undertaken through semistructured interviews with 21 stoma patients. The analysis was based on the constant comparison of the data, the progressive incorporation of subjects and triangulation among researchers and stomal therapy nurses. The software Atlas.ti was used. two main categories emerge: "Coping with the news about receiving a stoma" and "Meaning and experience of the new bodily reality". The informants' answer varies, showing situations that range from the natural acceptance of the process to resignation and rejection. The previous experiences of other family members, the possible reconstruction of the stoma or the type of illness act as conditioning factors. the coping with the news about the stoma is conditioned by the type of illness, although the normalization of the process is the trend observed in most informants. Nursing plays a fundamental role in the implementation of cognitive-behavioral interventions and other resources to promote the patients' autonomy in everything related to care for the stoma. descrever o enfrentamento de pessoas ostomizadas diante da notícia da realização do estoma, assim como analisar o significado e a vivência diante de sua nova realizada corporal. estudo qualitativo fenomenológico mediante entrevistas semiestruturadas com 21 personas ostomizadas. Foi desenvolvido através da comparação constante de dados, incorporação progressiva de sujeitos e triangulação entre investigadores e enfermeiras especialistas em estomaterapia. Foi utilizado o software Atlas.ti. emergiram duas categorias centrais: "Enfrentamento diante da notícia de que serão ostomizados" e "Significado e vivência da nova realidade corporal". A resposta dos informantes é variável, revelando situações que vão desde a aceitação natural do seu processo até a resignação e a rejeição. As experiências prévias de outros familiares, a possibilidade de reconstrução do estoma ou o tipo de doença são fatores condicionantes. o enfrentamento diante da notícia do estoma está condicionado pelo tipo de doença. Apesar disso, observa-se que a maioria dos informantes tende a normalizar o processo. A enfermagem tem papel fundamental na implementação de intervenções cognitivas-comportamentais e outros recursos destinados à promoção da autonomia dos pacientes em tudo relacionado ao cuidado do estoma. describir el afrontamiento de personas ostomizadas ante la noticia de la realización de la ostomía, así como analizar el significado y la vivencia ante su nueva realidad corporal. estudio cualitativo fenomenológico mediante entrevistas semiestructuradas a 21 personas ostomizadas. Se realizó análisis mediante comparación constante de datos, incorporación progresiva de sujetos y triangulación entre investigadores y enfermeras expertas en estomaterapia. Se empleó el programa Atlas.ti. emergen dos categorías centrales: "Afrontamiento ante la noticia de que van a ser ostomizados" y "Significado y vivencia de la nueva realidad corporal". La respuesta de los informantes es variable, percibiéndose situaciones que van desde la aceptación natural de su proceso hasta la resignación y el rechazo. Las experiencias previas de otros familiares, la posibilidad de reconstrucción del estoma o el tipo de enfermedad, son factores condicionantes. el afrontamiento ante la noticia del estoma está condicionado por el tipo de enfermedad, aunque la normalización del proceso es la tendencia observada en la mayoría de los informantes. Enfermería tiene un papel fundamental en la puesta en marcha de intervenciones cognitivos-conductuales y otros recursos destinados a la promoción de la autonomía de los pacientes en todo lo relacionado con el cuidado del estoma.

The predictive factors of α1-D/A adrenoceptor antagonist, naftopidil, dose increase therapy for male lower urinary tract symptoms caused by benign prostatic hyperplasia: INFORM study.

PubMed

Tanuma, Yasushi; Tanaka, Yoshinori; Takeyama, Ko; Okamoto, Tomoshi

2017-01-01

We evaluated the predictive factors which affect the efficacy of naftopidil 50 mg/day therapy and dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. A total of 92 patients with male lower urinary tract symptoms/benign prostatic hyperplasia were administrated naftopidil 50 mg/day for 4 weeks (50 mg therapy). At week 4, the patients were divided into an effective and an ineffective group (Group E and Group I, respectively). For further 4 weeks, the dosage of naftopidil was increased to 75 mg/day in all patients. At week 8, the patients of Group E and Group I were divided into an effective and an ineffective group (Group EE, Group EI, Group IE, and Group II, respectively). Postvoid residual (PVR) urine volume at baseline was a predictive factor for efficacy of 50 mg therapy. In Group E, change in International Prostate Symptom Score storage symptoms subscore from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. In Group I, change in maximum flow rate from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. The short term of naftopidil 50 mg therapy was ineffective for the patients who had large PVR. The predictive factor of this dose increase therapy might be a dynamic variable in 50 mg/day of dose period, but not a baseline variable at the time of 75 mg/day dosage starts.

Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease

PubMed Central

Xiong, Nian; Huang, Jinsha; Zhang, Zhentao; Zhang, Zhaowen; Xiong, Jing; Liu, Xingyuan; Jia, Min; Wang, Fang; Chen, Chunnuan; Cao, Xuebing; Liang, Zhihou; Sun, Shenggang; Lin, Zhicheng; Wang, Tao

2009-01-01

A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research. PMID:19924288

Dopamine and Octopamine Influence Avoidance Learning of Honey Bees in a Place Preference Assay

PubMed Central

Agarwal, Maitreyi; Giannoni Guzmán, Manuel; Morales-Matos, Carla; Del Valle Díaz, Rafael Alejandro; Abramson, Charles I.; Giray, Tugrul

2011-01-01

Biogenic amines are widely characterized in pathways evaluating reward and punishment, resulting in appropriate aversive or appetitive responses of vertebrates and invertebrates. We utilized the honey bee model and a newly developed spatial avoidance conditioning assay to probe effects of biogenic amines octopamine (OA) and dopamine (DA) on avoidance learning. In this new protocol non-harnessed bees associate a spatial color cue with mild electric shock punishment. After a number of experiences with color and shock the bees no longer enter the compartment associated with punishment. Intrinsic aspects of avoidance conditioning are associated with natural behavior of bees such as punishment (lack of food, explosive pollination mechanisms, danger of predation, heat, etc.) and their association to floral traits or other spatial cues during foraging. The results show that DA reduces the punishment received whereas octopamine OA increases the punishment received. These effects are dose-dependent and specific to the acquisition phase of training. The effects during acquisition are specific as shown in experiments using the antagonists Pimozide and Mianserin for DA and OA receptors, respectively. This study demonstrates the integrative role of biogenic amines in aversive learning in the honey bee as modeled in a novel non-appetitive avoidance learning assay. PMID:21980435

[Effect of bitumen fume on neurotransmitter and ultrastructure in mice brain].

PubMed

Li, Hai-Ling; Guo, Xiang-Yun; Feng, San-Wei; Liu, Chang-Hai

2006-12-01

To observe the effects of bitumen fume on neurotransmitter and ultrastructure of mice brain and to investigate the toxicity of bitumen fume on nerve system of mice brain. The experimental mice were forced to inhale the bitumen fume at different exposure level and in different time periods. The contents of the three transmitters dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) in mice brain were measured by the fluorescence meanwhile ultrastructure of mice brain was observed by electronic microscope. The ultrastructure of mice brain was observed under transmission electron microscopy. The contents of DA, NE and 5-HT in all groups decreased with the increasing of dose and prolonging of time (after 8 week, with the increasing of exposure lever, the content of DA, NE, 5-HT was respectively 2.194, 2.190, 2.181, 2.178 microg/g and 1.148, 1.138, 1.135 and 1.407, 1.403, 1.395 microg), but the results did not show significant differences. The structure of the mitochondria changes included the swollen mitochondria, chromatin margination, pyknosis and apoptosis in neuro cells and the processes of swollen astrocyte cells. The bitumen fume could induce changes of the ultrastructure of mice brain and affect the contents of neurotransmitter of mice brain.

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

PubMed Central

Krishnan, Vyjayanthi; Andersen, Bo H.; Shoemaker, Christine; Sivko, Gloria S.; Tordoff, Kevin P.; Stark, Gregory V.; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew

2015-01-01

AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 107, 1.5 × 109, or 3.5 × 1010 viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 1010 viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. PMID:25673303

Learning of Unknown Environments in Goal-Directed Guidance and Navigation Tasks: Autonomous Systems and Humans

NASA Astrophysics Data System (ADS)

Vidal, Joao Vasco Silvestres

Este trabalho expoe um estudo teorico e experimental das propriedades anisotropicas magnetoeletricas (ME) em diferentes compositos contendo monocristais piezoeletricos (PE), maioritariamente sem chumbo na sua composicao, com vista a diversas aplicacoes multifuncionais. Uma descricao linear do efeito ME em termos de campos eletricos, magneticos e elasticos e constantes materiais e apresentada. Um modelo fenomenologico quasi-estatico e usado para ilustrar a relacao entre as constantes materiais, sua anisotropia e os coeficientes MEs transversais de tensao e carga. Subsequentemente, este modelo e empregue para estimar o maximo coeficiente ME direto de tensao expectavel numa serie de compositos tri-camadas de Metglas/Piezocristal/Metglas em funcao da orientacao do cristal PE. Demonstra-se assim como os efeitos MEs sao fortemente dependentes da orientacao cristalina, o que suporta a possibilidade de se gerarem coeficientes MEs de tensao elevados em compositos contendo monocristais PEs sem chumbo como o niobato de litio (LiNbO3; LNO), tantalato de litio (LiTaO3), ortofosfato de galio (GaPO4; GPO), quartzo (SiO2), langatato (La3Ga5.5Ta0.5O14) e langasite (La3Ga5SiO14) atraves da otimizacao da orientacao cristalina. Uma tecnica experimental dinâmica de lock-in para a medicao da impedância e efeito ME direto e exposta. O formalismo descritivo desta tecnica, assim como um arranjo experimental desenvolvido para o efeito sao apresentados. O esquema e caracteristicas deste, assim como diferentes formas de reduzir o ruido e a indesejavel inducao mutua sao exploradas. Um estudo comparativo do efeito ME direto em compositos tri-camadas de Metglas e monocristais de LNO e PMN-PT conectados de forma simples e exposto. Embora o PMN-PT possua piezocoeficientes de carga muito superiores aos do LNO, o coeficiente ME direto de tensao demonstrou-se comparavel entre ambos os compositos devido a uma muito menor permitividade dieletrica do LNO. Calculos teoricos indicam ainda que as propriedades MEs poderao ser significativamente melhoradas (ate 500 V/(cm.Oe)) atraves da otimizacao do ângulo de corte do LNO, espessura relativa entre camadas ferroeletrica/ferromagnetica e uma melhor colagem entre o Metglas e o LNO. Vantagens da utilizacao do material ferroeletrico LNO em compositos MEs sao discutidas. Num estudo subsequente, as propriedades dinâmicas anisotropicas de impedância e MEs em compositos tri-camadas de Metglas e monocristais PEs sem chumbo de LNO e GPO sao exploradas. Medicoes foram realizadas em funcao do corte de cristal, magnitude e orientacao do campo magnetico de polarizacao e frequencia do campo de modulacao. Coeficientes MEs altamente intensos em certos modos de ressonância sao explorados, e a sua relacao com as propriedades materiais dos cristais e geometria dos compositos e investigada. Um coeficiente ME de ate 249 V/(cm.Oe) foi aqui observado num composito com um cristal de LNO com corte 41ºY a 323.1 kHz. Mostramos assim que compositos multicamadas contendo cristais sem chumbo de LNO e GPO podem exibir efeitos MEs anisotropicos relativamente elevados. Demonstramos tambem que o controlo da orientacao dos cristais PEs pode em principio ser usado na obtencao de propriedades MEs anisotropicas desejaveis para qualquer aplicacao. Caracteristicas unicas como elevada estabilidade quimica, piezoeletricidade linear e robusteza termica abrem verdadeiras perspetivas para a utilizacao de compositos baseados no LNO e GPO em diversas aplicacoes. Eventualmente, compositos bi-camadas contendo lâminas PEs com bidominios de LNO com corte 127ºY foram estudados tanto teoricamente como experimentalmente. Estas lâminas de LNO possuem uma estrutura de bidominios com vetores de polarizacao espontânea opostos ao longo da direcao da sua espessura (i.e. uma estrutura de macrodominios ferroeletricos "head-to-head" ou "tail-to-tail") Medicoes de impedância, efeito ME e densidade de ruido magnetico equivalente foram realizadas nos compositos operando sob condicoes quasi-estaticas e de ressonância. Coeficientes MEs de ate 578 V/(cm.Oe) foram obtidos a ca. 30 kHz sob ressonâncias de dobramento usando cristais PEs com 0.5 mm de espessura. Medicoes de densidade de ruido magnetico equivalente demosntraram valores de ate 153 pT/Hz1/2 a 1 kHz (modo quasi-estatico) e 524 fT/Hz1/2 sob condicoes de ressonância. E de esperar que uma otimizacao adicional das tecnicas de fabrico, geometria dos compositos e circuitos de detencao possa permitir reduzir estes valores ate pelo menos 10 pT/Hz1/2 e 250 fT/Hz1/2, respetivamente, e a frequencia de ressonância em pelo menos duas ordens de grandeza. Estes sistemas poderao assim no futuro ser usados em sensores vetoriais de campo magnetico simples e sensiveis, passivos e estaveis e operaveis a elevadas temperaturas. None

77 FR 69490 - Delaware; Emergency and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-19

... Title V of the Stafford Act, to save lives and to protect property and public health and safety, and to... Unemployment Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to... Assistance--Disaster Housing Operations for Individuals and Households; 97.050, Presidentially Declared...

77 FR 69490 - West Virginia; Emergency and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-19

..., authorized under Title V of the Stafford Act, to save lives and to protect property and public health and... Unemployment Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to... Assistance--Disaster Housing Operations for Individuals and Households; 97.050, Presidentially Declared...

20 CFR 625.4 - Eligibility requirements for Disaster Unemployment Assistance.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Unemployment Assistance. 625.4 Section 625.4 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.4 Eligibility requirements for Disaster Unemployment Assistance. An individual shall be eligible to receive a payment of DUA with respect to a week of...

20 CFR 625.4 - Eligibility requirements for Disaster Unemployment Assistance.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Unemployment Assistance. 625.4 Section 625.4 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.4 Eligibility requirements for Disaster Unemployment Assistance. An individual shall be eligible to receive a payment of DUA with respect to a week of...

20 CFR 625.4 - Eligibility requirements for Disaster Unemployment Assistance.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Unemployment Assistance. 625.4 Section 625.4 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.4 Eligibility requirements for Disaster Unemployment Assistance. An individual shall be eligible to receive a payment of DUA with respect to a week of...

20 CFR 625.4 - Eligibility requirements for Disaster Unemployment Assistance.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Unemployment Assistance. 625.4 Section 625.4 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.4 Eligibility requirements for Disaster Unemployment Assistance. An individual shall be eligible to receive a payment of DUA with respect to a week of...

20 CFR 625.4 - Eligibility requirements for Disaster Unemployment Assistance.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Unemployment Assistance. 625.4 Section 625.4 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR DISASTER UNEMPLOYMENT ASSISTANCE § 625.4 Eligibility requirements for Disaster Unemployment Assistance. An individual shall be eligible to receive a payment of DUA with respect to a week of...

76 FR 34090 - Missouri; Major Disaster and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-10

... President issued a major disaster declaration under the authority of the Robert T. Stafford Disaster Relief... warrant a major disaster declaration under the Robert T. Stafford Disaster Relief and Emergency Assistance... (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to Individuals and...

78 FR 36556 - Oklahoma; Major Disaster and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-18

... President issued a major disaster declaration under the authority of the Robert T. Stafford Disaster Relief... major disaster declaration under the Robert T. Stafford Disaster Relief and Emergency Assistance Act, 42... Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to...

78 FR 45547 - North Dakota; Major Disaster and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-29

... President issued a major disaster declaration under the authority of the Robert T. Stafford Disaster Relief... major disaster declaration under the Robert T. Stafford Disaster Relief and Emergency Assistance Act, 42... Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to...

77 FR 20043 - Indiana; Major Disaster and Related Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-03

... President issued a major disaster declaration under the authority of the Robert T. Stafford Disaster Relief... and magnitude to warrant a major disaster declaration under the Robert T. Stafford Disaster Relief and... Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048, Disaster Housing Assistance to...

Switching from an oral dopamine receptor agonist to rotigotine transdermal patch: a review of clinical data with a focus on patient perspective.

PubMed

Chung, Sun Ju; Asgharnejad, Mahnaz; Bauer, Lars; Benitez, Arturo; Boroojerdi, Babak; Heidbrede, Tanja; Little, Allison; Kim, Han Joon

2017-07-01

Dopamine receptor agonists (DAs) are commonly used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms ('dopamine receptor agonist' OR 'rotigotine') AND 'switch'. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h rotigotine) may be switched overnight.

ISOLATION, CHARACTERIZATION AND IMMUNOCHEMICAL STUDIES ON FIBROUS PROTEINS FROM COWRY SHELL (CYPRAEA MONETA, LINNAEUS)

PubMed Central

Togun, R.A.; Balogun, R. O.; Adeyemi, D.O.; Esan, T.A.; Oyatogun, G.M; Oziegbe, E.O; Okonji, R. E.; Kuku, A.

2017-01-01

Background: Biomaterials are non-drug substances used to treat, enhance or replace functions of body tissues or organs. Natural sources of biomaterials have recently become the focus of several research activities. Cowry shell constitutes one of the most promising natural sources of biomaterials because of its chemical stability, biodegradability and biocompatibility in the body. However, its applications may be limited due to immunogenic and toxic responses that may occur following implantation, hence this study. Materials and Methods: Crude fibrous protein extracted with citrate buffer from pulverised cowry shells (Cypraea moneta (L)), was resolved into two components (CSP1 and CSP2) by gel filtration. Immunological studies were performed with antisera obtained from rabbits by double immunodiffusion and immunoelectrophoresis techniques. Mice treated with the proteins were observed for signs of toxicity and their liver, kidney, lungs and spleen were processed histologically. Results: The native molecular weight of CSP1 and CSP2 determined by gel filtration were 91kDa and 33kDa respectively. CSP1 and CSP2 displayed single bands on SDS-PAGE with subunit molecular weight values of 19kDa and 19.5kDa respectively. Antisera obtained from rabbits immunised with the crude citrate buffer extracts precipitated the antigen in double immunodiffusion tests. Histopathological examinations revealed a dose-dependent damaging effect of the shell proteins on liver, kidney, lung and spleen tissues of the treated mice. Conclusion: This study showed that cowry shells contain fibrous proteins which are immunogenic and toxic in mice at relatively high concentrations, causing visible organ damage without concurrent physical manifestations. PMID:28480388

Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

PubMed Central

Hou, Lijuan; Chen, Wei; Liu, Xiaoli; Qiao, Decai; Zhou, Fu-Ming

2017-01-01

Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD), and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA) system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN) dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise-induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients. PMID:29163139

MAOA expression predicts vulnerability for alcohol use.

PubMed

Cervera-Juanes, R; Wilhem, L J; Park, B; Lee, R; Locke, J; Helms, C; Gonzales, S; Wand, G; Jones, S R; Grant, K A; Ferguson, B

2016-04-01

The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.

The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys.

PubMed

Weed, M R; Paul, I A; Dwoskin, L P; Moore, S E; Woolverton, W L

1997-10-01

The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission and stimulation of central nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been found to function as positive reinforcers. The present experiments were designed to examine why some, but not all, D1 receptor agonists can function as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) schedule until stable responding was established. Various doses of D1 agonists, previously reported to function as positive reinforcers, were then made available for self-administration. Stimulation of cAMP production in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive reinforcers in monkeys (SKF 38393, SKF 77434 and S(-)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR schedule and did not differ significantly in efficacy as positive reinforcers; SKF 81297 was less potent than the other two agonists. SKF 81297, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP production in rhesus striata than did SKF 38393, SKF 77434 and S(-)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing efficacy among D1 agonists increases with efficacy in stimulating D1 receptors.

Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity

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

Wang, Wenxiang; Zhang, Wenchang, E-mail: wenchang2002@sina.com; Liu, Jin

Female Wistar rats at 21 days of age were treated with one of three concentrations of soy isoflavones (SIF) (50, 100 or 200 mg/kg body weight, orally, once per day) from weaning until sexual maturity (3 months) in order to evaluate the influence of SIF on ovarian follicle development. After treatment, the serum sex hormone levels and enumeration of ovarian follicles of the ovary were measured. The metabolic profile of follicular fluid was determined using HPLC-MS. Principal component analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was used to identify differences in metabolites and reveal useful toxic biomarkers. The results indicatedmore » that modest doses of SIF affect ovarian follicle development, as demonstrated by decreased serum estradiol levels and increases in both ovarian follicle atresia and corpora lutea number in the ovary. SIF treatment-related metabolic alterations in follicular fluid were also found in the PCA and PLS-DA models. The 24 most significantly altered metabolites were identified, including primary sex hormones, amino acids, fatty acids and metabolites involved in energy metabolism. These findings may indicate that soy isoflavones affect ovarian follicle development by inducing metabolomic variations in the follicular fluid. - Highlights: ► Modest doses of soy isoflavones (SIF) do affect ovarian follicle development. ► SIF treatment-related metabolic alterations in follicular fluid were found. ► The 24 most significantly altered metabolites were identified.« less

Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice.

PubMed

Wu, Chun Fu; Liu, Yan Li; Song, Ming; Liu, Wen; Wang, Jin Hui; Li, Xian; Yang, Jing Yu

2003-08-01

In the present study, pseudoginsenoside-F(11) (PF(11)), a saponin that existed in American ginseng, was studied on its protective effect on methamphetamine (MA)-induced behavioral and neurochemical toxicities in mice. MA was intraperitoneally administered at the dose of 10 mg/kg four times at 2-h intervals, and PF(11) was orally administered at the doses of 4 and 8 mg/kg two times at 4-h intervals, 60 min prior to MA administration. The results showed that PF(11) did not significantly influence, but greatly ameliorated, the anxiety-like behavior induced by MA in the light-dark box task. In the forced swimming task, PF(11) significantly shortened the prolonged immobility time induced by MA. In the appetitively motivated T-maze task, PF(11) greatly shortened MA-induced prolonged latency and decreased the error counts. Similar results were also observed in the Morris water maze task. PF(11) significantly shortened the escape latency prolonged by MA. There were significant decreases in the contents of dopamine (DA), 3,4-dihydroxyphenacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoacetic acid (5-HIAA) in the brain of MA-treated mice. PF(11) could partially, but significantly, antagonize MA-induced decreases of DA. The above results demonstrate that PF(11) is effective in protection of MA-induced neurotoxicity and also suggest that natural products, such as ginseng, might be potential candidates for the prevention and treatment of the neurological disorders induced by MA abuse.

Stabilization of tetanus toxoid encapsulated in PLGA microspheres.

PubMed

Jiang, Wenlei; Schwendeman, Steven P

2008-01-01

Delivery of vaccine antigens from controlled-release poly(lactic/glycolic acid) (PLGA) microspheres is a novel approach to reduce the number of antigen doses required for protection against infection. A major impediment to developing single-shot vaccines is encapsulated antigen instability during months of exposure to physiological conditions. For example, efforts to control neonatal tetanus in developing countries with a single-dose TT vaccine based on PLGA microspheres have been plagued by poor stability of the 150 kDa formaldehyde-detoxified protein antigen, tetanus toxoid (TT), in the polymer. We examined the denatured states of PLGA-encapsulated TT, revealing two primary TT instability mechanisms: (1) protein aggregation mediated by formaldehyde and (2) acid-induced protein unfolding and epitope damage. Further, we systematically identified excipients, which can efficiently inhibit TT aggregation and retain TT antigenicity under simulated deleterious conditions, i.e., elevated temperature and humidity. By employing these novel additives in the PLGA system, we report the slow and continuous release of high doses of TT for one month with retained antigen stability during bioerosion of PLGA.

Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

PubMed Central

Williams, Jason H; Schray, Rebecca C; Sirsi, Shashank R; Lutz, Gordon J

2008-01-01

Background Exon skipping oligonucleotides (ESOs) of 2'O-Methyl (2'OMe) and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD). However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA) muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG) or adsorbtion of colloidal gold (CG), respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal levels were found at 6 weeks after 10 twice-weekly injections of the NG-PEI2K-PEG550 copolymer complexed with 5 μg of ESO per injection. This injection and dosing regimen showed over 1000 dystrophin-positive fibers. H&E staining of all treated muscle groups revealed no overt signs of cytotoxicity. Conclusion We conclude that PEGylated PEI2K copolymers are efficient carriers for local delivery of 2'OMe ESOs and warrant further development as potential therapeutics for treatment of DMD. PMID:18384691

Omitted Arguments and Complexity of Predication

ERIC Educational Resources Information Center

Port, Martin

2010-01-01

This work focuses on the licensing conditions and logical structure of understood-argument constructions, or complement-drop constructions, in English. There are two main types of such arguments: Indefinite Understood Arguments (IUA) and Definite Understood Arguments (DUA). IUA readings occur in such cases in "He ate, He cooked". In such cases,…