Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker

PubMed Central

Patrick, Kennerly S.; Corbin, Timothy R.; Murphy, Cristina E.

2014-01-01

We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery; drug interactions; biomarker for dl-methylphenidate (MPH)-ethanol exposure; potentiation of dl-MPH abuse liability; contemporary “designer drug”; pertinence to the newer transdermal and chiral switch MPH formulations; as well as problematic internal standard. d-EPH selectively targets the dopamine transporter while d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol co-abuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: An otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; A sub-stimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; Ethanol elevates blood, brain and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. PMID:25303048

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.

PubMed

Patrick, Kennerly S; Corbin, Timothy R; Murphy, Cristina E

2014-12-01

We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task.

PubMed

Goldstein, Rita Z; Woicik, Patricia A; Maloney, Thomas; Tomasi, Dardo; Alia-Klein, Nelly; Shan, Juntian; Honorio, Jean; Samaras, Dimitris; Wang, Ruiliang; Telang, Frank; Wang, Gene-Jack; Volkow, Nora D

2010-09-21

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

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

Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A.

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function)more » in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.« less

Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

PubMed

Bell, Guinevere H; Novak, Andrew J; Griffin, William C; Patrick, Kennerly S

2011-07-01

We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

ABCB1 c.2677G>T variation is associated with adverse reactions of OROS-methylphenidate in children and adolescents with ADHD.

PubMed

Kim, So Won; Lee, Ji Hyun; Lee, Sung Hee; Hong, Hyun Ju; Lee, Min Goo; Yook, Ki-Hwan

2013-08-01

Osmotic-release oral system (OROS)-methylphenidate (MPH) is a safe and well-tolerated drug. Some patients cannot continue this regimen with adverse drug reactions (ADRs). As drug efflux transporters of the central nervous system, ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues. We hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH. We analyzed ADRs of OROS-MPH in 134 children and adolescents with attention-deficit hyperactivity disorder who completed a 4-week trial of OROS-MPH. The ADRs of OROS-MPH were evaluated by administering the Barkley Stimulant Side Effects Rating Scale. Our study proved that MPH is a substrate for ABCB1 by using membrane vesicle assay. We analyzed the influence of ABCB1 polymorphisms on ADRs to OROS-MPH. From the association study between ABCB1 polymorphisms and ADRs of OROS-MPH, c.2677G>T (p.Ala893Ser, rs2032582) showed a strong association with OROS-MPH-related ADRs (P = 0.008; odds ratio, 5.72). Furthermore, logistic regression analysis indicated that the TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH. In a functional study, the 893Ser variant markedly reduced MPH transport across the cell membrane. This is the first study to demonstrate that the TT genotype at position 2677 in the ABCB1 gene is associated with ADRs to OROS-MPH.

Prenatal exposure to methylphenidate affects the dopamine system and the reactivity to natural reward in adulthood in rats.

PubMed

Lepelletier, François-Xavier; Tauber, Clovis; Nicolas, Céline; Solinas, Marcello; Castelnau, Pierre; Belzung, Catherine; Emond, Patrick; Cortese, Samuele; Faraone, Stephen V; Chalon, Sylvie; Galineau, Laurent

2014-10-31

Methylphenidate (MPH) is a commonly-used medication for the treatment of children with Attention-Deficit/Hyperactivity Disorders (ADHD). However, its prescription to adults with ADHD and narcolepsy raises the question of how the brain is impacted by MPH exposure during pregnancy. The goal of this study was to elucidate the long-term neurobiological consequences of prenatal exposure to MPH using a rat model. We focused on the effects of such treatment on the adult dopamine (DA) system and on the reactivity of animals to natural rewards. This study shows that adult male rats prenatally exposed to MPH display elevated expression of presynaptic DA markers in the DA cell bodies and the striatum. Our results also suggest that MPH-treated animals could exhibit increased tonic DA activity in the mesolimbic pathway, altered signal-to-noise ratio after a pharmacological stimulation, and decreased reactivity to the locomotor effects of cocaine. Finally, we demonstrated that MPH rats display a decreased preference and motivation for sucrose. This is the first preclinical study reporting long-lasting neurobiological alterations of DA networks as well as alterations in motivational behaviors for natural rewards after a prenatal exposure to MPH. These results raise concerns about the possible neurobiological consequences of MPH treatment during pregnancy. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Cognitive effects of methylphenidate and levodopa in healthy volunteers.

PubMed

Linssen, A M W; Sambeth, A; Vuurman, E F P M; Riedel, W J

2014-02-01

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory. © 2013 Published by Elsevier B.V. and ECNP.

Design of a Multi-Pinhole Collimator for I-123 DaTscan Imaging on Dual-Headed SPECT Systems in Combination with a Fan-Beam Collimator.

PubMed

King, Michael A; Mukherjee, Joyeeta M; Könik, Arda; Zubal, I George; Dey, Joyoni; Licho, Robert

2016-02-01

For the 2011 FDA approved Parkinson's Disease (PD) SPECT imaging agent I-123 labeled DaTscan, the volume of interest (VOI) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity for imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR's. Herein we focus on the design of the MPH component of the combined system. Combined reconstruction will be addressed in a subsequent publication. An analysis of 46 clinical DaTscan studies was performed to provide information to define the VOI, and design of a MPH collimator to image this VOI. The system spatial resolution for the MPH was set to 4.7 mm, which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. With this set, we compared system sensitivities for three aperture array designs, and selected the 3 × 3 array due to it being the highest of the three. The combined sensitivity of the apertures for it was similar to that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high-resolution fan-beam collimator (LEHRF). On the basis of these results we propose the further exploration of this design through simulations, and the development of combined MPH and fan-beam reconstruction.

Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence.

PubMed

Crunelle, Cleo L; van den Brink, Wim; Veltman, Dick J; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Schoevers, Robert A; Booij, Jan

2013-12-01

Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [(123)I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients. This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

PubMed

Zhang, Chun-Lei; Feng, Ze-Jun; Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+) increase, but does not require PKA and extracellular Ca(2+) influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

PubMed Central

Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects. PMID:23284812

Methylphenidate and environmental enrichment ameliorate the deleterious effects of prenatal stress on attention functioning.

PubMed

Zubedat, Salman; Aga-Mizrachi, Shlomit; Cymerblit-Sabba, Adi; Ritter, Ami; Nachmani, Maayan; Avital, Avi

2015-01-01

Either pre- or post-natal environmental factors seem to play a key role in brain and behavioral development and to exert long-term effects. Increasing evidence suggests that exposure to prenatal stress (PS) leads to motor and learning deficits and elevated anxiety, while enriched environment (EE) shows protective effects. The dopaminergic system is also sensitive to environmental life circumstances and affects attention functioning, which serves as the preliminary gate to cognitive processes. However, the effects of methylphenidate (MPH) on the dopaminergic system and attentional functioning, in the context of these life experiences, remain unclear. Therefore, we aimed to examine the effects of EE or PS on distinct types of attention, along with possible effects of MPH exposure. We found that PS impaired selective attention as well as partial sustained attention, while EE had beneficial effects. Both EE and MPH ameliorated the deleterious effects of PS on attention functioning. Considering the possible psychostimulant effect of MPH, we examined both anxiety-like behavior as well as motor learning. We found that PS had a clear anxiogenic effect, whereas EE had an anxiolytic effect. Nevertheless, the treatment with both MPH and/or EE recovered the deleterious effects of PS. In the motor-learning task, the PS group showed superior performance while MPH led to impaired motor learning. Performance decrements were prevented in both the PS + MPH and EE + MPH groups. This study provides evidence that peripubertal exposure to EE (by providing enhanced sensory, motor, and social opportunities) or MPH treatments might be an optional therapeutic intervention in preventing the PS long-term adverse consequences.

Design and evaluation of two multi-pinhole collimators for brain SPECT.

PubMed

Chen, Ling; Tsui, Benjamin M W; Mok, Greta S P

2017-10-01

SPECT is a powerful tool for diagnosing or staging brain diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) but is limited by its inferior resolution and sensitivity. At the same time, pinhole SPECT provides superior resolution and detection efficiency trade-off as compared to the conventional parallel-hole collimator for imaging small field-of-view (FOV), which fits for the case of brain imaging. In this study, we propose to develop and evaluate two multi-pinhole (MPH) collimator designs to improve the imaging of cerebral blood flow and striatum. We set the target resolutions to be 12 and 8 mm, respectively, and the FOV at 200 mm which is large enough to cover the whole brain. The constraints for system optimization include maximum and minimum detector-to-center-of-FOV (CFOV) distances of 344 and 294 mm, respectively, and minimal radius-of-rotation (ROR) of 135 mm to accommodate patients' shoulder. According to the targeted FOV, resolutions, and constraints, we determined the pinhole number, ROR, focal length, aperture acceptance angle, and aperture diameter which maximized the system sensitivity. We then assessed the imaging performance of the proposed MPH and standard low-energy high-resolution (LEHR) collimators using analytical simulations of a digital NCAT brain phantom with 99m Tc-HMPAO/ 99m Tc-TRODAT-1 distributions; Monte Carlo simulations of a hot-rod phantom; and a Defrise phantom using GATE v6.1. Projections were generated over 360° and reconstructed using the 3D MPH/LEHR OS-EM methods with up to 720 updates. The normalized mean square error (NMSE) was calculated over the cerebral and striatal regions extracted from the reconstructed images for 99m Tc-HMPAO and 99m Tc-TRODAT-1 simulations, respectively, and average normalized standard deviation (NSD) based on 20 noise realizations was assessed on selected uniform 3D regions as the noise index. Visual assessment and image profiles were applied to the results of Monte Carlo simulations. The optimized design parameters of the MPH collimators were 9 pinholes with 4.7 and 2.8 mm pinhole diameter, 73° acceptance angle, 127 mm focal length, 167 mm ROR for 12 mm and 8 mm target resolution, respectively. According to the optimization results, the detection efficiencies of the proposed collimators were 270 and 40% more as compared to LEHR. The Monte Carlo simulations showed that 7.9 and 6.4 mm rods can be discriminated for the MPH collimators with target resolutions of 12 and 8 mm, respectively. The eight 12 mm-thick discs of the Defrise phantom can also be resolved clearly in the axial plane as demonstrated by the image profiles generated with the MPH collimators. The two collimator designs provide superior image quality as compared to the conventional LEHR, and shows potential to improve current brain SPECT imaging based on a conventional SPECT scanner.

Short-term efficacy and tolerability of methylphenidate in children with traumatic brain injury and attention problems.

PubMed

Ekinci, Ozalp; Direk, Meltem Çobanoğulları; Gunes, Serkan; Teke, Halenur; Ekinci, Nuran; Yıldırım, Fatma; Okuyaz, Çetin

2017-04-01

This study aims to investigate the short-term efficacy and tolerability of immediate-release methylphenidate (IR-MPH) in children with a history of traumatic brain injury (TBI). Twenty children with TBI (mean age: 12.7±3.1years) who had clinically significant attention deficit and/or hyperactivity-impulsivity symptoms and twenty children with primary Attention Deficit Hyperactivity Disorder (ADHD) (mean age: 12.3±3.05years) were included. Study measures, which included the Turgay DSM-IV based ADHD rating Scale (T-DSM-IV-S), Conners' Parent Rating Scale (CPRS), Conners' Teacher Rating Scale (CTRS-R) and Clinical Global Impression-Improvement Scale (CGI-I), were completed at the baseline for both of the groups. For the TBI group, study measures and an adverse effect scale developed by the authors were completed 8weeks after IR-MPH treatment (10mg dose t.i.d). No significant difference was found regarding the baseline scale scores between the study groups. Among children with TBI, most of the scores on T-DSM-IV-S, CPRS and CTRS-R were found to improve significantly after MPH treatment, (p<0.05). 70% (N=14) of the sample were much improved at the endpoint. MPH was generally well-tolerated (95% had either no adverse effect or mild adverse effects). In this preliminary open-label study, IR-MPH was found as a safe and effective treatment option for ADHD symptoms after TBI. However, future controlled studies are needed to confirm our findings. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Genetic imaging study with [Tc-99m] TRODAT-1 SPECT in adolescents with ADHD using OROS-methylphenidate.

PubMed

Akay, Aynur Pekcanlar; Kaya, Gamze Çapa; Kose, Samet; Yazıcıoğlu, Çiğdem Eresen; Erkuran, Handan Özek; Güney, Sevay Alşen; Oğuz, Kaya; Keskin, Duygu; Baykara, Burak; Emiroğlu, Neslihan İnal; Eren, Mine Şencan; Kızıldağ, Sefa; Ertay, Türkan; Özsoylu, Dua; Miral, Süha; Durak, Hatice; Gönül, Ali Saffet; Rohde, Luis Augusto

2018-04-20

To examine theeffects on the brain of 2-month treatment withamethylphenidate extended-release formulation (OROS-MPH) using [Tc- 99m ] TRODAT-1SPECT in a sample of treatment-naïve adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). In addition, to assess whether risk alleles (homozygosity for 10-repeat allele at the DAT1 gene were associated with alterations in striatal DAT availability. Twenty adolescents with ADHD underwent brain single-photon emission computed tomography (SPECT) scans with [Tc- 99m ] TRODAT-1 at baseline and two months after starting OROS-MPH treatment with dosages up to 1 mg/kg/day. Severity of illness was estimated using the Clinical Global Impression Scale (CGI-S) and DuPaul ADHD Rating Scale-Clinician version (ARS) before treatment,1 month and 2 months after initiating OROS-MPH treatment. Decreased DAT availability was found in both the right caudate (pretreatment DAT binding: 224.76 ± 33.77, post-treatment DAT binding: 208.86 ± 28.75, p = 0.02) and right putamen (pre-treatment DAT binding: 314.41 ± 55.24, post-treatment DAT binding: 285.66 ± 39.20, p = 0.05) in adolescents with ADHD receiving OROS-MPH treatment. Adolescents with ADHD who showed a robust response to OROS-MPH (n = 7) had significantly greater reduction of DAT density in the right putamen than adolescents who showed less robust response to OROS-MPH (n = 13) (p = 0.02). However, between-group differences by treatment responses were not related with DAT density in the right caudate. Risk alleles (homozygosity for the 10-repeat allele of DAT1 gene) in the DAT1 gene were not associated with alterations in striatal DAT availability. Two months of OROS-MPH treatment decreased DAT availability in both the right caudate and putamen. Adolescents with ADHD who showed a robust response to OROS-MPH had greater reduction of DAT density in the right putamen. However,our findings did not support an association between homozygosity for a 10-repeat allele in the DAT1 gene and DAT density, assessedusing[Tc- 99m ] TRODAT-1SPECT. Copyright © 2018 Elsevier Inc. All rights reserved.

Verbal working memory-related functional connectivity alterations in boys with attention-deficit/hyperactivity disorder and the effects of methylphenidate.

PubMed

Wu, Zhao-Min; Bralten, Janita; An, Li; Cao, Qing-Jiu; Cao, Xiao-Hua; Sun, Li; Liu, Lu; Yang, Li; Mennes, Maarten; Zang, Yu-Feng; Franke, Barbara; Hoogman, Martine; Wang, Yu-Feng

2017-08-01

Few studies have investigated verbal working memory-related functional connectivity patterns in participants with attention-deficit/hyperactivity disorder (ADHD). Thus, we aimed to compare working memory-related functional connectivity patterns in healthy children and those with ADHD, and study effects of methylphenidate (MPH). Twenty-two boys with ADHD were scanned twice, under either MPH (single dose, 10 mg) or placebo, in a randomised, cross-over, counterbalanced placebo-controlled design. Thirty healthy boys were scanned once. We used fMRI during a numerical n-back task to examine functional connectivity patterns in case-control and MPH-placebo comparisons, using independent component analysis. There was no significant difference in behavioural performance between children with ADHD, treated with MPH or placebo, and healthy controls. Compared with controls, participants with ADHD under placebo showed increased functional connectivity within fronto-parietal and auditory networks, and decreased functional connectivity within the executive control network. MPH normalized the altered functional connectivity pattern and significantly enhanced functional connectivity within the executive control network, though in non-overlapping areas. Our study contributes to the identification of the neural substrates of working memory. Single dose of MPH normalized the altered brain functional connectivity network, but had no enhancing effect on (non-impaired) behavioural performance.

Methylphenidate DAT binding in adolescents with Attention-Deficit/ Hyperactivity Disorder comorbid with Substance Use Disorder--a single photon emission computed tomography with [Tc(99m)]TRODAT-1 study.

PubMed

Szobot, Claudia M; Shih, Ming Chi; Schaefer, Thais; Júnior, Neivo; Hoexter, Marcelo Q; Fu, Ying Kai; Pechansky, Flávio; Bressan, Rodrigo A; Rohde, Luis A P

2008-04-15

Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent among adolescents with Substance Use Disorders (SUD). Effects of methylphenidate (MPH) on ADHD are attributed to its properties of blocking the dopamine transporter (DAT) in the striatum. However, it has been demonstrated that drug addiction is associated with dopaminergic system changes that may affect MPH brain effects, emphasizing the need to better understand MPH actions in subjects with ADHD+SUD. To evaluate the effect of an extended release formulation of MPH (MPH-SODAS) on DAT availability in 17 stimulant-naive ADHD adolescents with comorbid SUD (cannabis and cocaine). Subjects underwent two single photon emission computed tomography (SPECT) scans with [Tc(99m)]TRODAT-1, at baseline and after 3 weeks on MPH-SODAS. Clinical assessment for ADHD relied on the Swanson, Nolan and Pelham Scale - version IV (SNAP-IV). Caudate and putamen DAT binding potential (BP) was calculated. After 3 weeks on MPH-SODAS, there was a significant reduction of SNAP-IV total scores (p<0.001), and approximately 52% reductions of DAT BP at the left and right caudate. Similar decreases were found at the left and right putamen (p<0.001 for all analyses). This study shows that the magnitude of DAT blockade induced by MPH in this population is similar to what is found in ADHD patients without SUD comorbidity, providing neurobiological support for trials with stimulants in adolescents with ADHD+SUD, an important population excluded from studies.

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Siciliano, Cody A.; Zimmer, Benjamin A.

2014-01-01

Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well. PMID:24566123

Traumatic Brain Injury Screening: Preliminary Findings in a US Army Brigade Combat Team

DTIC Science & Technology

2009-01-01

Screening: Preliminary Findings in a US Army Brigade Combat Team Heidi Terrio, MD, MPH; Lisa A. Brenner, PhD; Brian J. Ivins, MS; John M. Cho, MD; Katherine...Sheila Saliman and Lisa Betthauser is greatly appreciated. Corresponding author: Heidi Terrio, MD, MPH, 1853 O’Connell Blvd, Bldg 1042, Room 107, Fort...more mild TBI symptoms among injured soldiers with and without TBI (n = 1208)∗,† Parameter Adjusted 95% CI adjusted Variable estimate (β) SE β Wald P

An evaluation of the pharmacokinetics of methylphenidate for the treatment of attention-deficit/ hyperactivity disorder.

PubMed

Frölich, Jan; Banaschewski, Tobias; Döpfner, Manfred; Görtz-Dorten, Anja

2014-08-01

Methylphenidate (MPH) plays a principal role in the multimodal treatment of attention-deficit/hyperactivity disorder (ADHD). Controlled studies have demonstrated an effective reduction in the core symptoms of the disorder following MPH therapy, although long-term studies also demonstrate that the therapeutic benefits dissipate in the absence of combined psychosocial interventions. This review article focuses on the pharmacological characteristics of MPH, examining its effects on brain metabolism and the neurotransmitter system. Neuropsychological and clinical effects of different immediate and extended release MPH formulations are discussed to aid clinicians in choosing the appropriate formulation. The drug's addictive potency and abuse potential is also discussed. Data came from a literature search of relevant studies performed using the PubMed database up to June 2013. MPH is effective in the treatment of the core symptoms of ADHD. Considerable clinical expertise is required to identify an individually well-adapted dosage which will produce the optimal clinical effects with potential side effects minimized. Due to low adherence to medication, especially in adolescents, motivation to treatment and attentive clinical monitoring is mandatory, as is the consideration of risks of abuse or the presence of a comorbid addictive disorder.

In Vivo [11C]Dihydrotetrabenazine ([11C]DTBZ) Binding in Rat Striatum: Sensitivity to Dopamine Concentrations

PubMed Central

Kilbourn, Michael R.; Butch, Elizabeth R.; Desmond, Timothy; Sherman, Phillip; Harris, Paul E.; Frey, Kirk A.

2009-01-01

Introduction The sensitivity of the in vivo binding of [11C]dihydrotetrabenazine ([11C]DTBZ) and [11C]methylphenidate ([11C]MPH) to their respective targets, the vesicular monoamine transporter (VMAT2) and the neuronal membrane dopamine transporter (DAT), after alterations of endogenous levels of dopamine were examined in the rat brain. Methods In vivo binding of [11C]DTBZ and [11C]MPH were determined using a bolus+infusion protocol. In vitro numbers of VMAT2 binding sites were determined by autoradiography. Results Repeated dosing with α-methyl-p-tyrosine (AMPT) at doses that significantly (−75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [11C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed by treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in total numbers of VMAT2 binding sites as measured using in vitro autoradiography. No changes were observed for in vivo [11C]MPH binding to the DAT in the striatum following AMPT pretreatment. Conclusion These results indicate that large reductions of dopamine concentrations in the rat brain can produce modest but significant changes in binding of radioligands to the VMAT2, which can be reversed by repleneshment of dopamine using exogenous L-DOPA. PMID:20122661

Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.

PubMed

Szobot, Claudia M; Roman, Tatiana; Hutz, Mara H; Genro, Júlia P; Shih, Ming Chi; Hoexter, Marcelo Q; Júnior, Neivo; Pechansky, Flávio; Bressan, Rodrigo A; Rohde, Luis A P

2011-02-01

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56). In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response. Copyright © 2010 Wiley-Liss, Inc.

Neuroprotective effects of various doses of topiramate against methylphenidate-induced oxidative stress and inflammation in isolated rat amygdala: the possible role of CREB/BDNF signaling pathway.

PubMed

Motaghinejad, Majid; Motevalian, Manijeh; Falak, Reza; Heidari, Mansour; Sharzad, Mahshid; Kalantari, Elham

2016-12-01

Methylphenidate (MPH) abuse damages brain cells. The neuroprotective effects of topiramate (TPM) have been reported previously, but its exact mechanism of action still remains unclear. This study investigated the in vivo role of various doses of TPM in the protection of rat amygdala cells against methylphenidate-induced oxidative stress and inflammation. Seventy adult male rats were divided into seven groups. Groups 1 and 2 received normal saline (0.7 ml/rat) and MPH (10 mg/kg), respectively, for 21 days. Groups 3, 4, 5, 6, and 7 were concurrently treated with MPH (10 mg/kg) and TPM (10, 30, 50, 70, and 100 mg/kg), respectively, for 21 days. elevated plus maze (EPM) was used to assess motor activity disturbances. In addition, oxidative, antioxidantand inflammatory factors and CREB, Ak1, CAMK4, MAPK3, PKA, BDNF, and c FOS gene levels were measured by RT-PCR, and also, CREB and BDNF protein levels were measured by WB in isolated amygdalae. MPH significantly disturbed motor activity and TPM (70 and 100 mg/kg) neutralized its effects. MPH significantly increased lipid peroxidation, mitochondrial GSSG levels and IL-1β and TNF-α level and CAMK4 gene expression in isolated amygdala cells. In contrast, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and CREB, BDNF Ak1, MAPK3, PKA, BDNF, and c FOS expression significantly decreased. The various doses of TPM attenuated these effects of MPH. It seems that TPM can be used as a neuroprotective agent and is a good candidate against MPH-induced neurodegeneration.

A randomized controlled trial into the effects of neurofeedback, methylphenidate, and physical activity on EEG power spectra in children with ADHD.

PubMed

Janssen, Tieme W P; Bink, Marleen; Geladé, Katleen; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2016-05-01

The clinical and neurophysiological effects of neurofeedback (NF) as treatment for children with ADHD are still unclear. This randomized controlled trial (RCT) examined electroencephalogram (EEG) power spectra before and after NF compared to methylphenidate (MPH) treatment and physical activity (PA) - as semi-active control group - during resting and active (effortful) task conditions to determine whether NF can induce sustained alterations in brain function. Using a multicentre three-way parallel group RCT design, 112 children with a DSM-IV diagnosis of ADHD, aged between 7 and 13 years, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10-week period. PA training was a semi-active control group, matched in frequency and duration. Methylphenidate was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. EEG power spectra measures during eyes open (EO), eyes closed (EC) and task (effortful) conditions were available for 81 children at pre- and postintervention (n = 29 NF, n = 25 MPH, n = 27 PA). Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/;NCT01363544, Ref. No. NCT01363544. Both NF and MPH resulted in comparable reductions in theta power from pre- to postintervention during the EO condition compared to PA (ηp (2)  = .08 and .12). For NF, greater reductions in theta were related to greater reductions in ADHD symptoms. During the task condition, only MPH showed reductions in theta and alpha power compared to PA (ηp (2)  = .10 and .12). This study provides evidence for specific neurophysiological effects after theta/beta NF and MPH treatment in children with ADHD. However, for NF these effects did not generalize to an active task condition, potentially explaining reduced behavioural effects of NF in the classroom. © 2016 Association for Child and Adolescent Mental Health.

Decreased dopamine activity predicts relapse in methamphetamine abusers

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

Wang G. J.; Wang, G.-J.; Smith, L.

2011-01-20

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested withinmore » 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.« less

Decreased dopamine activity predicts relapse in methamphetamine abusers.

PubMed

Wang, G J; Smith, L; Volkow, N D; Telang, F; Logan, J; Tomasi, D; Wong, C T; Hoffman, W; Jayne, M; Alia-Klein, N; Thanos, P; Fowler, J S

2012-09-01

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Use of Stimulants in Bipolar Disorder.

PubMed

Perugi, Giulio; Vannucchi, Giulia; Bedani, Fulvio; Favaretto, Ettore

2017-01-01

Several international guidelines indicate stimulants, including methylphenidate (MPH), amphetamines and derivatives, modafinil, and armodafinil among the second-third-line choices for bipolar depression. Efficacy of stimulants has been also reported for the management of residual depressive symptoms such as fatigue and sleepiness and for the management of affective, cognitive, and behavioral symptoms in children and adult bipolar patients with comorbid ADHD. Few case reports show positive results with MPH in the treatment of resistant mania. Finally, MPH might be an option in some bipolar forms observed in psychiatric presentations of frontotemporal dementia and traumatic brain injury. In spite of these preliminary observations, the use of stimulants in bipolar patients is still controversial. Potential of misuse and abuse and mood destabilization with induction of (hypo)manic switches, mixed states, and rapid cycling are the concerns most frequently reported. Our aims are to summarize available literature on this topic and discuss practical management implications.

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

Wang, g.j.; Wang, G.-J.; Geliebter, A.

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [{sup 11}C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocksmore » the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.« less

Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder.

PubMed

Bottelier, Marco A; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G H; Bouziane, Cheima; Kooij, J J Sandra; de Ruiter, Michiel B; Reneman, Liesbeth

2017-11-30

In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats.

PubMed

Beaudin, Stéphane A; Strupp, Barbara J; Lasley, Stephen M; Fornal, Casimir A; Mandal, Shyamali; Smith, Donald R

2015-04-01

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure. © 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.

Mixed-Effects Modeling of Neurofeedback Self-Regulation Performance: Moderators for Learning in Children with ADHD.

PubMed

Zuberer, Agnieszka; Minder, Franziska; Brandeis, Daniel; Drechsler, Renate

2018-01-01

Neurofeedback (NF) has gained increasing popularity as a training method for children and adults with attention deficit hyperactivity disorder (ADHD). However, it is unclear to what extent children learn to regulate their brain activity and in what way NF learning may be affected by subject- and treatment-related factors. In total, 48 subjects with ADHD (age 8.5-16.5 years; 16 subjects on methylphenidate (MPH)) underwent 15 double training sessions of NF in either a clinical or a school setting. Four mixed-effects models were employed to analyze learning: training within-sessions, across-sessions, with continuous feedback, and with transfer in which performance feedback is delayed. Age and MPH affected the NF performance in all models. Cross-session learning in the feedback condition was mainly moderated by age and MPH, whereas NF learning in the transfer condition was mainly boosted by MPH. Apart from IQ and task types, other subject-related or treatment-related effects were unrelated to NF learning. This first study analyzing moderators of NF learning in ADHD with a mixed-effects modeling approach shows that NF performance is moderated differentially by effects of age and MPH depending on the training task and time window. Future studies may benefit from using this approach to analyze NF learning and NF specificity. The trial name Neurofeedback and Computerized Cognitive Training in Different Settings for Children and Adolescents With ADHD is registered with NCT02358941.

A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2

ClinicalTrials.gov

2018-04-09

Malignant Glioma of Brain; Astrocytoma; Malignant Astrocytoma; Oligodendroglioma; Anaplastic Oligodendroglioma of Brain (Diagnosis); Mixed Oligo-Astrocytoma; Ependymoma; Ganglioglioma; Pylocytic/Pylomyxoid Astrocytoma; Brain Tumor; Glioma; Brain Cancer; Glioblastoma; Glioblastoma Multiforme

Enhanced Striatal Dopamine Release During Food Stimulation in Binge Eating Disorder

PubMed Central

Wang, Gene-Jack; Geliebter, Allan; Volkow, Nora D.; Telang, Frank W.; Logan, Jean; Jayne, Millard C.; Galanti, Kochavi; Selig, Peter A.; Han, Hao; Zhu, Wei; Wong, Christopher T.; Fowler, Joanna S.

2011-01-01

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [11C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating. PMID:21350434

Effectiveness of Neurofeedback Versus Medication in Treatment of ADHD.

PubMed

Sudnawa, Khemika Khemakanok; Chirdkiatgumchai, Vilawan; Ruangdaraganon, Nichara; Khongkhatithum, Chaiyos; Udomsubpayakul, Umaporn; Jirayucharoensak, Suwicha; Israsena, Pasin

2018-06-22

Neurofeedback (NF) is an operant conditioning procedure that trains participants for self-regulation of brain activity. Previous studies have shown that NF is a promising treatment of ADHD. However, there have been only a few RCT studies comparing effectiveness of NF with medication with various NF protocol and results. The aim of this study was to evaluate theeffectiveness of unipolar electrodeneurofeedback (NF) using theta/beta protocol compared with methylphenidate (MPH) in the treatment of ADHD. Children with newly diagnosed ADHD were randomly organised into NF and MPH groups. Each of children in NF group received 30 sessions of NF. Children in MPH group were prescribed methylphenidate for 12 weeks. Vanderbilt ADHD rating scales were completed by parents and teachers to evaluate ADHD symptoms pre- and post-treatment. Student's t-tests and Cohen's dwere used to compare symptoms between groups and evaluate effect size (ES) of each treatment respectively. Forty children participated in the study. No differences in ADHD baseline symptoms between groups were found. Post-treatment, teachers reported significantly lower ADHD symptoms in the MPH group (p = 0.01), but parents reported no differences betweenthe groups (p = 0.55). MPH demonstrated large ES (Cohen's d 1.30 - 1.69), while NF showed moderate ES (Cohen's d 0.49 - 0.68) for treatment of ADHD symptoms. This study supports NF as a promising alternative treatment for ADHD in children who do not respond or experience significant adverse effects to ADHD medications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Causes and costs of injuries in multiple trauma patients requiring extrication from motor vehicle crashes.

PubMed

Siegel, J H; Mason-Gonzalez, S; Dischinger, P C; Read, K M; Cushing, B M; Badellino, M C; Goodarzi, S; Smialek, J E; Heatfield, B M; Robinson, R M

1993-12-01

Prospective and contemporaneous medical and economic cost studies of 144 victims of motor vehicle crashes admitted to a regional level I trauma center with multiple injuries (ISS > or = 16) revealed 122 non-ejected patients, of whom 102 required extrication (EXTRIC) from the vehicle for physical or medical reasons and 20 who did not (N group). There were no differences in age (EXTRIC, 34 +/- 17 years; N, 41 +/- 24 years), type of crash (Frontal: 57% EXTRIC, 60% N; Lateral: 32% EXTRIC, 35% N) restraint use (35% EXTRIC, 35% N), or mortality (29% EXTRIC, 30% N). However, the estimated maximum speed before the crash was higher in EXTRIC patients (50 +/- 16 mph vs. 46 +/- 18 mph N, p < 0.04), as was the change in velocity (delta V) on impact (EXTRIC 30 +/- 15 mph; N, 24 +/- 8 mph, p < 0.01). Brain injuries (51% EXTRIC vs. 35% N) and lower extremity injuries were more numerous in EXTRIC patients (59% vs. 20% N, p < 0.003) and the number of splenic, lower extremity, and pelvic injuries associated with shock was greater in EXTRIC patients, p < 0.02; as were postinjury complications. As a result, operating room costs from orthopedic and plastic surgery increased professional charges in the EXTRIC group versus the N group ($20,000, EXTRIC; $17,000, N) and critical care costs ($13,000, EXTRIC; $4,000, N) with total costs of $72,000 and $77,000, respectively. The lower extremity injuries in EXTRIC patients were primarily a result of body part contacts with intrusions (CIs) of the car occupant compartment structures [73% with vs. 24% without (p < 0.0001)]. In lateral MVCs, brain injuries were also more commonly associated with CIs of the side window frame or A pillar (72% CI vs. 25% no CI; p < 0.035); but as a whole in MVCs in which extrication was necessary, lower extremity injuries from instrument panel or toepan CIs appeared more frequent than those resulting from contacts only (p < 0.0001). In EXTRIC patients, 69% of those in shock had CI injuries, and 80% of the deaths in the EXTRIC group were associated with CI injury. These data suggest that measures designed to prevent CIs by strengthening car passenger compartment structures may reduce the incidence of severe brain and lower extremity injuries and may reduce the need for extrication after MVCs.

Methylphenidate administration determines enduring changes in neuroglial network in rats.

PubMed

Cavaliere, Carlo; Cirillo, Giovanni; Bianco, Maria Rosaria; Adriani, Walter; De Simone, Antonietta; Leo, Damiana; Perrone-Capano, Carla; Papa, Michele

2012-01-01

Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring. Copyright © 2011. Published by Elsevier B.V.

Fluid Intake Related to Brain Edema in Acute Middle Cerebral Artery Infarction.

PubMed

Dharmasaroja, Pornpatr A

2016-02-01

Evidence of the appropriate amount of fluid intake during the first few days after acute stroke was scarce. Concerns were raised in patients with acute malignant middle cerebral infarction, who tended to have malignant brain edema later. The purpose of the study was to evaluate the effect of fluid intake on the occurrence of malignant brain edema in patients with acute middle cerebral artery infarction. Patients with acute middle cerebral artery infarction who had National Institute of Health Stroke Scale (NIHSS) score of at least 15 were included. Baseline characteristics and amount of fluid intake during the first few days were compared in patients with and without malignant brain edema. One hundred ninety-three patients were studied. Mean NIHSS score was 20. Malignant brain edema occurred in 69 patients (36%). Higher amount of fluid intake (>1650 ml or >28 ml/kg/day or >93% of daily maintenance fluid) showed a significant association with malignant brain edema (OR = 13.86, 95% CI 5.11-37.60, p value <0.001). Decompressive surgery was performed in 35 patients (18%). With mean follow-up of 12 months, 49 patients (49/184, 27%) had favorable outcomes (modified Rankin scale (mRS) 0-2) at final follow-up. Seventy-nine patients (79/184, 43%) died. In the subgroup of patients with malignant brain edema, 39 patients (39/65, 60%) died and only 11% (7/65 patients) had favorable outcome. High amount of fluid intake in the first few days of acute middle cerebral infarction was related to the occurrence of malignant brain edema.

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

PubMed Central

Straughn, Arthur B.; Reeves, Owen T.; Bernstein, Hilary; Bell, Guinevere H.; Anderson, Erica R.; Malcolm, Robert J.

2013-01-01

Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1–2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44–99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of “high,” “good,” “like,” “stimulated,” and overall “effect” were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)0-inf by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC0.5–2 hours was 2.1 times greater and the time to maximum concentration (Tmax) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability. PMID:23104969

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.

Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE)

PubMed Central

Pedersen, Marie; Weinmayr, Gudrun; Stafoggia, Massimo; Galassi, Claudia; Jørgensen, Jeanette T; Sommar, Johan N; Forsberg, Bertil; Olsson, David; Oftedal, Bente; Aasvang, Gunn Marit; Schwarze, Per; Pyko, Andrei; Pershagen, Göran; Korek, Michal; Faire, Ulf De; Östenson, Claes-Göran; Fratiglioni, Laura; Eriksen, Kirsten T; Poulsen, Aslak H; Tjønneland, Anne; Bräuner, Elvira Vaclavik; Peeters, Petra H; Bueno-de-Mesquita, Bas; Jaensch, Andrea; Nagel, Gabriele; Lang, Alois; Wang, Meng; Tsai, Ming-Yi; Grioni, Sara; Marcon, Alessandro; Krogh, Vittorio; Ricceri, Fulvio; Sacerdote, Carlotta; Migliore, Enrica; Vermeulen, Roel; Sokhi, Ranjeet; Keuken, Menno; de Hoogh, Kees; Beelen, Rob; Vineis, Paolo; Cesaroni, Giulia; Brunekreef, Bert; Hoek, Gerard; Raaschou-Nielsen, Ole

2018-01-01

Abstract Background Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent. Methods In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM2.5, PM10, and PMcoarse), PM2.5 absorbance, nitrogen oxides (NO2 and NOx) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. Results Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89–3.14 per 10–5/m3), and weak positive or null associations with the other pollutants. Hazard ratio for PM2.5 absorbance (1.01; 0.38–2.71 per 10–5/m3) and all other pollutants were lower for nonmalignant than for malignant brain tumors. Conclusion We found suggestive evidence of an association between long-term exposure to PM2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors. PMID:29016987

Neurosurgical sapphire handheld probe for intraoperative optical diagnostics, laser coagulation and aspiration of malignant brain tissue

NASA Astrophysics Data System (ADS)

Shikunova, Irina A.; Zaytsev, Kirill I.; Stryukov, Dmitrii O.; Dubyanskaya, Evgenia N.; Kurlov, Vladimir N.

2017-07-01

In this paper, a handheld contact probe based on sapphire shaped crystal was developed for the intraoperative optical diagnosis and aspiration of malignant brain tissue combined with the laser hemostasis. Such a favorable combination of several functions in a single instrument significantly increases its clinical relevance. It makes possible highly-accurate real-time detection and removal of either large-scale malignancies or even separate invasive cancer cells. The proposed neuroprobe was integrated into the clinical neurosurgical workflow for the intraoperative fluorescence identification and removal of malignant tissues of the brain.

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

PubMed

Bjarnadottir, G D; Johannsson, M; Magnusson, A; Rafnar, B O; Sigurdsson, E; Steingrimsson, S; Asgrimsson, V; Snorradottir, I; Bragadottir, H; Haraldsson, H M

2017-09-01

Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Use and Characteristics of Antipsychotic/Methylphenidate Combination Therapy in Children and Adolescents with a Diagnosis of Attention-Deficit/Hyperactivity Disorder.

PubMed

Scholle, Oliver; Banaschewski, Tobias; Enders, Dirk; Garbe, Edeltraut; Riedel, Oliver

2018-05-16

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) frequently have comorbidities that are potential indications for antipsychotics (APs). Some studies have suggested that the combined use of methylphenidate (MPH) and APs is increasing in this population group. Longitudinal analyses and in-depth investigations on the substance level are lacking. This study aimed to estimate the cumulative proportion of concomitant AP/MPH use in children and adolescents with ADHD over a follow-up of up to 9 years and to describe patient characteristics stratified by specific AP drug. Based on claims data, concomitant AP/MPH use was identified among 67,595 children and adolescents with ADHD starting MPH treatment between 2005 and 2013. Characteristics and diagnoses-including those indicating appropriateness of AP use according to approved indications and/or guidelines-were examined at the time of first AP/MPH combination therapy. In addition, subsequent use of AP/MPH combination therapy was evaluated. The cumulative proportion of individuals with any AP/MPH combination therapy rose to over 6% within 9 years after initiating MPH. The most frequent APs first used in combination with MPH were risperidone (72%), pipamperone (15%), and tiapride (8%). Percentages of psychiatric hospitalization in the year preceding the first combination therapy with MPH were 33%, 43%, and 19%, respectively. The proportion of individuals with potentially appropriate use was high (>72%) in risperidone/MPH and tiapride/MPH and low (15%) in pipamperone/MPH combination users. Conduct disorders and tic disorders were frequent in users who were prescribed MPH with risperidone and tiapride, respectively. One-quarter of patients with AP/MPH combination therapy were one-time-only combination users. Our study suggests that a considerable proportion of children and adolescents with ADHD receive MPH in combination with APs and that this is a factor not only during the first years of MPH treatment. ADHD guidelines should specify algorithms concerning the use of AP medication.

Comparative Ethanol-Induced Potentiation of Stimulatory Responses to Dexmethylphenidate Versus Methylphenidate.

PubMed

Patrick, Kennerly S; Straughn, Arthur B; Reeves, Owen T; Bernstein, Hilary; Malcolm, Robert

2015-08-01

The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the time course of maximal drug exposure after a single dose. In a 4-way, randomized, crossover study design, 12 men and 12 women normal volunteers received d-MPH (0.15 mg/kg) or dl-MPH (0.3 mg/kg) with or without ethanol (0.6 g/kg). Serial visual analog scales were used as surrogates for drug abuse liability ("high," "good," "like," "stimulated," and "any drug effect"). Combining pure d-MPH with ethanol significantly (P < 0.005) increased the area under the effect curves (AUC(0-5.25h)) of all 5 subscales. The dl-MPH-ethanol combination significantly (P < 0.05) increased these AUCs with the exception of like (P = 0.08). Effects of the pure d-MPH-ethanol combination exhibited delayed potentiation relative to dl-MPH-ethanol. A pharmacokinetic interaction between the l-isomer of dl-MPH and ethanol has previously been shown to increase early exposure to d-MPH. Administration of the pure isomer d-MPH precludes this absorption phase pharmacokinetic interaction with ethanol. This notwithstanding, the pure d-MPH-ethanol combination resulted in comparable, if not greater, cumulative stimulant potentiation than the dl-MPH-ethanol combination. These findings provide evidence of a pharmacodynamic component to d-MPH-ethanol synergistic interactions and carry implications for the rational drug individualization in the treatment of attention-deficit/hyperactivity disorder.

The effects of methylphenidate on cerebral responses to conflict anticipation and unsigned prediction error in a stop-signal task.

PubMed

Manza, Peter; Hu, Sien; Ide, Jaime S; Farr, Olivia M; Zhang, Sheng; Leung, Hoi-Chung; Li, Chiang-shan R

2016-03-01

To adapt flexibly to a rapidly changing environment, humans must anticipate conflict and respond to surprising, unexpected events. To this end, the brain estimates upcoming conflict on the basis of prior experience and computes unsigned prediction error (UPE). Although much work implicates catecholamines in cognitive control, little is known about how pharmacological manipulation of catecholamines affects the neural processes underlying conflict anticipation and UPE computation. We addressed this issue by imaging 24 healthy young adults who received a 45 mg oral dose of methylphenidate (MPH) and 62 matched controls who did not receive MPH prior to performing the stop-signal task. We used a Bayesian Dynamic Belief Model to make trial-by-trial estimates of conflict and UPE during task performance. Replicating previous research, the control group showed anticipation-related activation in the presupplementary motor area and deactivation in the ventromedial prefrontal cortex and parahippocampal gyrus, as well as UPE-related activations in the dorsal anterior cingulate, insula, and inferior parietal lobule. In group comparison, MPH increased anticipation activity in the bilateral caudate head and decreased UPE activity in each of the aforementioned regions. These findings highlight distinct effects of catecholamines on the neural mechanisms underlying conflict anticipation and UPE, signals critical to learning and adaptive behavior. © The Author(s) 2016.

The effects of methylphenidate on cerebral responses to conflict anticipation and unsigned prediction error in a stop-signal task

PubMed Central

Manza, Peter; Hu, Sien; Ide, Jaime S; Farr, Olivia M; Zhang, Sheng; Leung, Hoi-Chung; Li, Chiang-shan R

2016-01-01

To adapt flexibly to a rapidly changing environment, humans must anticipate conflict and respond to surprising, unexpected events. To this end, the brain estimates upcoming conflict on the basis of prior experience and computes unsigned prediction error (UPE). Although much work implicates catecholamines in cognitive control, little is known about how pharmacological manipulation of catecholamines affects the neural processes underlying conflict anticipation and UPE computation. We addressed this issue by imaging 24 healthy young adults who received a 45 mg oral dose of methylphenidate (MPH) and 62 matched controls who did not receive MPH prior to performing the stop-signal task. We used a Bayesian Dynamic Belief Model to make trial-by-trial estimates of conflict and UPE during task performance. Replicating previous research, the control group showed anticipation-related activation in the presupplementary motor area and deactivation in the ventromedial prefrontal cortex and parahippocampal gyrus, as well as UPE-related activations in the dorsal anterior cingulate, insula, and inferior parietal lobule. In group comparison, MPH increased anticipation activity in the bilateral caudate head and decreased UPE activity in each of the aforementioned regions. These findings highlight distinct effects of catecholamines on the neural mechanisms underlying conflict anticipation and UPE, signals critical to learning and adaptive behavior. PMID:26755547

Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

ClinicalTrials.gov

2017-03-22

Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Primary Melanocytic Lesion of Meninges; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma; Metastatic Malignant Neoplasm in the Brain; Multiple Sclerosis; Recurrent Adult Brain Neoplasm

Efficacy and Safety of Omega-3/6 Fatty Acids, Methylphenidate, and a Combined Treatment in Children With ADHD.

PubMed

Barragán, Eduardo; Breuer, Dieter; Döpfner, Manfred

2017-03-01

To compare efficacy of Omega-3/6 fatty acids (Equazen eye q™) with methylphenidate (MPH) and combined MPH + Omega-3/6 in children with ADHD. Participants ( N = 90) were randomized to Omega-3/6, long-acting MPH, or combination for 12 months. ADHD symptoms were assessed using the ADHD Rating Scale and Clinical Global Impressions-Severity (CGI-S) scale. ADHD symptoms decreased in all treatment arms. Although significant differences favoring Omega + MPH over Omega-3/6 alone were found for ADHD Total and Hyperactivity-Impulsivity subscales, results on the Inattention subscale were similar. CGI-S scores decreased slowly and consistently with Omega-3/6, compared with a rapid decrease and subsequent slight increase in the MPH-containing arms. Adverse events were numerically less frequent with Omega-3/6 or MPH + Omega-3/6 than MPH alone. The tested combination of Omega-3/6 fatty acids had similar effects to MPH, whereas the MPH + Omega combination appeared to have some tolerability benefits over MPH.

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

PubMed Central

Cheng, Jia; Xiong, Zhe; Duffney, Lara J.; Wei, Jing; Liu, Aiyi; Liu, Sihang; Chen, Guo-Jun; Yan, Zhen

2014-01-01

Background Methylphenidate (MPH), a psychostimulant drug for the treatment of attention-deficit hyperactivity disorder (ADHD), produces the effects of increasing alertness and improving attention, while its misuse has been associated with an increased risk of aggression and psychosis. In this study, we sought to determine the molecular mechanism underlying the complex actions of MPH. Methods Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex (PFC) was measured. MPH-induced behavioral changes were also examined in parallel. Results We found that administration of low-dose (0.5 mg/kg) MPH selectively potentiated NMDAR-mediated excitatory synaptic currents (EPSCs) via adrenergic receptor activation, while the high-dose (10 mg/kg) MPH suppressed both NMDAR- and AMPAR-EPSCs. The dual effects of MPH on EPSCs were associated with bi-directional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated the PFC-mediated temporal order recognition memory (TORM) and attention, while animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of SNAP-25, a key SNARE proteins involved in NMDAR exocytosis, blocked the increase of NMDAR-EPSC by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and TORM via a mechanism dependent on SNAP-25. Conclusions Our results have provided a potential mechanism underlying the cognitive enhancing effects of low-dose MPH, as well as the psychosis-inducing effects of high-dose MPH. PMID:24832867

32 CFR 636.22 - Speed regulations.

Code of Federal Regulations, 2014 CFR

2014-07-01

...). (d) The following special speed limits apply: (1) When passing troop formations, 10 miles per hour... vehicles and will obey the following off-road driving speeds: Day Driving: Trails, 16 MPH Cross County, 6 MPH Night Driving: Trails, 5 MPH (with headlights) Cross Country, 5 MPH Night Driving: Trails, 4 MPH...

32 CFR 636.22 - Speed regulations.

Code of Federal Regulations, 2012 CFR

2012-07-01

...). (d) The following special speed limits apply: (1) When passing troop formations, 10 miles per hour... vehicles and will obey the following off-road driving speeds: Day Driving: Trails, 16 MPH Cross County, 6 MPH Night Driving: Trails, 5 MPH (with headlights) Cross Country, 5 MPH Night Driving: Trails, 4 MPH...

Case-control study on the use of cellular and cordless phones and the risk for malignant brain tumours.

PubMed

Hardell, L; Mild, K H; Carlberg, M

2002-10-01

To investigate the use of cellular and cordless phones and the risk for malignant brain tumours. A case-control study was performed on 649 patients aged 20-80 years of both sexes with malignant brain tumour diagnosed from 1 January 1997 to 30 June 2000. All patients were alive during the time of the study and had histopathology verified brain tumours. One matched control to each case was selected from the Swedish Population Register. The study area was the Uppsala-Orebro, Stockholm, Linköping and Göteborg medical regions of Sweden. Exposure was assessed by a questionnaire answered by 588 (91%) cases and 581 (90%) controls. Phone usage was defined as 'ever use' and usage starting within 1 year before diagnosis was disregarded. Overall, no significantly increased risks were found: analogue cellular phones yielded an odds ratio (OR)=1.13, 95% confidence interval (CI)=0.82-1.57, digital cellular phones OR=1.13, CI=0.86-1.48, and cordless phones OR=1.13, CI=0.85-1.50. For ipsilateral (same side) radiofrequency exposure, analogue mobile phones gave OR=1.85, CI=1.16-2.96, for all malignant brain tumours. For astrocytoma, this risk was OR=1.95, CI=1.12-3.39. For all malignant brain tumours, digital mobile phones yielded OR=1.59, CI=1.05-2.41, and cordless phones yielded OR=1.46, CI=0.96-2.23, in the analysis of ipsilateral exposure. The ipsilateral use of an analogue cellular phone yielded a significantly increased risk for malignant brain tumours.

Single-Dose Pharmacokinetics of Methylphenidate Extended-Release Multiple Layer Beads Administered as Intact Capsule or Sprinkles Versus Methylphenidate Immediate-Release Tablets (Ritalin®) in Healthy Adult Volunteers

PubMed Central

Teuscher, Nathan S.; Kupper, Robert J.; Chang, Wei-Wei; Greenhill, Laurence; Newcorn, Jeffrey H.; Connor, Daniel F.; Wigal, Sharon

2014-01-01

Abstract Objectives: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin®) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. Methods: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. Results: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3–112.4), 0.99 (95% CI, 95.3–102.8), and 0.99 (95% CI, 95.4–103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. Conclusions: MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR. PMID:25514542

Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin(®)) in healthy adult volunteers.

PubMed

Adjei, Akwete; Teuscher, Nathan S; Kupper, Robert J; Chang, Wei-Wei; Greenhill, Laurence; Newcorn, Jeffrey H; Connor, Daniel F; Wigal, Sharon

2014-12-01

The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin(®)) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR.

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.

Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD.

PubMed

Ebihara, Ken; Fujiwara, Hironori; Awale, Suresh; Dibwe, Dya Fita; Araki, Ryota; Yabe, Takeshi; Matsumoto, Kinzo

2017-09-15

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA A receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA A receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD. Copyright © 2017 Elsevier B.V. All rights reserved.

Similar and Different? Subjective Effects of Methylphenidate and Cocaine in Opioid-Maintained Patients.

PubMed

Vogel, Marc; Bucher, Patricia; Strasser, Johannes; Liechti, Matthias E; Krähenbühl, Stephan; Dürsteler, Kenneth M

2016-01-01

Methylphenidate (MPH) is commonly prescribed for attention deficit hyperactivity disorder (ADHD). Recreational nonmedical use has been described and also occurs in patients on opioid maintenance treatment (OMT). MPH has been proposed for use as replacement therapy in cocaine dependence, although evidence for efficacy is inconclusive. We conducted a cross-sectional interview study on patterns of MPH use in a sample of 20 MPH-using patients on OMT with a history of cocaine use. We assessed symptoms of depression, ADHD during childhood, and retrospective subjective-effects profiles of MPH and cocaine. Risky patterns of MPH use were common, in particular illicit acquisition, use of high doses, and parenteral administration. Sixty percent of patients reported having used MPH as a substitute for cocaine. Correspondingly, the subjective-effect profiles of MPH and cocaine showed striking parallels, with overall effects of MPH being rated more positively than those of cocaine. Proportions of patients with elevated scores for depression or childhood ADHD were large, highlighting the importance of treating dual disorders in this population. Clinical studies on MPH substitution in cocaine-dependent patients on opioid maintenance treatment could benefit from consideration of the patterns of application of MPH in this population. Results are preliminary due to small sample size.

Evolution of stimulants to treat ADHD: transdermal methylphenidate

PubMed Central

Patrick, Kennerly S.; Straughn, Arthur B.; Perkins, Jeb S.; González, Mario A.

2009-01-01

Objective The following comprehensive review describes the evolution of stimulant drug formulations used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Emphasis is placed on the basic and clinical pharmacology of the dl-methylphenidate (MPH) transdermal system (MTS). Methods The pharmacokinetic and pharmacodynamic literature pertaining to MPH and amphetamine enantiomers was reviewed in the context of ADHD therapy and MTS as a treatment option. Results MTS incorporates MPH into an adhesive monolithic matrix, using the free base form of the drug to facilitate transdermal absorption. MTS technology minimizes contact dermatitis by eliminating to need for percutaneous penetration enhancers. After a lag time of approximately 2 h, plasma concentrations of the therapeutic d-MPH isomer become detectable, then continuously rise over the course of the recommended 9 h wear time. Concentrations of l-MPH typically attain 40−50% that of d-MPH (vs. 1−2% following oral MPH). Unauthorized MTS removal poses some misuse liability and over 50% of MTS drug content remains in the discarded system. Conclusions While liquid or chewable MPH formulations overcome potential swallowing difficulties, as do sprinkled once-daily extended-release (ER) MPH products, only MTS addresses swallowing difficulties while also offering a flexible individualized MPH exposure time in a once-daily MPH regimen. PMID:19051222

Saikosaponin A Alleviates Symptoms of Attention Deficit Hyperactivity Disorder through Downregulation of DAT and Enhancing BDNF Expression in Spontaneous Hypertensive Rats.

PubMed

Jichao, Sun; Xinmin, Han; Xianguo, Ren; Dongqi, Yin; Rongyi, Zhou; Shuang, Lei; Yue, You; Yuchen, Song; Jingnan, Ying

2017-01-01

The disturbed dopamine availability and brain-derived neurotrophic factor (BDNF) expression are due in part to be associated with attention deficit hyperactivity disorder (ADHD). In this study, we investigated the therapeutical effect of saikosaponin a (SSa) isolated from Bupleurum Chinese DC, against spontaneously hypertensive rat (SHR) model of ADHD. Methylphenidate and SSa were orally administered for 3 weeks. Activity was assessed by open-field test and Morris water maze test. Dopamine (DA) and BDNF were determined in specific brain regions. The mRNA or protein expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicles monoamine transporter (VMAT) was also studied. Both MPH and SSa reduced hyperactivity and improved the spatial learning memory deficit in SHRs. An increased DA concentration in the prefrontal cortex (PFC) and striatum was also observed after treating with the SSa. The increased DA concentration may partially be attributed to the decreased mRNA and protein expression of DAT in PFC while SSa exhibited no significant effects on the mRNA expression of TH and VMAT in PFC of SHRs. In addition, BDNF expression in SHRs was also increased after treating with SSa or MPH. The obtained result suggested that SSa may be a potential drug for treating ADHD.

Comorbidities in ADHD children treated with methylphenidate: a database study

PubMed Central

2013-01-01

Background Methylphenidate (MPH) is the most common drug treatment of attention deficit / hyperactivity disorder (ADHD) in children. Treatment with MPH is contraindicated in the presence of certain psychiatric, cerebro- and cardiovascular conditions. We assessed MPH treatment prevalence and incidence and the frequency of comorbid conditions related to these contraindications in new MPH users compared to a control group without ADHD and ADHD medication. Methods We used health care data for the years 2004 to 2006 from the German Pharmacoepidemiological Research Database (GePaRD) which includes about 18% of the German population. MPH treatment prevalence and incidence was assessed based on at least one MPH prescription in the given year. In MPH users, the prevalence of psychiatric and other comorbidities was assessed in the quarter of the first MPH prescription and the three preceding quarters, whereas in controls it was assessed in the earliest four quarters of continuous insurance time starting at 01.01.2004 or the start of insurance if this was later. Differences in the presence of comorbid diagnoses between MPH users and controls were tested by logistic regression. Results In 2005, 1.5% of all children and adolescents aged 3 to 17 years (2.3% of males and 0.6% of females) received MPH in Germany. The proportion of children with a record of a psychiatric comorbidity in any of the nine ICD categories of diagnoses was substantially higher in new MPH users (83%) compared to controls (20%). Cerebro- and cardiovascular comorbidities were rare in general. Still, among new MPH users, 2% of males and females had a diagnosis of a pre-existing cardiovascular disorder but only 1.2% of controls. Conclusions Besides MPH treatment prevalence we first publish age-specific incidence rates for Germany. A high proportion of children who were started on MPH had a record of a psychiatric comorbidity preceding the first prescription. Cerebro- and cardiovascular conditions were rare in the studied age range, but still higher among children who received MPH than in the control group. Results show that in a substantial subgroup of patients, comorbidities require a thorough weighting of possible risks of MPH medication against the risks of untreated ADHD. PMID:23294623

Deregulated proliferation and differentiation in brain tumors

PubMed Central

Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

2014-01-01

Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

Malignant neuroleptic syndrome following deep brain stimulation surgery: a case report.

PubMed

Themistocleous, Marios S; Boviatsis, Efstathios J; Stavrinou, Lampis C; Stathis, Pantelis; Sakas, Damianos E

2011-06-29

The neuroleptic malignant syndrome is an uncommon but dangerous complication characterized by hyperthermia, autonomic dysfunction, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigor. It is most often caused by an adverse reaction to anti-psychotic drugs or abrupt discontinuation of neuroleptic or anti-parkinsonian agents. To the best of our knowledge, it has never been reported following the common practice of discontinuation of anti-parkinsonian drugs during the pre-operative preparation for deep brain stimulation surgery for Parkinson's disease. We present the first case of neuroleptic malignant syndrome associated with discontinuation of anti-parkinsonian medication prior to deep brain stimulation surgery in a 54-year-old Caucasian man. The characteristic neuroleptic malignant syndrome symptoms can be attributed to other, more common causes associated with deep brain stimulation treatment for Parkinson's disease, thus requiring a high index of clinical suspicion to timely establish the correct diagnosis. As more centers become eligible to perform deep brain stimulation, neurologists and neurosurgeons alike should be aware of this potentially fatal complication. Timely activation of the deep brain stimulation system may be important in accelerating the patient's recovery.

Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

2015-12-01

Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

Expression of hypoxia-inducible carbonic anhydrases in brain tumors

PubMed Central

Proescholdt, Martin A.; Mayer, Christina; Kubitza, Marion; Schubert, Thomas; Liao, Shu-Yuan; Stanbridge, Eric J.; Ivanov, Sergey; Oldfield, Edward H.; Brawanski, Alexander; Merrill, Marsha J.

2005-01-01

Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel–Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1α staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target. PMID:16212811

Brain Metastasis in Bone and Soft Tissue Cancers: A Review of Incidence, Interventions, and Outcomes

PubMed Central

Shweikeh, Faris; Bukavina, Laura; Saeed, Kashif; Sarkis, Reem; Suneja, Aarushi; Sweiss, Fadi; Drazin, Doniel

2014-01-01

Bone and soft tissue malignancies account for a small portion of brain metastases. In this review, we characterize their incidence, treatments, and prognosis. Most of the data in the literature is based on case reports and small case series. Less than 5% of brain metastases are from bone and soft tissue sarcomas, occurring most commonly in Ewing's sarcoma, malignant fibrous tumors, and osteosarcoma. Mean interval from initial cancer diagnosis to brain metastasis is in the range of 20–30 months, with most being detected before 24 months (osteosarcoma, Ewing sarcoma, chordoma, angiosarcoma, and rhabdomyosarcoma), some at 24–36 months (malignant fibrous tumors, malignant peripheral nerve sheath tumors, and alveolar soft part sarcoma), and a few after 36 months (chondrosarcoma and liposarcoma). Overall mean survival ranges between 7 and 16 months, with the majority surviving < 12 months (Ewing's sarcoma, liposarcoma, malignant fibrous tumors, malignant peripheral nerve sheath tumors, angiosarcoma and chordomas). Management is heterogeneous involving surgery, radiosurgery, radiotherapy, and chemotherapy. While a survival advantage may exist for those given aggressive treatment involving surgical resection, such patients tended to have a favorable preoperative performance status and minimal systemic disease. PMID:24757391

Plasma methylphenidate concentrations in youths treated with high-dose osmotic release oral system formulation.

PubMed

Stevens, Jonathan R; George, Robert A; Fusillo, Steven; Stern, Theodore A; Wilens, Timothy E

2010-02-01

Children and adolescents are being treated increasingly for attention-deficit/hyperactivity disorder (ADHD) with a variety of stimulants in higher than Food and Drug Administration (FDA)-approved doses and in combination with other medications. We sought to determine methylphenidate (MPH) concentrations in children and adolescents treated with high-dose, extended-release osmotic release oral system (OROS) MPH plus concomitant medications, and to examine MPH concentrations with respect to the safety and tolerability of treatment. Plasma MPH concentrations were measured by liquid chromatography-mass spectrometry 4-5 hours after administration of medication in a sample of youths diagnosed with ADHD. These youths were treated naturalistically with higher than FDA-approved doses of OROS MPH in addition to their concomitant medications. Markers of safety and tolerability (e.g., measures of blood pressure and heart rate) were also examined. Among the 17 patients (with a mean age of 16.2 +/- 2 years and a mean number of concurrent medications of 2.23 +/- 0.94), the mean plasma MPH concentration was 28 +/- 9.1 ng/mL, despite a mean daily dose of OROS MPH of 169 +/- 5 mg (3.0 +/- 0.8 mg/kg per day). No patient had a plasma MPH level >or=50 ng/mL or clinical signs of stimulant toxicity. No correlation was found between plasma MPH concentrations and OROS MPH dose or changes in vital signs. High-dose OROS MPH, used in combination with other medications, was not associated with either unusually elevated plasma MPH concentrations or with clinically meaningful changes in vital signs. Study limitations include a single time-point sampling of MPH concentrations, a small sample size, and a lack of outcome measures to address treatment effectiveness.

Pharmacokinetics and therapeutic effect of OROS methylphenidate under different breakfast conditions in children with attention-deficit/hyperactivity disorder.

PubMed

Wigal, Sharon B; Gupta, Suneel; Heverin, Erica; Starr, H Lynn

2011-06-01

To examine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of OROS methylphenidate (OROS MPH) dosed once daily (QD) versus an early standard regimen (immediate-release [IR] MPH dosed three times daily [TID]) under various breakfast conditions. This single-center, double-blind, double-dummy, randomized, crossover study of OROS MPH (NCT00269815) in children aged 6 to 12 years with attention-deficit/hyperactivity disorder evaluated the PKs and PDs of MPH given with different breakfast conditions: OROS MPH administered after a high-fat breakfast, after a normal breakfast, or after fasting and IR MPH administered after a normal breakfast or after fasting in the morning and at two subsequent time points during the day. To maximize information, patients were divided into two groups, each receiving three of the five treatments for 1 day in a three-period, randomized, crossover design. Patients were assigned to 1 of 3 dosage levels (OROS MPH 18, 36, and 54 mg QD, and an assumed equivalent regimen of IR MPH 5, 10, and 15 mg given TID) based on their prestudy established clinical dose of IR MPH. PD measurements included Combined-Attention and Deportment scores on a rating scale of school behavior (the Swanson, Kotkin, Agler, M-Flynn, and Pelham), global assessments of efficacy, and activity monitor levels during academic seatwork. Serial blood samples for PK analysis were taken predose, and then every 60 to 90 minutes until 11.5 hours postdose. Vital signs were assessed predose, and then every 1.5 to 2.5 hours until 11.5 hours postdose. Of the 32 patients enrolled, 31 completed the study. The PK profiles for MPH after OROS MPH administration were similar under all conditions (with normal, high-fat breakfast, or fasting). No bioequivalence tests of OROS MPH and IR MPH under various breakfast conditions were done because there were so few patients in each dose level of treatment. The two IR MPH conditions (after normal breakfast and fasting) were not compared. The drug-to-metabolite ratios (area under the curve) for all OROS MPH and IR MPH treatments were similar. OROS MPH and IR MPH provided a similar therapeutic effect, irrespective of breakfast conditions, as demonstrated by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Attention and Deportment measures and global assessments. No serious adverse events, no deaths, and no clinically significant changes in vital signs were reported, except for one patient who was discontinued early because of repeated systolic blood pressure elevations on study day 1. The results of this study demonstrate that in children with attention-deficit/hyperactivity disorder, administering OROS MPH with or without food produces similar PK and PD profiles.

A Comparison of 2 Current-Issue Army Boots.

DTIC Science & Technology

2000-01-01

at 3.5 mph, mean (SD) 32 21 .Maximum heel- strike vertical force (N) while walking at 3.5 mph, mean (SD) 33 22 Maximum heel- strike braking force...while running at 6.5 mph, mean (SD) 38 34 Maximum force on the hip (N) while running at 6.5 mph, mean (SD) 38 35 Maximum vertical heel- strike force (N...during 6.5 mph running, mean (SD) 39 36. Maximum heel- strike braking force (N) while running at 6.5 mph, mean (SD) 39 37. Maximum vertical push

Effects of perinatal methylphenidate (MPH) treatment in male and female Sprague-Dawley offspring.

PubMed

Panos, John J; Law, C Delbert; Ferguson, Sherry A

2014-01-01

MPH is a common treatment for adult Attention Deficit Hyperactivity Disorder (ADHD). However, little information exists regarding its safety during pregnancy and thus, women with ADHD face difficult decisions regarding continued use during pregnancy. Here, Sprague-Dawley rats were orally treated 3 ×/day with 0 (control), 6 (low), 18 (mid), or 42 (high) mg MPH/kg/day (i.e., 0, 2, 6, or 14 mg/kg at each treatment time) on gestational days 6-21. On postnatal days (PNDs) 1-21, all offspring/litter were orally treated 2 ×/day with the same dose. Righting reflex (PNDs 3-6) and slant board performance (PNDs 8-11) were assessed. T3, T4, E2, testosterone, LH and corticosterone were measured at PND 22. Separate pregnant dams and resulting litters were used for serum MPH measurements. MPH treatment had mild, but significant, effects on gestational body weight and food intake. Birth weight of high MPH offspring was 5% more than controls (p<0.0500). Relative to same-sex controls on PNDs 1-22, low and mid MPH males weighed more (p<0.0094), low MPH females weighed more (p<0.0001), while high MPH females weighed less (p<0.0397). PND 22 serum E2 levels were significantly decreased (20-25%) in high MPH males and females (p<0.0500). Behavioral performance was unaffected by treatment. Serum MPH levels of the low MPH pregnant dams were within the range produced by therapeutic MPH doses in adults; however, offspring levels in all groups were substantially higher. These results indicate that developmental MPH treatment has mild effects on gestational body weight and food intake and offspring preweaning body weight. Potential functional consequences of decreased serum E2 levels are not clear, but may impact later behavior or physiology. Published by Elsevier Inc.

Laser treatments of deep-seated brain lesions

NASA Astrophysics Data System (ADS)

Ward, Helen A.

1997-06-01

The five year survival rate of deep-seated malignant brain tumors after surgery/radiotherapy is virtually 100 percent mortality. Special problems include: (1) Lesions often present late. (2) Position: lesion overlies vital structures, so complete surgical/radiotherapy lesion destruction can damage vital brain-stem functions. (3) Difficulty in differentiating normal brain form malignant lesions. This study aimed to use the unique properties of the laser: (a) to minimize damage during surgical removal of deep-seated brain lesions by operating via fine optic fibers; and (b) to employ the propensity of certain lasers for absorption of dyes and absorption and induction of fluorescence in some brain substances, to differentiate borders of malignant and normal brain, for more complete tumor removal. In the method a fine laser endoscopic technique was devised for removal of brain lesions. The results of this technique, were found to minimize and accurately predict the extent of thermal damage and shock waves to within 1-2mm of the surgical laser beam. Thereby it eliminated the 'popcorn' effect.

Effects of Methylphenidate on Attention Deficits in Childhood Cancer Survivors

ClinicalTrials.gov

2015-03-16

ALL, Childhood; Leukemia, Lymphoblastic; Leukemia, Lymphoblastic, Acute; Leukemia, Lymphoblastic, Acute, L1; Leukemia, Lymphoblastic, Acute, L2; Leukemia, Lymphoblastic, Acute, Philadelphia-Positive; Leukemia, Lymphocytic, Acute; Leukemia, Lymphocytic, Acute, L1; Leukemia, Lymphocytic, Acute, L2; Lymphoblastic Leukemia; Lymphoblastic Leukemia, Acute; Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Leukemia, Acute, L1; Lymphoblastic Leukemia, Acute, L2; Lymphoblastic Lymphoma; Lymphocytic Leukemia, Acute; Lymphocytic Leukemia, L1; Lymphocytic Leukemia, L2; Brain Tumors; Cancer of the Brain; Cancer of Brain; Malignant Primary Brain Tumors; Brain Neoplasms, Malignant

49 CFR 213.307 - Class of track: operating speed limits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... operating speed for trains 1 is— Class 6 track 110 m.p.h. Class 7 track 125 m.p.h. Class 8 track 160 m.p.h. 2 Class 9 track 200 m.p.h. 1 Freight may be transported at passenger train speeds if the following... 150 m.p.h. are authorized by this part only in conjunction with a rule of particular applicability...

Plasma Methylphenidate Levels in Youths With Attention Deficit Hyperactivity Disorder Treated With OROS Formulation.

PubMed

Yorbik, Ozgur; Mutlu, Caner; Ozilhan, Selma; Eryilmaz, Gul; Isiten, Nuket; Alparslan, Serdar; Saglam, Esra

2015-06-01

There are limited studies investigating the relationship between oral release osmotic system-methylphenidate (OROS-MPH) doses and plasma methylphenidate (MPH) concentrations in children and adolescents. The aim of this study was to investigate the relationship between the doses of OROS-MPH and the plasma levels of the drug. We also examined the effects of the other drugs including aripiprazole, risperidone, fluoxetine, and sertraline on the levels of the MPH in the plasma. The files of 100 attention deficit hyperactivity disorder (ADHD) subjects (76 male, 24 female) who were diagnosed as ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria, were screened. The ages of subjects were between 6 and 18 years (mean = 11.5 ± 3.8 years). Plasma MPH levels were determined by high-performance liquid chromatography-tandem mass spectrometry assay. Daily mean OROS-MPH dose used in ADHD children was 0.7 ± 0.2 mg/kg (range: 0.3-1.3 mg/kg). The mean plasma OROS-MPH was 11.6 ± 7.3 ng/mL (range: 0.5-43.4 ng/mL). There was no group difference in the mean plasma MPH and dose-related MPH levels between the groups that used any additional drug including aripiprazole (n = 25), risperidone (n = 10), fluoxetine (n = 16), sertraline (n = 10), and did not use these drugs (P > 0.05). There was a positive correlation between the OROS-MPH doses (mg/kg) and the blood MPH levels (Pearson correlation = 0.40; P < 0.001). The plasma levels of MPH were found to be less than 13 ng/mL in 65% of the subjects. Our findings point to the fact that plasma levels of MPH show a wide range of changes at similar doses, correlate positively with the doses and, as expected, are not affected by using risperidone, sertraline, fluoxetine, and aripiprazole. Therapeutic drug monitoring may help to optimize MPH dose in patients not responding to treatment or in those experiencing serious side effects, but not in routine clinical practice. The presence of intermediate dose formulations such as 45-mg tablets for OROS-MPH may contribute to the optimization.

Interaction of chronic food restriction and methylphenidate in sensation seeking of rats.

PubMed

Talishinsky, Aleksandr D; Nicolas, Celine; Ikemoto, Satoshi

2017-07-01

It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis. We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses. Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH. CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH. CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli.

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.

The incidence rate and mortality of malignant brain tumors after 10 years of intensive cell phone use in Taiwan.

PubMed

Hsu, Min-Huei; Syed-Abdul, Shabbir; Scholl, Jeremiah; Jian, Wen-Shan; Lee, Peisan; Iqbal, Usman; Li, Yu-Chuan

2013-11-01

The issue of whether cell phone usage can contribute toward the development of brain tumors has recently been reignited with the International Agency for Research on Cancer classifying radiofrequency electromagnetic fields as 'possibly' carcinogenic to humans in a WHO report. To our knowledge, this is the largest study reporting on the incidence and mortality of malignant brain tumors after long-term use of the cell phone by more than 23 million users. A population-based study was carried out the numbers of cell phone users were collected from the official statistics provided by the National Communication Commission. According to National Cancer Registry, there were 4 incidences and 4 deaths due to malignant neoplasms in Taiwan during the period 2000-2009. The 10 years of observational data show that the intensive user rate of cell phones has had no significant effect on the incidence rate or on the mortality of malignant brain tumors in Taiwan. In conclusion, we do not detect any correlation between the morbidity/mortality of malignant brain tumors and cell phone use in Taiwan. We thus urge international agencies to publish only confirmatory reports with more applicable conclusions in public. This will help spare the public from unnecessary worries.

History and current state of immunotherapy in glioma and brain metastasis.

PubMed

McGranahan, Tresa; Li, Gordon; Nagpal, Seema

2017-05-01

Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

PubMed

McGovern, Robin; Luderman, Lauryn; Knecht, Kelly; Griffin, William C

2014-12-01

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

Charge transfer process at the Ag/MPH/TiO2 interface by SERS: alignment of the Fermi level.

PubMed

Zhang, Xiaolei; Sui, Huimin; Wang, Xiaolei; Su, Hongyang; Cheng, Weina; Wang, Xu; Zhao, Bing

2016-11-02

A nanoscale metal-molecule-semiconductor assembly (Ag/4-mercaptophenol/TiO 2 ) has been fabricated over Au nanoparticle (NP) films as a model to study the interfacial charge transfer (CT) effects involved in Ag/MPH/TiO 2 . Due to the interaction between Au NPs and Ag NPs, some distinct differences occur in the SERS spectra. We also measured the SERS of Ag/MPH (4-mercaptophenol), Ag/MPH/TiO 2 , and Au/Ag/MPH/TiO 2 assemblies at excitation wavelengths of 477, 514, 532, 633, and 785 nm. We found that the changes in the CT process, caused by the introduction of TiO 2 and Au, can be reflected in SERS. Then in combination with other detection methods, we proposed a possible CT process involved in the Ag/MPH, Ag/MPH/TiO 2 , and Au/Ag/MPH/TiO 2 assemblies. A Pt/Ag/MPH/TiO 2 assembly was also constructed to verify our proposed CT mechanism. This work not only provides more details about CT between metal-molecule-semiconductor interfaces but also aids in constructing nanoscale models to study interfacial problems with the SERS technique.

Strain Differences in Self-Administration of Methylphenidate and Sucrose Pellets in a Rat Model of ADHD

PubMed Central

Marusich, Julie A.; McCuddy, W. Travis; Beckmann, Joshua S.; Gipson, Cassandra D.; Bardo, Michael T.

2011-01-01

Despite its abuse potential, methylphenidate (MPH) is widely prescribed for treatment of attention deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine MPH self-administration in a rat model of ADHD. Experiment 1 examined the acquisition of MPH self-administration and assessed the MPH dose-effect curve in spontaneously hypertensive rats (SHR), an inbred rat model of ADHD, Wistar Kyotos (WKY), the progenitor strain for SHR, and Sprague-Dawleys (SD), an outbred control strain. Experiment 2 replicated Experiment 1, but replaced MPH infusions with sucrose pellets. Initial acquisition of MPH self-administration was greater in SHR and SD than WKY. With extended training using an incrementing fixed ratio schedule, however, SHR and WKY did not differ in responding for MPH using the training dose (0.3 mg/kg/infusion) or other unit doses, except that SHR showed greater responding than WKY at 0.1 mg/kg/infusion. SHR also showed greater acquisition and maintenance of sucrose-reinforced responding compared to both WKY and SD. Greater initial acquisition of MPH self-administration in SHR than WKY may not be due to a strain specific difference in sensitivity to the reinforcing effect of MPH. PMID:22015805

Biochemical studies of the Saccharomyces cerevisiae Mph1 helicase on junction-containing DNA structures

PubMed Central

Kang, Young-Hoon; Munashingha, Palinda Ruvan; Lee, Chul-Hwan; Nguyen, Tuan Anh; Seo, Yeon-Soo

2012-01-01

Saccharomyces cerevisiae Mph1 is a 3–5′ DNA helicase, required for the maintenance of genome integrity. In order to understand the ATPase/helicase role of Mph1 in genome stability, we characterized its helicase activity with a variety of DNA substrates, focusing on its action on junction structures containing three or four DNA strands. Consistent with its 3′ to 5′ directionality, Mph1 displaced 3′-flap substrates in double-fixed or equilibrating flap substrates. Surprisingly, Mph1 displaced the 5′-flap strand more efficiently than the 3′ flap strand from double-flap substrates, which is not expected for a 3–5′ DNA helicase. For this to occur, Mph1 required a threshold size (>5 nt) of 5′ single-stranded DNA flap. Based on the unique substrate requirements of Mph1 defined in this study, we propose that the helicase/ATPase activity of Mph1 play roles in converting multiple-stranded DNA structures into structures cleavable by processing enzymes such as Fen1. We also found that the helicase activity of Mph1 was used to cause structural alterations required for restoration of replication forks stalled due to damaged template. The helicase properties of Mph1 reported here could explain how it resolves D-loop structure, and are in keeping with a model proposed for the error-free damage avoidance pathway. PMID:22090425

Pembrolizumab With Intratumoral Injection of Clostridium Novyi-NT

ClinicalTrials.gov

2018-06-22

Malignant Neoplasm of Breast; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract

The microenvironmental landscape of brain tumors

PubMed Central

Quail, Daniela F.; Joyce, Johanna A.

2017-01-01

The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases. PMID:28292436

The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome.

PubMed

Green, Tamar; Weinberger, Ronnie; Diamond, Adele; Berant, Michael; Hirschfeld, Leora; Frisch, Amos; Zarchi, Omer; Weizman, Abraham; Gothelf, Doron

2011-12-01

Methylphenidate (MPH) is commonly used to treat attention-deficit/hyperactivity disorder (ADHD) in all children, including those with velocardiofacial syndrome (VCFS). Yet concerns have been raised regarding its safety and efficacy in VCFS. The goal of this study was to examine the safety and efficacy of MPH in children with VCFS. Thirty-four children and adolescents with VCFS and ADHD participated in a randomized, controlled trial with a 2:1 ratio of MPH versus placebo. All subjects underwent a cardiological evaluation before and after MPH administration. The primary outcome measure was prefrontal cognitive performance following a single dose of MPH or placebo. A follow-up assessment was conducted after a 6-month treatment with MPH. Compared with placebo, single MPH administration was associated with a more robust improvement in prefrontal cognitive performance, including achievements in the Hearts and Flowers executive function task and the visual continuous performance task. After 6 months of treatment, a 40% reduction in severity of ADHD symptoms was reported by parents on the Revised Conners Rating Scale. All subjects treated with MPH reported at least one side effect, but it did not necessitate discontinuation of treatment. MPH induced an increase in heart rate and blood pressure that was usually minor, but was clinically significant in two cases. No differences in response to MPH were observed between catechol-O-methyltransferase Met versus Val carriers. The use of MPH in children with VCFS appears to be effective and relatively safe. A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended.

32 CFR 636.22 - Speed regulations.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) of this section). (d) The following special speed limits apply: (1) When passing troop formations, 10... tactical vehicles and will obey the following off-road driving speeds: Day Driving: Trails, 16 MPH Cross County, 6 MPH Night Driving: Trails, 5 MPH (with headlights) Cross Country, 5 MPH Night Driving: Trails...

Evaluation of 70 mph speed limit in Kentucky.

DOT National Transportation Integrated Search

2008-05-01

The objective of this study was to document the change in operating speeds of cars and trucks on rural interstates and parkways as a result of the change in speed limit from 65 mph to 70 mph. The 85th percentile speed increased 1.3 mph for cars (74.6...

Potential roles of hyperbaric oxygenation in the treatments of brain tumors.

PubMed

Kohshi, Kiyotaka; Beppu, Takaaki; Tanaka, Katsuyuki; Ogawa, Kazuhiko; Inoue, Osamu; Kukita, Ichiro; Clarke, Richard E

2013-01-01

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain. HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas. The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

40 CFR Appendix V to Part 86 - The Standard Road Cycle (SRC)

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) Pt. 86, App. V... engine) Idle 10 sec 0 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to 20 MPH −5 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to stop −5 1 Idle 5 sec 0 1...

40 CFR Appendix V to Part 86 - The Standard Road Cycle (SRC)

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) Pt. 86, App. V... engine) Idle 10 sec 0 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to 20 MPH −5 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to stop −5 1 Idle 5 sec 0 1...

40 CFR Appendix V to Part 86 - The Standard Road Cycle (SRC)

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Pt. 86, App. V Appendix V... engine) Idle 10 sec 0 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to 20 MPH −5 1 Mod accel to 30 MPH 4 1 Cruise at 30 MPH for 1/4 lap 0 1 Mod. decel to stop −5 1 Idle 5 sec 0 1...

Malignant Brain Tumours in Children : Present and Future Perspectives.

PubMed

Rutka, James T

2018-05-01

In contrast to many of the malignant tumors that occur in the central nervous system in adults, the management, responses to therapy, and future perspectives of children with malignant lesions of the brain hold considerable promise. Within the past 5 years, remarkable progress has been made with our understanding of the basic biology of the molecular genetics of several pediatric malignant brain tumors including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumour, and high grade glioma/diffuse intrinsic pontine glioma. The recent literature in pediatric neuro-oncology was reviewed, and a summary of the major findings are presented. Meaningful sub-classifications of these tumors have arisen, placing children into discrete categories of disease with requirements for targeted therapy. While the mainstay of therapy these past 30 years has been a combination of central nervous system irradiation and conventional chemotherapy, now with the advent of high resolution genetic mapping, targeted therapies have emerged, and less emphasis is being placed on craniospinal irradiation. In this article, the present and future perspective of pediatric brain malignancy are reviewed in detail. The progress that has been made offers significant hope for the future for patients with these tumours.

Brain tumor - children

MedlinePlus

... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

Attention enhancing effects of methylphenidate are age-dependent

PubMed Central

Bhattacharya, Shevon E.; Shumsky, Jed S.; Waterhouse, Barry D.

2014-01-01

The psychostimulant methylphenidate (MPH, Ritalin®) is used to treat a variety of cognitive disorders. MPH is also popular among healthy individuals, including the elderly, for its ability to focus attention and improve concentration, but these effects have not been shown to be comparable between aged and adult subjects. Thus, we tested whether MPH would improve performance in sustained attention in both adult and aged rats. In addition, we tested the impact of visual distraction on performance in this task and the ability of MPH to mitigate the effects of distraction. Adult (6–12 months) and aged (18–22 months) male Sprague-Dawley rats were given oral MPH, and their cognitive and motor abilities were tested. Results suggest that while MPH improves task performance in adults; there is no improvement in the aged animals. These outcomes suggest that use of MPH for cognitive enhancement in elderly individuals may be ineffective. PMID:25449855

Optimal speed limits for school buses on Virginia highways : a report to Virginia's Superintendent of Public Instruction.

DOT National Transportation Integrated Search

1990-01-01

On Virginia's rural interstate highways there is a three-tiered speed limit: 45 mph for school buses, 55 mph for trucks, and 65 mph for other vehicles. On the urban interstate highways, school buses are restricted to 45 mph, but other traffic has a 5...

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature

PubMed Central

Tong, Hoi Y.; Díaz, Carmen; Collantes, Elena; Medrano, Nicolás; Borobia, Alberto M.; Jara, Paloma; Ramírez, Elena

2015-01-01

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended. PMID:25688317

A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors

NASA Astrophysics Data System (ADS)

Rubin, Joshua B.; Kung, Andrew L.; Klein, Robyn S.; Chan, Jennifer A.; Sun, Yanping; Schmidt, Karl; Kieran, Mark W.; Luster, Andrew D.; Segal, Rosalind A.

2003-11-01

The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

Better efficacy for the osmotic release oral system methylphenidate among poor adherents to immediate-release methylphenidate in the three ADHD subtypes.

PubMed

Chou, Wen-Jiun; Chou, Miao-Chun; Tzang, Ruu-Fen; Hsu, Ya-Chen; Gau, Susan Shur-Fen; Chen, Shin-Jaw; Wu, Yu-Yu; Huang, Ya-Fen; Liang, Hsin-Yi; Cheng, Helen

2009-04-01

To determine factors for switching to osmotic release oral system methylphenidate (OROS-MPH) among poor adherents to immediate-release methylphenidate (IR-MPH); and to compare the efficacy of OROS-MPH on the three attention-deficit/hyperactivity disorder (ADHD) subtypes in a multi-site prospective observational study in Taiwan. The sample included 240 children with ADHD, aged 6-16 years, who were poor adherents to IR-MPH, 137 of whom were switched to OROS-MPH. The child psychiatrists diagnosed the Diagnostic Statistical Manual of Mental Disorders (4th edition) ADHD subtypes and assessed the medical history, adherence, side-effects, global ADHD severity, and family/school effectiveness. Parents reported their child's behavioral symptoms. The determinants for an OROS-MPH switch were higher dosage, shorter treatment and thrice-daily administration of IR-MPH, and more severe inattention symptoms. Hyperactivity and oppositional symptoms were greater in the ADHD combined and hyperactive-impulsive subtypes than the inattentive subtype. Switching to OROS-MPH significantly improved behavioral symptoms and family/school measures, and this was most evident in the ADHD-combined group, followed by the ADHD-inattentive group. Inattention influenced not only academic performance, but also overall classroom behaviors and the parent-child relationship, with the latter two also influenced by oppositional symptoms. This study suggests better efficacy for the OROS-MPH among poor adherents to IR-MPH; however, its effectiveness varied across the three ADHD subtypes (ClinicalTrials.gov number NCT00460720).

An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

PubMed

Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

2015-01-01

Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. Copyright © 2014 Elsevier Inc. All rights reserved.

An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

PubMed Central

Kollins, Scott H.; Schoenfelder, Erin N.; English, Joseph S.; Holdaway, Alex; Van Voorhees, Elizabeth; O’Brien, Benjamin R.; Dew, Rachel; Chrisman, Allan K.

2014-01-01

Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

Factors that influence full-time MPH Students' willingness in China: would You apply again for an MPH graduate degree if you had another opportunity?

PubMed

Wang, Nan; Jia, Jinzhong; Wu, Ke; Wang, Yuanyuan; Zhang, Chi; Cao, Wei; Duan, Liping; Wang, Zhifeng

2017-02-14

Current and emerging challenges to public health in the 21st century are vastly different from those faced in previous centuries. And the shortage of health personnel and their low level of educational qualifications hindered the development of Chinese public health services. In order to fulfill this requirement, the Ministry of Education initiated a full-time, Master of Public Health (MPH) graduate programme in 2009. This study aimed to evaluate the level of graduate students' satisfaction with full-time Master of Public Health (MPH) education in China, and whether they would apply again for an MPH graduate degree if they had another opportunity to do so, as well as to identify the factors influencing their decision-making process. An anonymous, web-based survey questionnaire containing 61 items was distributed to 702 MPH students in 35 universities or colleges. The questions covered the categories of student admission, training goals, lecture courses, practical training, research activities and mentorship. Levels of satisfaction were compared between MPH students who would choose MPH again as their graduate degree if they had another opportunity to do so and those who would not. Key influencing factors of training satisfaction were identified using logistic regression models. A total of 65.10% of the participants would apply again for MPH education if they had another opportunity to do so. The factors influencing students' willingness included their university type, the time since admission and their initial willingness. In addition, the four common factors (admissions & lecture courses, research activities & mentorship, practical training and training goals) emerging from factor analysis were all significantly positively correlated with student willingness (p < 0.001). Most MPH students surveyed were highly satisfied with their MPH education and, although they advocated for improvements and reforms in some aspects, they would still choose MPH as their graduate degree again if they had another opportunity to do so.

Raising the speed limit from 75 to 80mph on Utah rural interstates: Effects on vehicle speeds and speed variance.

PubMed

Hu, Wen

2017-06-01

In November 2010 and October 2013, Utah increased speed limits on sections of rural interstates from 75 to 80mph. Effects on vehicle speeds and speed variance were examined. Speeds were measured in May 2010 and May 2014 within the new 80mph zones, and at a nearby spillover site and at more distant control sites where speed limits remained 75mph. Log-linear regression models estimated percentage changes in speed variance and mean speeds for passenger vehicles and large trucks associated with the speed limit increase. Logistic regression models estimated effects on the probability of passenger vehicles exceeding 80, 85, or 90mph and large trucks exceeding 80mph. Within the 80mph zones and at the spillover location in 2014, mean passenger vehicle speeds were significantly higher (4.1% and 3.5%, respectively), as were the probabilities that passenger vehicles exceeded 80mph (122.3% and 88.5%, respectively), than would have been expected without the speed limit increase. Probabilities that passenger vehicles exceeded 85 and 90mph were non-significantly higher than expected within the 80mph zones. For large trucks, the mean speed and probability of exceeding 80mph were higher than expected within the 80mph zones. Only the increase in mean speed was significant. Raising the speed limit was associated with non-significant increases in speed variance. The study adds to the wealth of evidence that increasing speed limits leads to higher travel speeds and an increased probability of exceeding the new speed limit. Results moreover contradict the claim that increasing speed limits reduces speed variance. Although the estimated increases in mean vehicle speeds may appear modest, prior research suggests such increases would be associated with substantial increases in fatal or injury crashes. This should be considered by lawmakers considering increasing speed limits. Copyright © 2017 Elsevier Ltd and National Safety Council. All rights reserved.

Extended-release dexmethylphenidate 30 mg/d versus 20 mg/d: duration of attention, behavior, and performance benefits in children with attention-deficit/hyperactivity disorder.

PubMed

Silva, Raul R; Brams, Matthew; McCague, Kevin; Pestreich, Linda; Muniz, Rafael

2013-01-01

This study aimed to compare the effects of dexmethylphenidate (D-MPH) extended-release (ER) 30 mg and D-MPH-ER 20 mg on attention, behavior, and performance in children with attention-deficit/hyperactivity disorder. In a randomized, double-blind, 3-period-by-3-treatment, crossover study, children aged 6 to 12 years with attention-deficit/hyperactivity disorder stabilized on methylphenidate (40-60 mg/d) or D-MPH (20-30 mg/d) received D-MPH-ER 20 mg/d, 30 mg/d, and placebo for 7 days each (final dose of each treatment period administered in a laboratory classroom). Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Combined (Attention and Deportment) rating scale and Permanent Product Measure of Performance (PERMP) math test assessments were conducted at baseline and 3, 6, 9, 10, 11, and 12 hours postdose. A total of 165 children (94 boys; mean age, 9.6 years) were randomized (162 included in intent-to-treat analyses). Significant improvements were noted for D-MPH-ER 30 mg over D-MPH-ER 20 mg at various late time points on the SKAMP scales (Combined scores at 9, 10, 11, and 12 hours postdose; Attention scores at 10, 11, and 12 hours postdose; deportment scores at 9 and 12 hours postdose). The PERMP math test-attempted and -correct scores (change from predose) were significantly higher with D-MPH-ER 30 mg than with D-MPH-ER 20 mg at 10, 11, and 12 hours postdose. Both D-MPH-ER doses were superior to placebo at all time points. D-MPH-ER 30 mg was superior to D-MPH-ER 20 mg at later time points in the day, suggesting that higher doses of D-MPH-ER may be more effective later in the day.

Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial.

PubMed

Ishii-Takahashi, Ayaka; Takizawa, Ryu; Nishimura, Yukika; Kawakubo, Yuki; Hamada, Kasumi; Okuhata, Shiho; Kawasaki, Shingo; Kuwabara, Hitoshi; Shimada, Takafumi; Todokoro, Ayako; Igarashi, Takashi; Watanabe, Kei-Ichiro; Yamasue, Hidenori; Kato, Nobumasa; Kasai, Kiyoto; Kano, Yukiko

2015-11-01

Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near-infrared spectroscopy (NIRS). After baseline assessment, we performed a double-blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naïve and eight previously treated children with ADHD (NAÏVE and NON-NAÏVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or ΔNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI-S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. ΔNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. ΔNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAÏVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON-NAÏVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAÏVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAÏVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD.

TAK228 With Carbo and Taxol in Advanced Malignancies

ClinicalTrials.gov

2018-03-12

Malignant Neoplasm of Breast; Malignant Neoplasms of Bone and Articular Cartilage; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic

Towards tailored management of malignant brain tumors with nanotheranostics.

PubMed

Aparicio-Blanco, Juan; Torres-Suárez, Ana-Isabel

2018-06-01

Malignant brain tumors still represent an unmet medical need given their rapid progression and often fatal outcome within months of diagnosis. Given their extremely heterogeneous nature, the assumption that a single therapy could be beneficial for all patients is no longer plausible. Hence, early feedback on drug accumulation at the tumor site and on tumor response to treatment would help tailor therapies to each patient's individual needs for personalized medicine. In this context, at the intersection between imaging and therapy, theranostic nanomedicine is a promising new technique for individualized management of malignant brain tumors. Although brain nanotheranostics has yet to be translated into clinical practice, this field is now a research hotspot due to the growing demand for personalized therapies. In this review, the barriers to the clinical implementation of theranostic nanomedicine for tracking tumor responses to treatment and for guiding stimulus-activated therapies and surgical resection of malignant brain tumors are discussed. Likewise, the criteria that nanotheranostic systems need to fulfil to become clinically relevant formulations are analyzed in depth, focusing on theranostic agents already tested in vivo. Currently, magnetic nanoparticles exploiting brain targeting strategies represent the first generation of preclinical theranostic nanomedicines for the management of malignant brain tumors. The development of nanocarriers that can be used both in imaging studies and the treatment of brain tumors could help identify which patients are most and least likely to respond to a given treatment. This will enable clinicians to adapt the therapy to the needs of the patient and avoid overdosing non-responders. Given the many different approaches to non-invasive techniques for imaging and treating brain tumors, it is important to focus on the strategies most likely to be implemented and to design the most feasible theranostic biomaterials that will bring nanotheranostics one step closer to clinical practice. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Complete prevalence of malignant primary brain tumors registry data in the United States compared with other common cancers, 2010

PubMed Central

Zhang, Adah S.; Ostrom, Quinn T.; Kruchko, Carol; Rogers, Lisa; Peereboom, David M.

2017-01-01

Abstract Background. Complete prevalence proportions illustrate the burden of disease in a population. This study estimates the 2010 complete prevalence of malignant primary brain tumors overall and by Central Brain Tumor Registry of the United States (CBTRUS) histology groups, and compares the brain tumor prevalence estimates to the complete prevalence of other common cancers as determined by the Surveillance, Epidemiology, and End Results Program (SEER) by age at prevalence (2010): children (0–14 y), adolescent and young adult (AYA) (15–39 y), and adult (40+ y). Methods. Complete prevalence proportions were estimated using a novel regression method extended from the Completeness Index Method, which combines survival and incidence data from multiple sources. In this study, two datasets, CBTRUS and SEER, were used to calculate complete prevalence estimates of interest. Results. Complete prevalence for malignant primary brain tumors was 47.59/100000 population (22.31, 48.49, and 57.75/100000 for child, AYA, and adult populations). The most prevalent cancers by age were childhood leukemia (36.65/100000), AYA melanoma of the skin (66.21/100000), and adult female breast (1949.00/100000). The most prevalent CBTRUS histologies in children and AYA were pilocytic astrocytoma (6.82/100000, 5.92/100000), and glioblastoma (12.76/100000) in adults. Conclusions. The relative impact of malignant primary brain tumors is higher among children than any other age group; it emerges as the second most prevalent cancer among children. Complete prevalence estimates for primary malignant brain tumors fills a gap in overall cancer knowledge, which provides critical information toward public health and health care planning, including treatment, decision making, funding, and advocacy programs. PMID:28039365

New developments in surgery of malignant gliomas

PubMed Central

Vranic, Andrej

2011-01-01

Background Malignant gliomas account for a high proportion of brain tumours. With new advances in neurooncology, the recurrence-free survival of patients with malignant gliomas has been substantially prolonged. It, however, remains dependent on the thoroughness of the surgical resection. The maximal tumour resection without additional postoperative deficit is the goal of surgery on patients with malignant gliomas. In order to minimize postoperative deficit, several pre- and intraoperative techniques have been developed. Conclusions Several techniques used in malignant glioma surgery have been developed, including microsurgery, neuroendoscopy, stereotactic biopsy and brachytherapy. Imaging and functional techniques allowing for safer tumour resection have a special value. Imaging techniques allow for better preoperative visualization and choice of the approach, while functional techniques help us locate eloquent regions of the brain. PMID:22933950

A 6-month follow-up of an RCT on behavioral and neurocognitive effects of neurofeedback in children with ADHD.

PubMed

Geladé, Katleen; Janssen, Tieme W P; Bink, Marleen; Twisk, Jos W R; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2018-05-01

To assess the long-term effects of neurofeedback (NFB) in children with attention deficit hyperactivity disorder (ADHD), we compared behavioral and neurocognitive outcomes at a 6-month naturalistic follow-up of a randomized controlled trial on NFB, methylphenidate (MPH), and physical activity (PA). Ninety-two children with a DSM-IV-TR ADHD diagnosis, aged 7-13, receiving NFB (n = 33), MPH (n = 28), or PA (n = 31), were re-assessed 6-months after the interventions. NFB comprised theta/beta training on the vertex (cortical zero). PA comprised moderate to vigorous intensity exercises. Outcome measures included parent and teacher behavioral reports, and neurocognitive measures (auditory oddball, stop-signal, and visual spatial working memory tasks). At follow-up, longitudinal hierarchical multilevel model analyses revealed no significant group differences for parent reports and neurocognitive measures (p = .058-.997), except for improved inhibition in MPH compared to NFB (p = .040) and faster response speed in NFB compared to PA (p = .012) during the stop-signal task. These effects, however, disappeared after controlling for medication use at follow-up. Interestingly, teacher reports showed less inattention and hyperactivity/impulsivity at follow-up for NFB than PA (p = .004-.010), even after controlling for medication use (p = .013-.036). Our findings indicate that the superior results previously found for parent reports and neurocognitive outcome measures obtained with MPH compared to NFB and PA post intervention became smaller or non-significant at follow-up. Teacher reports suggested superior effects of NFB over PA; however, some children had different teachers at follow-up. Therefore, this finding should be interpreted with caution. Clinical trial registration Train your brain and exercise your heart? Advancing the treatment for Attention Deficit Hyperactivity Disorder (ADHD), Ref. no. NCT01363544, https://clinicaltrials.gov/show/NCT01363544 .

An RCT into the effects of neurofeedback on neurocognitive functioning compared to stimulant medication and physical activity in children with ADHD.

PubMed

Geladé, Katleen; Bink, Marleen; Janssen, Tieme W P; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2017-04-01

Neurofeedback (NFB) is a potential alternative treatment for children with ADHD that aims to optimize brain activity. Whereas most studies into NFB have investigated behavioral effects, less attention has been paid to the effects on neurocognitive functioning. The present randomized controlled trial (RCT) compared neurocognitive effects of NFB to (1) optimally titrated methylphenidate (MPH) and (2) a semi-active control intervention, physical activity (PA), to control for non-specific effects. Using a multicentre three-way parallel group RCT design, children with ADHD, aged 7-13, were randomly allocated to NFB (n = 39), MPH (n = 36) or PA (n = 37) over a period of 10-12 weeks. NFB comprised theta/beta training at CZ. The PA intervention was matched in frequency and duration to NFB. MPH was titrated using a double-blind placebo controlled procedure to determine the optimal dose. Neurocognitive functioning was assessed using parameters derived from the auditory oddball-, stop-signal- and visual spatial working memory task. Data collection took place between September 2010 and March 2014. Intention-to-treat analyses showed improved attention for MPH compared to NFB and PA, as reflected by decreased response speed during the oddball task [η p 2  = 0.21, p < 0.001], as well as improved inhibition, impulsivity and attention, as reflected by faster stop signal reaction times, lower commission and omission error rates during the stop-signal task (range η p 2  = 0.09-0.18, p values <0.008). Working memory improved over time, irrespective of received treatment (η p 2  = 0.17, p < 0.001). Overall, stimulant medication showed superior effects over NFB to improve neurocognitive functioning. Hence, the findings do not support theta/beta training applied as a stand-alone treatment in children with ADHD.

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder.

PubMed

Findling, Robert L; Quinn, Declan; Hatch, Simon J; Cameron, Sara J; DeCory, Heleen H; McDowell, Michael

2006-12-01

To compare the efficacy and safety of two methylphenidate (MPH) formulations--once-daily modified-release MPH (EqXL, Equasym XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin)--and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Children aged 6-12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher's IOWA Conners' Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (-1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.

Methylphenidate-induced motor activity in rats: modulation by melatonin and vasopressin.

PubMed

Appenrodt, Edgar; Schwarzberg, Helmut

2003-04-01

Methylphenidate (MPH), a dopamine (DA) reuptake inhibitor, is well known to enhance motor activity, in part depending on the time of its application during the light-dark cycle. Moreover, after MPH administration, the hypothalamo-neurohypophysial axis including the neuropeptide vasopressin (AVP) was found influenced. Both the latter and behavioural effects of central AVP can also be modulated by the pineal gland with its light-dark-dependent activity. The present study was performed to investigate whether the pineal gland, its hormone melatonin (Mel), and AVP are involved in the MPH-evoked stimulation of activity. After application of 10 mg/kg MPH, the motor activity in pinealectomised (PE) rats was significantly higher than in sham-operated (SO) animals. After application of 250 microg Mel before MPH treatment, the stimulation of motor activity was diminished in PE rats and augmented in SO animals; however, when SO and PE rats were compared after Mel pretreatment, the reaction to MPH was nearly identical. Blocking the endogenous AVP by 25 or 1 microg of the V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP (AAVP) before MPH treatment significantly augmented the motor activity in SO rats only and abolished the differences seen between SO and PE animals after MPH application. The present results indicate that the behavioural stimulation of MPH was modulated by both the pineal gland with its hormone Mel as well as the neuropeptide AVP.

76 FR 31800 - Airworthiness Directives; Viking Air Limited Model DHC-3 (Otter) Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-02

...: ``Airspeed limitation: VMO = 144 MPH for the effective date of this land/ski plane and VMO = 134 MPH for... limit for land/ in-service (TIS) after the ski plane and 134 MPH, VMO speed limit for seaplane... land/ski the effective date of this plane and/or with a red radial at 134 MPH for a seaplane. This...

Results of baseline tests of the Lucas Limousine

NASA Technical Reports Server (NTRS)

Soltis, R. F.; Dustin, M. O.; Sargent, N. B.

1977-01-01

The Lucas Limousine, an electric vehicle, was tested to assess the state-of-the-art of electric vehicles. All tests were made without the regenerative braking system and were conducted at the gross vehicle weight of 7,700 pounds. Over a 30 mph stop and go driving cycle the vehicle went 48.4 miles. The vehicle was able to accelerate to 30 mph in about 15 seconds with a gradeability limit of 16.5 percent. As determined by coast down tests the road power and road energy consumption for the vehicle were 2.92 kilowatts and 0.146 kWh/mi, respectively, at 20 mph. At 40 mph the road power requirement was 11.12 kilowatts and the road energy requirement was 0.278 kWh/mi. The maximum energy economy measured 0.45 kilowatt hours per mile at 30 mph and increased to 0.76 kilowatt hours per mile at 50 mph. Over the 30 mph stop and go driving cycle the energy economy was 0.92 kilowatt hours per mile.

Early Non Invasive Ventilation and Hematological Malignancies

ClinicalTrials.gov

2018-01-03

Hematological Malignancies; Chronic Hypoxemic Respiratory Failure; Blood And Marrow Transplantation; Malignant Neoplasm of Breast; Malignant Neoplasms of Bone and Articular Cartilage; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic

Validation of the National Institutes of Health Patient-Reported Outcomes Measurement Information System Survey as a Quality-of-Life Instrument for Patients with Malignant Brain Tumors and Their Caregivers.

PubMed

Romero, Melissa M; Flood, Lisa Sue; Gasiewicz, Nanci K; Rovin, Richard; Conklin, Samantha

2015-12-01

At present there is a lack of well-validated surveys used to measure quality of life in patients with malignant brain tumors and their caregivers. The main objective of this pilot study was to validate the National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH PROMIS) survey for use as a quality-of-life measure in this population. This article presents the rationale for using the NIH PROMIS instrument as a quality-of-life measure for patients with malignant brain tumors and their caregivers. Copyright © 2015 Elsevier Inc. All rights reserved.

A multicenter study of primary brain tumor incidence in Australia (2000–2008)

PubMed Central

Dobes, Martin; Shadbolt, Bruce; Khurana, Vini G.; Jain, Sanjiv; Smith, Sarah F.; Smee, Robert; Dexter, Mark; Cook, Raymond

2011-01-01

There are conflicting reports from Europe and North America regarding trends in the incidence of primary brain tumor, whereas the incidence of primary brain tumors in Australia is currently unknown. We aimed to determine the incidence in Australia with age-, sex-, and benign-versus-malignant histology-specific analyses. A multicenter study was performed in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), which has a combined population of >7 million with >97% rate of population retention for medical care. We retrospectively mined pathology databases servicing neurosurgical centers in NSW and ACT for histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008. Data were weighted for patient outflow and data completeness. Incidence rates were age standardized and trends analyzed using joinpoint analysis. A weighted total of 7651 primary brain tumors were analyzed. The overall US-standardized incidence of primary brain tumors was 11.3 cases 100 000 person-years (±0.13; 95% confidence interval, 9.8–12.3) during the study period with no significant linear increase. A significant increase in primary malignant brain tumors from 2000 to 2008 was observed; this appears to be largely due to an increase in malignant tumor incidence in the ≥65-year age group. This collection represents the most contemporary data on primary brain tumor incidence in Australia. Whether the observed increase in malignant primary brain tumors, particularly in persons aged ≥65 years, is due to improved detection, diagnosis, and care delivery or a true change in incidence remains undetermined. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence that can be independent of multiple interstate cancer registries. PMID:21727214

Brain Cancer—Patient Version

Cancer.gov

Brain cancer refers to growths of malignant cells in tissues of the brain. Tumors that start in the brain are called primary brain tumors. Tumors that spread to the brain are called metastatic brain tumors. Start here to find information on brain cancer treatment, research, and statistics.

40 CFR Appendix I to Part 600 - Highway Fuel Economy Driving Schedule (Applicable to 1978 and Later Model Year Automobiles)

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 30 2011-07-01 2011-07-01 false Highway Fuel Economy Driving Schedule (Applicable to 1978 and Later Model Year Automobiles) I Appendix I to Part 600 Protection of Environment... to 1978 and Later Model Year Automobiles) [ speed (mph) vs time (sec) ] SEC MPH SEC MPH SEC MPH SEC...

Validity of the Smarthealth Watch to Measure Heart Rate during Rest and Exercise

ERIC Educational Resources Information Center

Lee, C. Matthew; Gorelick, Mark

2011-01-01

The purpose of this study was to examine the validity of the Smarthealth watch (Salutron, Inc., Fremont, California, USA), a heart rate monitor that includes a wristwatch without an accompanying chest strap. Twenty-five individuals participated in 3-min periods of standing, 2.0 mph walking, 3.5 mph walking, 4.5 mph jogging, and 6.0 mph running.…

Effects of Methylphenidate on Sleep Functioning in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Becker, Stephen P; Froehlich, Tanya E; Epstein, Jeffery N

2016-06-01

To examine the effects of stimulant medication on the sleep functioning of children with attention-deficit/hyperactivity disorder (ADHD) and identify predictors of sleep problems as a side effect of taking stimulant medication. One hundred sixty-three stimulant-naïve children (72% boys) aged 7 to 11 years diagnosed with ADHD (120 with ADHD predominantly inattentive type, 43 with ADHD combined type) participated in a 4-week, randomized, double-blind, placebo-controlled trial of once-daily (long-acting) methylphenidate (MPH). Parents completed weekly side-effect ratings including an item related to sleep problems. Ten percent of patients had parent-rated sleep problems before the initiation of medication. Rates of parent-rated sleep problems during MPH titration generally increased with increasing MPH dose (placebo: 8%; low dose: 18%; medium dose: 15%; high dose: 25%). Differences emerged between children with (n = 16) or without (n = 147) preexisting sleep problems. Although 23% of children without preexisting sleep problems went on to have sleep problems at the highest MPH dose, only 37.5% of children with preexisting sleep problems still had sleep problems at the highest MPH dose. Lower weight and lower body mass index (BMI) were associated with increased sleep problems during MPH titration. This study demonstrated a general association between increased MPH dose and increased sleep problems in children with ADHD, particularly for children of lower weight/BMI. However, a substantial proportion of children with preexisting sleep difficulties no longer had sleep problems on the highest MPH dose, which may help explain mixed findings reported to date in studies examining the impact of MPH on sleep functioning in children with ADHD and suggests that MPH dose titration should not be avoided solely on the basis of a child's premorbid sleep problems. Future research is needed to replicate and extend these findings to more specific domains of sleep functioning and to identify differences between children with persistent or improved sleep functioning as a result of MPH use.

Preparing Master of Public Health Graduates to Work in Local Health Departments.

PubMed

Hemans-Henry, Calaine; Blake, Janice; Parton, Hilary; Koppaka, Ram; Greene, Carolyn M

2016-01-01

To identify key competencies and skills that all master of public health (MPH) graduates should have to be prepared to work in a local health department. In 2011-2012, the New York City Department of Health and Mental Hygiene administered electronic surveys to 2 categories of staff: current staff with an MPH as their highest degree, and current hiring managers. In all, 312 (77%) staff members with an MPH as their highest degree and 170 (57%) hiring managers responded to the survey. Of the respondents with an MPH as their highest degree, 85% stated that their MPH program prepared them for work at the New York City Health Department. Skills for which MPH graduates most often stated they were underprepared included facility in using SAS® statistical software, quantitative data analysis/statistics, personnel management/leadership, and data collection/database management/data cleaning. Among the skills hiring managers identified as required of MPH graduates, the following were most often cited as those for which newly hired MPH graduates were inadequately prepared: quantitative data analysis, researching/conducting literature reviews, scientific writing and publication, management skills, and working with contracts/requests for proposals. These findings suggest that MPH graduates could be better prepared to work in a local health department upon graduation. To be successful, new MPH graduate hires should possess fundamental skills and knowledge related to analysis, communication, management, and leadership. Local health departments and schools of public health must each contribute to the development of the current and future public health workforce through both formal learning opportunities and supplementary employment-based training to reinforce prior coursework and facilitate practical skill development.

Current status of master of public health programmes in India: a scoping review.

PubMed

Tiwari, Ritika; Negandhi, Himanshu; Zodpey, Sanjay

2018-04-01

There is a recognized need to improve training in public health in India. Currently, several Indian institutions and universities offer the Master of Public Health (MPH) programme. However, in the absence of any formal body or council for regulating public health education in the country, there is limited information available on these programmes. This scoping review was therefore undertaken to review the current status of MPH programmes in India. Information on MPH programmes was obtained using a two-step process. First, a list of all institutions offering MPH programmes in India was compiled by use of an internet and literature search. Second, detailed information on each programme was collected via an internet and literature search and through direct contact with the institutions and recognized experts in public health education. Between 1997 and 2016-2017, the number of institutions offering MPH programmes increased from 2 to 44. The eligibility criteria for the MPH programmes are variable. All programmes include some field experience. The ratio of faculty number to students enrolled ranged from 1:0.1 to 1:42. In the 2016-2017 academic year, 1190 places were being offered on MPH programmes but only 704 students were enrolled. MPH programmes being offered in India have witnessed a rapid expansion in the past two decades. This growth in supply of public health graduates is not yet matched by an increased demand. Despite the recognized need to strengthen the public health workforce in India, there is no clearly defined career pathway for MPH graduates in the national public health infrastructure. Institutions and public health bodies must collaborate to design and deliver MPH programmes to overcome the shortage of public health professionals, such that the development goals for India might be met.

Differentiation of rodent behavioral phenotypes and methylphenidate action in sustained and flexible attention tasks.

PubMed

Chu, Richard; Shumsky, Jed; Waterhouse, Barry D

2016-06-15

Methyphenidate (MPH) is the primary drug treatment of choice for ADHD. It is also frequently used off-label as a cognitive enhancer by otherwise healthy individuals from all age groups and walks of life. Military personnel, students, and health professionals use MPH illicitly to increase attention and improve workplace performance over extended periods of work activity. Despite the frequency of its use, the efficacy of MPH to enhance cognitive function across individuals and in a variety of circumstances is not well characterized. We sought to better understand MPH׳s cognitive enhancing properties in two different rodent models of attention. We found that MPH could enhance performance in a sustained attention task, but that its effects in this test were subject dependent. More specifically, MPH increased attention in low baseline performing rats but had little to no effect on high performing rats. MPH exerted a similar subject specific effect in a test of flexible attention, i.e. the attention set shifting task. In this test MPH increased behavioral flexibility in animals with poor flexibility but impaired performance in more flexible animals. Overall, our results indicate that the effects of MPH are subject-specific and depend on the baseline level of performance. Furthermore, good performance in in the sustained attention task was correlated with good performance in the flexible attention task; i.e. animals with better vigilance exhibited greater behavioral flexibility. The findings are discussed in terms of potential neurobiological substrates, in particular noradrenergic mechanisms, that might underlie subject specific performance and subject specific responses to MPH. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

Wind tunnel test of Teledyne Geotech model 1564B cup anemometer

NASA Astrophysics Data System (ADS)

Parker, M. J.; Addis, R. P.

1991-04-01

The Department of Energy (DOE) Environment, Safety, and Health Compliance Assessment (Tiger Team) of the Savannah River Site (SRS) questioned the method by which wind speed sensors (cup anemometers) are calibrated by the Environmental Technology Section (ETS). The Tiger Team member was concerned that calibration data was generated by running the wind tunnel to only 26 miles per hour (mph) when speeds exceeding 50 mph are readily obtainable. A wind tunnel experiment was conducted and confirmed the validity of the practice. Wind speeds common to SRS (6 mph) were predicted more accurately by 0-25 mph regression equations than 0-50 mph regression equations. Higher wind speeds were slightly overpredicted by the 0-25 mph regression equations when compared to 0-50 mph regression equations. However, the greater benefit of more accurate lower wind speed predictions accuracy outweigh the benefit of slightly better high (extreme) wind speed predictions. Therefore, it is concluded that 0-25 mph regression equations should continue to be utilized by ETS at SRS. During the Department of Energy Tiger Team audit, concerns were raised about the calibration of SRS cup anemometers. Wind speed is measured by ETS with Teledyne Geotech model 1564B cup anemometers, which are calibrated in the ETS wind tunnel. Linear regression lines are fitted to data points of tunnel speed versus anemometer output voltages up to 25 mph. The regression coefficients are then implemented into the data acquisition computer software when an instrument is installed in the field. The concern raised was that since the wind tunnel at SRS is able to generate a maximum wind speed higher than 25 mph, errors may be introduced in not using the full range of the wind tunnel.

The Effect of Microporous Polysaccharide Hemospheres on Wound Healing and Scarring in Wild-Type and db/db Mice.

PubMed

Miller, Kyle J; Cao, Wei; Ibrahim, Mohamed M; Levinson, Howard

2017-04-01

Hemostasis, the initial phase of wound healing, sets the stage for tissue repair. Microporous polysaccharide hemosphere powder (MPH) is an FDA-approved hemostatic agent that may impact the wound-healing process. This study examined the role of MPH in murine wild-type and diabetic (db/db) wound-healing models and a foreign body response scarring model. The powder was topically applied to excisional wounds in wild-type C57BL/6 mice and db/db mice. The effect of MPH on scarring was evaluated by applying it to the expanded polytetrafluoroethylene tube implantation model. In wild-type mice, topically applied MPH increased epithelial thickness. Levels of α-smooth muscle actin (α-SMA) were decreased in MPH-treated wild-type wounds, whereas Rho-associated protein kinase 2 (ROCK2) and transforming growth factor β levels were increased. In db/db mice, topical wound MPH application decreased epithelial thickness and delayed wound closure. The db/db wounds displayed an increased collagen index. The ROCK2 was increased in a similar manner to wild-type mice, whereas α-SMA and transforming growth factor β levels were decreased. The MPH-treated expanded polytetrafluoroethylene tube mice showed increased α-SMA levels and depressed ROCK2 levels. There were no changes in histologic parameters of the foreign body response. The results suggest that MPH does not adversely impact wound healing in wild-type mice, both topically and around implants, but prolongs time to closure and diminishes thickness in db/db wounds. The MPH application alters contractile proteins in all wound models. These changes could have downstream effects on the wound healing process, and further investigation into the use of MPH in altered or impaired states of wound healing is warranted.

Study to Evaluate the Safety and Tolerability of Avelumab in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies

ClinicalTrials.gov

2018-04-27

Malignant Neoplasm of Breast; Malignant Neoplasms of Bone and Articular Cartilage; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Neoplasms of Uncertain or Unknown Behavior

Patterns of Invasive Growth in Malignant Gliomas-The Hippocampus Emerges as an Invasion-Spared Brain Region.

PubMed

Mughal, Awais A; Zhang, Lili; Fayzullin, Artem; Server, Andres; Li, Yuping; Wu, Yingxi; Glass, Rainer; Meling, Torstein; Langmoen, Iver A; Leergaard, Trygve B; Vik-Mo, Einar O

2018-05-21

Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a-/- PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the "lateral tumors" did not show signs of involvement of the amygdalo-hippocampal complex. Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

KSC-04pd1716

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, modules and equipment are being covered in plastic in preparation for the expected impact of Hurricane Frances on Saturday. KSC workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

Evaluation and reformulation of the maximum peak height algorithm (MPH) and application in a hypertrophic lagoon

NASA Astrophysics Data System (ADS)

Pitarch, Jaime; Ruiz-Verdú, Antonio; Sendra, María. D.; Santoleri, Rosalia

2017-02-01

We studied the performance of the MERIS maximum peak height (MPH) algorithm in the retrieval of chlorophyll-a concentration (CHL), using a matchup data set of Bottom-of-Rayleigh Reflectances (BRR) and CHL from a hypertrophic lake (Albufera de Valencia). The MPH algorithm produced a slight underestimation of CHL in the pixels classified as cyanobacteria (83% of the total) and a strong overestimation in those classified as eukaryotic phytoplankton (17%). In situ biomass data showed that the binary classification of MPH was not appropriate for mixed phytoplankton populations, producing also unrealistic discontinuities in the CHL maps. We recalibrated MPH using our matchup data set and found that a single calibration curve of third degree fitted equally well to all matchups regardless of how they were classified. As a modification to the former approach, we incorporated the Phycocyanin Index (PCI) in the formula, thus taking into account the gradient of phytoplankton composition, which reduced the CHL retrieval errors. By using in situ biomass data, we also proved that PCI was indeed an indicator of cyanobacterial dominance. We applied our recalibration of the MPH algorithm to the whole MERIS data set (2002-2012). Results highlight the usefulness of the MPH algorithm as a tool to monitor eutrophication. The relevance of this fact is higher since MPH does not require a complete atmospheric correction, which often fails over such waters. An adequate flagging or correction of sun glint is advisable though, since the MPH algorithm was sensitive to sun glint.

Mediators of methylphenidate effects on math performance in children with attention-deficit hyperactivity disorder.

PubMed

Froehlich, Tanya E; Antonini, Tanya N; Brinkman, William B; Langberg, Joshua M; Simon, John O; Adams, Ryan; Fredstrom, Bridget; Narad, Megan E; Kingery, Kathleen M; Altaye, Mekibib; Matheson, Heather; Tamm, Leanne; Epstein, Jeffery N

2014-01-01

Stimulant medications, such as methylphenidate (MPH), improve the academic performance of children with attention-deficit hyperactivity disorder (ADHD). However, the mechanism by which MPH exerts an effect on academic performance is unclear. We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task, inhibitory control, selective attention, and reaction time variability. Children with ADHD aged 7 to 11 years (N = 93) completed a timed math worksheet (with problems tailored to each individual's level of proficiency) and 2 neuropsychological tasks (Go/No-Go and Child Attention Network Test) at baseline, then participated in a 4-week, randomized, controlled, titration trial of MPH. Children were then randomly assigned to their optimal MPH dose or placebo for 1 week (administered double-blind) and repeated the math and neuropsychological tasks (posttest). Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task. Children taking MPH completed 23 more math problems at posttest compared to baseline, whereas the placebo group completed 24 fewer problems on posttest versus baseline, but the effects on math accuracy (percent correct) did not differ. Path analyses revealed that only change in time on-task was a significant mediator of MPH's improvements in math productivity. MPH-derived math productivity improvements may be explained in part by increased time spent on-task, rather than improvements in neurocognitive parameters, such as inhibitory control, selective attention, or reaction time variability.

Application of Physiologically Based Absorption Modeling to Characterize the Pharmacokinetic Profiles of Oral Extended Release Methylphenidate Products in Adults

PubMed Central

Yang, Xiaoxia; Duan, John; Fisher, Jeffrey

2016-01-01

A previously presented physiologically-based pharmacokinetic model for immediate release (IR) methylphenidate (MPH) was extended to characterize the pharmacokinetic behaviors of oral extended release (ER) MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI) tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations. A variety of mathematical functions can be utilized to account for the engineered release/dissolution technologies to achieve better model performance. The physiological absorption model tracked well the plasma concentration profiles in adults receiving a multilayer-release MPH formulation or Metadate CD, while some degree of discrepancy was observed between predicted and observed plasma concentration profiles for Ritalin LA and Medikinet Retard. A local sensitivity analysis demonstrated that model parameters associated with the GI tract significantly influenced model predicted plasma MPH concentrations, albeit to varying degrees, suggesting the importance of better understanding the GI tract physiology, along with the intestinal non-specific loss of MPH. The model provides a quantitative tool to predict the biphasic plasma time course data for ER MPH, helping elucidate factors responsible for the diverse plasma MPH concentration profiles following oral dosing of different ER formulations. PMID:27723791

Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates

PubMed Central

Yang, Xiaoxia; Morris, Suzanne M.; Gearhart, Jeffery M.; Ruark, Christopher D.; Paule, Merle G.; Slikker, William; Mattison, Donald R.; Vitiello, Benedetto; Twaddle, Nathan C.; Doerge, Daniel R.; Young, John F.; Fisher, Jeffrey W.

2014-01-01

The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species- and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra- and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH. PMID:25184666

MPH program adaptability in a competitive marketplace: the case for continued assessment.

PubMed

Caron, Rosemary M; Tutko, Holly

2010-06-01

In the last several years, the number of Master of Public Health (MPH) programs has increased rapidly in the US. As such, MPH programs, particularly smaller-sized ones, need to critically examine how their programs are meeting the needs and preferences of local public health practitioners. To assist in this necessity, the University of New Hampshire conducted a comprehensive educational assessment of its effectiveness as a smaller-sized, accredited MPH program. The aim of the assessment was to review the MPH program from the perspective of all stakeholders and then to agree on changes that would contribute to the fulfillment of the program's mission, as well as improve program quality and reach. The program's stakeholders examined the following components: policy development and implementation; target audience; marketing strategies; marketplace position; delivery model; curriculum design; and continuing education. Though assessment activities explored a wide array of program attributes, target audience, curriculum design, and delivery strategy presented significant challenges and opportunities for our smaller MPH Program to remain competitive. The effort put forth into conducting an in-depth assessment of the core components of our program also allowed for a comparison to the increasing number of MPH programs developing regionally. Since public health practice is changing and the education of public health practitioners must be adaptable, we propose that a routine assessment of an institution's MPH program could not only meet this need but also assist with keeping smaller, unbranded MPH programs competitive in a burgeoning marketplace.

Proceedings of the 2016 National Toxicology Program Satellite Symposium

PubMed Central

Elmore, Susan A.; Chen, Vivian S.; Hayes-Bouknight, Schantel; Hoane, Jessica S.; Janardhan, Kyathanahalli; Kooistra, Linda H.; Nolte, Thomas; Szabo, Kathleen A.; Willson, Gabrielle A.; Wolf, Jeffrey C.; Malarkey, David E.

2016-01-01

The 2016 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri” was held in San Diego, California, at the Society of Toxicologic Pathology’s (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers’ talks, along with select images that were used by the audience for voting and discussion. Some lesions and topics covered during the symposium included malignant glioma and histiocytic sarcoma in the rodent brain; a new statistical method designed for histopathology data evaluation; uterine stromal/glandular polyp in a rat; malignant plasma cell tumor in a mouse brain; Schwann cell proliferative lesions in rat hearts; axillary schwannoma in a cat; necrosis and granulomatous inflammation in a rat brain; adenoma/carcinoma in a rat adrenal gland; hepatocyte maturation defect and liver/spleen hematopoietic defects in an embryonic mouse; distinguishing malignant glioma, malignant mixed glioma and malignant oligodendroglioma in the rat; comparison of mammary gland whole mounts and histopathology from mice; and discussion of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) collaborations. PMID:27821709

Boron Neutron Capture Therapy for Malignant Brain Tumors

PubMed Central

MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

Boron Neutron Capture Therapy for Malignant Brain Tumors.

PubMed

Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji

2016-07-15

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.

Proceedings of the 2016 National Toxicology Program Satellite Symposium.

PubMed

Elmore, Susan A; Chen, Vivian S; Hayes-Bouknight, Schantel; Hoane, Jessica S; Janardhan, Kyathanahalli; Kooistra, Linda H; Nolte, Thomas; Szabo, Kathleen A; Willson, Gabrielle A; Wolf, Jeffrey C; Malarkey, David E

2017-01-01

The 2016 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in San Diego, CA, at the Society of Toxicologic Pathology's (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks, along with select images that were used by the audience for voting and discussion. Some lesions and topics covered during the symposium included malignant glioma and histiocytic sarcoma in the rodent brain; a new statistical method designed for histopathology data evaluation; uterine stromal/glandular polyp in a rat; malignant plasma cell tumor in a mouse brain; Schwann cell proliferative lesions in rat hearts; axillary schwannoma in a cat; necrosis and granulomatous inflammation in a rat brain; adenoma/carcinoma in a rat adrenal gland; hepatocyte maturation defect and liver/spleen hematopoietic defects in an embryonic mouse; distinguishing malignant glioma, malignant mixed glioma, and malignant oligodendroglioma in the rat; comparison of mammary gland whole mounts and histopathology from mice; and discussion of the International Harmonization of Nomenclature and Diagnostic Criteria collaborations.

Vascular Gene Expression in Nonneoplastic and Malignant Brain

PubMed Central

Madden, Stephen L.; Cook, Brian P.; Nacht, Mariana; Weber, William D.; Callahan, Michelle R.; Jiang, Yide; Dufault, Michael R.; Zhang, Xiaoming; Zhang, Wen; Walter-Yohrling, Jennifer; Rouleau, Cecile; Akmaev, Viatcheslav R.; Wang, Clarence J.; Cao, Xiaohong; St. Martin, Thia B.; Roberts, Bruce L.; Teicher, Beverly A.; Klinger, Katherine W.; Stan, Radu-Virgil; Lucey, Brenden; Carson-Walter, Eleanor B.; Laterra, John; Walter, Kevin A.

2004-01-01

Malignant gliomas are uniformly lethal tumors whose morbidity is mediated in large part by the angiogenic response of the brain to the invading tumor. This profound angiogenic response leads to aggressive tumor invasion and destruction of surrounding brain tissue as well as blood-brain barrier breakdown and life-threatening cerebral edema. To investigate the molecular mechanisms governing the proliferation of abnormal microvasculature in malignant brain tumor patients, we have undertaken a cell-specific transcriptome analysis from surgically harvested nonneoplastic and tumor-associated endothelial cells. SAGE-derived endothelial cell gene expression patterns from glioma and nonneoplastic brain tissue reveal distinct gene expression patterns and consistent up-regulation of certain glioma endothelial marker genes across patient samples. We define the G-protein-coupled receptor RDC1 as a tumor endothelial marker whose expression is distinctly induced in tumor endothelial cells of both brain and peripheral vasculature. Further, we demonstrate that the glioma-induced gene, PV1, shows expression both restricted to endothelial cells and coincident with endothelial cell tube formation. As PV1 provides a framework for endothelial cell caveolar diaphragms, this protein may serve to enhance glioma-induced disruption of the blood-brain barrier and transendothelial exchange. Additional characterization of this extensive brain endothelial cell gene expression database will provide unique molecular insights into vascular gene expression. PMID:15277233

Blood-Brain Barrier Permeable Gold Nanoparticles: An Efficient Delivery Platform for Enhanced Malignant Glioma Therapy and Imaging

PubMed Central

Cheng, Yu; Dai, Qing; Morshed, Ramin; Fan, Xiaobing; Wegscheid, Michelle L.; Wainwright, Derek A.; Han, Yu; Zhang, Lingjiao; Auffinger, Brenda; Tobias, Alex L.; Rincón, Esther; Thaci, Bart; Ahmed, Atique U.; Warnke, Peter; He, Chuan

2014-01-01

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, we demonstrate that a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd3+ contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, we demonstrate that TAT-Au NPs are capable of delivering Gd3+ chelates for enhanced brain tumor imaging with a prolonged retention time of Gd3+ when compared to the free Gd3+ chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging. PMID:25104165

42 CFR Appendix A to Part 81 - Glossary of ICD-9 Codes and Their Cancer Descriptions 1

Code of Federal Regulations, 2013 CFR

2013-10-01

... Malignant neoplasm of brain. 192 Malignant neoplasm of other and unspecified parts of nervous system. 193... and ill-defined sites within the respiratory system and intrathoracic organs. 170 Malignant neoplasm...

42 CFR Appendix A to Part 81 - Glossary of ICD-9 Codes and Their Cancer Descriptions 1

Code of Federal Regulations, 2014 CFR

2014-10-01

... Malignant neoplasm of brain. 192 Malignant neoplasm of other and unspecified parts of nervous system. 193... and ill-defined sites within the respiratory system and intrathoracic organs. 170 Malignant neoplasm...

42 CFR Appendix A to Part 81 - Glossary of ICD-9 Codes and Their Cancer Descriptions 1

Code of Federal Regulations, 2012 CFR

2012-10-01

... Malignant neoplasm of brain. 192 Malignant neoplasm of other and unspecified parts of nervous system. 193... and ill-defined sites within the respiratory system and intrathoracic organs. 170 Malignant neoplasm...

42 CFR Appendix A to Part 81 - Glossary of ICD-9 Codes and Their Cancer Descriptions 1

Code of Federal Regulations, 2011 CFR

2011-10-01

... Malignant neoplasm of brain. 192 Malignant neoplasm of other and unspecified parts of nervous system. 193... and ill-defined sites within the respiratory system and intrathoracic organs. 170 Malignant neoplasm...

Wavelet-domain de-noising of OCT images of human brain malignant glioma

NASA Astrophysics Data System (ADS)

Dolganova, I. N.; Aleksandrova, P. V.; Beshplav, S.-I. T.; Chernomyrdin, N. V.; Dubyanskaya, E. N.; Goryaynov, S. A.; Kurlov, V. N.; Reshetov, I. V.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have proposed a wavelet-domain de-noising technique for imaging of human brain malignant glioma by optical coherence tomography (OCT). It implies OCT image decomposition using the direct fast wavelet transform, thresholding of the obtained wavelet spectrum and further inverse fast wavelet transform for image reconstruction. By selecting both wavelet basis and thresholding procedure, we have found an optimal wavelet filter, which application improves differentiation of the considered brain tissue classes - i.e. malignant glioma and normal/intact tissue. Namely, it allows reducing the scattering noise in the OCT images and retaining signal decrement for each tissue class. Therefore, the observed results reveals the wavelet-domain de-noising as a prospective tool for improved characterization of biological tissue using the OCT.

A Randomized Controlled Trial Investigating the Effects of Neurofeedback, Methylphenidate, and Physical Activity on Event-Related Potentials in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Janssen, Tieme Willem Pieter; Bink, Marleen; Geladé, Katleen; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2016-05-01

Electroencephalographic (EEG) neurofeedback (NF) is considered a nonpharmacological alternative for medication in attention-deficit/hyperactivity disorder (ADHD). Comparisons of the behavioral efficacy of NF and medication have produced inconsistent results. EEG measures can provide insight into treatment mechanisms, but have received little consideration. In this randomized controlled trial (RCT), effects of NF were compared with methylphenidate (MPH), and physical activity (PA) in children with ADHD on event-related potential (ERP) indices of response inhibition, which are involved in ADHD psychopathology. Using a multicenter three way parallel group RCT design, 112 children with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (American Psychiatric Association 1994 ) diagnosis of ADHD, between 7 and 13 years of age, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10 week period. PA training was a semiactive control group, matched in frequency and duration. MPH was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. ERP measures of response inhibition, N2 and P3, were available for 81 children at pre- and postintervention (n = 32 NF, n = 25 MPH, n = 24 PA). Only the medication group showed a specific increase in P3 amplitude compared with NF (partial eta-squared [ηp(2) ] = 0.121) and PA (ηp(2) = 0.283), which was related to improved response inhibition. Source localization of medication effects on P3 amplitude indicated increased activation primarily in thalamic and striatal nuclei. This is the first study that simultaneously compared NF with stimulant treatment and a semiactive control group. Only stimulant treatment demonstrated specific improvements in brain function related to response inhibition. These results are in line with recent doubts on the efficacy and specificity of NF as treatment for ADHD. Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/NCT01363544 , Ref. No. NCT01363544.

Methylphenidate as a treatment for stuttering: a case report.

PubMed

Devroey, D; Beerens, G; Van De Vijver, E

2012-10-01

A randomized placebo controlled trial with methylphenidate (MPH) was set up to identify the effects of MPH on cognition in healthy young adults (ea. without attention deficit hyperactivity disorder, ADHD). Subjects repeatedly performed tests of the immediate and delayed memory and vigilance tasks after administration of placebo or 20 mg MPH. We report the case of an 18 year old man who participated in the study. He suffered from stuttering since childhood. During the study phase he reported a remarkable relief of the stuttering after the intake of 20 mg MPH. For D-amphetamine the beneficial effect on stuttering has been demonstrated but it was never implemented in clinical practice because of important adverse events. MPH, an amphetamine analogue, doesn't present these side effects. For this reason, MPH seems to merit further investigation in a randomized-controlled trial as a possible agent in the treatment of stuttering.Methylphenidate, Stuttering.

KSC-04pd1714

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, workers cover with plastic the Multi-Purpose Logistics Module Donatello in preparation for the expected impact of Hurricane Frances on Saturday. Other modules and equipment are being covered as well. Workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1712

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, workers cover with plastic the U.S. Node 2 in preparation for the expected impact of Hurricane Frances on Saturday. Other modules and equipment are being covered as well. Workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1713

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, workers cover with plastic the Multi-Purpose Logistics Module Raffaello in preparation for the expected impact of Hurricane Frances on Saturday. Other modules and equipment are being covered as well. Workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1715

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, modules wrapped in plastic line one wall. The modules and equipment are being covered in preparation for the expected impact of Hurricane Frances on Saturday. KSC workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

Effect of transitioning from extended-release methylphenidate onto osmotic, controlled-release methylphenidate in children/adolescents with ADHD: results of a 3-month non-interventional study.

PubMed

Wolff, Christian; Alfred, Adam; Lindermüller, Anton; Rettig, Klaus; Mattejat, Fritz; Gerwe, Martin; Slawik, Lara; Schäuble, Barbara

2011-01-01

To explore the clinical outcomes of children/adolescents with ADHD who transitioned from extended-release methylphenidate (ER MPH, Medikinet Retard) to osmotic release oral system (OROS) MPH (Concerta). Medikinet Retard is a registered trade name of Medice, Bad Iserlohn, Germany. Concerta is a registered trade name of Janssen-Cilag GmbH, Neuss, Germany. This prospective, non-interventional study included patients aged 6 to 18 years with a confirmed diagnosis of ADHD who experienced insufficient clinical response and/or poor tolerability on ER MPH. Patients transitioned onto OROS MPH and were followed for 12 weeks. Symptoms, functional outcome, health-related quality of life, safety and tolerability were assessed. 180 patients were included in the intention-to-treat analysis. The mean ER MPH dose before switching was 28.2 mg/day; mean OROS MPH starting dose was 38.1 mg/day, increasing to 41.2 mg/day at the final visit. Mean treatment duration was 79.49 ± 24.22 days (median 85; range 7-136). Several symptomatic and functional outcomes under OROS MPH treatment changed from baseline and included the Conners' Parent Rating Scale (CPRS; -11.7 ± 11.3; p < 0.0001), C-GAS (12.3 ± 15.2; p < 0.0001) and ILC-LQ0-28 (parents' rating 2.9 ± 4.3 and patients' rating 2.8 ± 3.8; both p < 0.0001). Improvements in social interactions, playing with other children, doing household chores, or school homework, going to bed, and behavior towards visitors/at visits were noted (p < 0.0001). Approximately 40% of patients reported better sleep quality and appetite (p < 0.0001), and 72.8% expressed satisfaction with OROS MPH therapy compared to previous ER MPH. OROS MPH was well tolerated; the most common AEs after switching, with an incidence >2% and possibly related to therapy, were involuntary muscle contractions (tics; 8.9%), insomnia (7.2%) and anorexia (5.0%). No relevant changes in body weight or vital signs were observed. Three patients reported four serious AEs, but none were considered related to OROS MPH. Limitations included those associated with the uncontrolled, open-label design, possible inclusion bias and non-validation of the CPRS in a German population. Transitioning onto OROS MPH improved functionality, symptom control and decreased burden of disease in patients with ADHD who had insufficient response to, and/or poor tolerability of ER MPH. Similarly, care givers benefited from patients' treatment and reported significant reduction in their burden of disease and improvement of their quality of life upon the child's transition onto OROS MPH.

Complete prevalence of malignant primary brain tumors registry data in the United States compared with other common cancers, 2010

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

Zhang, Adah S.; Ostrom, Quinn T.; Kruchko, Carol

Complete prevalence proportions illustrate the burden of disease in a population. Here, this study estimates the 2010 complete prevalence of malignant primary brain tumors overall and by Central Brain Tumor Registry of the United States (CBTRUS) histology groups, and compares the brain tumor prevalence estimates to the complete prevalence of other common cancers as determined by the Surveillance, Epidemiology, and End Results Program (SEER) by age at prevalence (2010): children (0–14 y), adolescent and young adult (AYA) (15–39 y), and adult (40+ y).

Complete prevalence of malignant primary brain tumors registry data in the United States compared with other common cancers, 2010

DOE PAGES

Zhang, Adah S.; Ostrom, Quinn T.; Kruchko, Carol; ...

2016-12-29

Complete prevalence proportions illustrate the burden of disease in a population. Here, this study estimates the 2010 complete prevalence of malignant primary brain tumors overall and by Central Brain Tumor Registry of the United States (CBTRUS) histology groups, and compares the brain tumor prevalence estimates to the complete prevalence of other common cancers as determined by the Surveillance, Epidemiology, and End Results Program (SEER) by age at prevalence (2010): children (0–14 y), adolescent and young adult (AYA) (15–39 y), and adult (40+ y).

Novel Nanotechnologies for Brain Cancer Therapeutics and Imaging.

PubMed

Ferroni, Letizia; Gardin, Chiara; Della Puppa, Alessandro; Sivolella, Stefano; Brunello, Giulia; Scienza, Renato; Bressan, Eriberto; D'Avella, Domenico; Zavan, Barbara

2015-11-01

Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.

Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects

ClinicalTrials.gov

2018-06-20

Brain Cancer; Brain Neoplasm; Glioma; Glioblastoma; Gliosarcoma; Malignant Brain Tumor; Neoplasm, Neuroepithelial; Neuroectodermal Tumors; Neoplasm by Histologic Type; Neoplasm, Nerve Tissue; Nervous System Diseases

‘Why do an MPH?’ Motivations and intentions of physicians undertaking postgraduate public health training at the University of Cape Town

PubMed Central

Zweigenthal, Virginia E.M.; Marquez, Emma; London, Leslie

2016-01-01

Background Public health (PH) approaches underpin the management and transformation of health systems in low- and middle-income countries. Despite the Master of Public Health (MPH) rarely being a prerequisite for health service employment in South Africa, many physicians pursue MPH qualifications. Objectives This study identifies their motivations and career intentions and explored MPH programme strengths and gaps in under- and post-graduate PH training. Design A cross-sectional study using an online questionnaire was completed by physicians graduating with an MPH between 2000 and 2009 and those enrolled in the programme in 2010 at the University of Cape Town. Results Nearly a quarter of MPH students were physicians. Of the 65 contactable physicians, 48% responded. They were mid-career physicians who wished to obtain research training (55%), who wished to gain broader perspectives on health (32%), and who used the MPH to advance careers (90%) as researchers, policy-makers, or managers. The MPH widened professional opportunities, with 62% changing jobs. They believed that inadequate undergraduate exposure should be remedied by applying PH approaches to clinical problems in community settings, which would increase the attractiveness of postgraduate PH training. Conclusions The MPH allows physicians to transition from pure clinical to research, policy and/or management work, preparing them to innovate changes for effective health systems, responsive to the health needs of populations. Limited local job options and incentives are important constraining factors. Advocacy for positions requiring qualifications and benchmarking exit competencies of programmes nationally may promote enrolment. PMID:27741958

The effect of methylphenidate on sustained attention among adolescents with attention-deficit hyperactivity disorder.

PubMed

Lufi, Dubi; Bassin-Savion, Shiry; Rubel, Lilach

2015-01-01

Twenty-seven adolescents diagnosed as having attention-deficit hyperactivity disorder (ADHD) were tested twice with a computerized MATH-CPT (mathematics continuous performance test). In one administration, the participants took medication (methylphenidate, MPH) 1.5 hr before being tested. In another administration, the MATH-CPT was administered without the medication. Treatment with MPH improved the "overall attention level" and in measures of "reaction time" and "impulsivity." MPH did not improve the performance in the four measures of sustained attention. Knowing that treatment with MPH does not improve sustained attention can be helpful in reaching a decision of whether or not a child should be treated with MPH.

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

PubMed

Linssen, A M W; Sambeth, A; Vuurman, E F P M; Riedel, W J

2014-06-01

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Effects of methylphenidate on body index and physical fitness in Korean children with attention deficit hyperactivity disorder.

PubMed

Kang, Kyoung Doo; Yun, Sin Weon; Chung, Unsun; Kim, Tae Ho; Park, Jeong Ha; Park, In Hui; Han, Doug Hyun

2016-03-01

The side effects of methylphenidate (MPH) on growth remain a controversial concern. This study aimed to investigate the effect of MPH on clinical symptoms, growth, and physical fitness in Korean children. Fifty male children with attention deficit hyperactivity disorder (ADHD) treated with methylphenidate (MPH-ADHD), 69 MPH-naïve male children with ADHD (Naïve-ADHD), and 60 age-matched and sex-matched healthy control subjects were recruited. Intelligence quotient (IQ), clinical symptoms of ADHD, body index (height, weight, and body mass index [BMI]), and physical fitness (muscular strength, endurance, flexibility, agility, speed, and balance) were assessed. Total IQ and performance IQ scores were significantly different among the three groups, as were mean Korean Attention Deficit Hyperactivity Disorder (K-ARS)-total, K-ARS-inattention, and K-ARS-hyperactivity scores. There was no significant difference in height, weight, or BMI among the three groups. There were significant differences in skill-related fitness scores for balance (healthy controls > MPH-ADHD > Naïve-ADHD) and agility shuttle test time (healthy controls < MPH-ADHD < Naïve-ADHD). Our findings support the effectiveness of MPH treatment for improving IQ, attention, and balance and agility measures of skill-related fitness in Korean children with ADHD. MPH was not associated with growth delays in height, weight, and BMI. Copyright © 2016 John Wiley & Sons, Ltd.

Outcome and impact of Master of Public Health programs across six countries: education for change

PubMed Central

2014-01-01

Background The human resources for health crisis has highlighted the need for high-level public health education to add specific capacities to the workforce. Recently, it was questioned whether Master of Public Health (MPH) training prepared graduates with competencies relevant to low- and middle-income countries (LMICs). This study aims to examine the influence of the MPH programs geared towards LMICs offered in Vietnam, China, South Africa, Mexico, Sudan, and the Netherlands on graduates’ careers, application of acquired competencies, performance at the workplace, and their professional contribution to society. Methods A self-administered questionnaire was sent to graduates from six MPH programs. Frequency distributions of the answers were calculated, and a bivariate analysis and logistic regression of certain variables was performed. Results The response rate was 37.5%. Graduates reported change in leadership (69%), in technical position (69%), acquiring new responsibilities (80%), and increased remuneration (63%); they asserted that MPH programs contributed significantly to this. Graduates’ attribution of their application of 7 key competencies ‘substantially to the MPH program’ ranged from 33% to 48%. Of the 26 impact variables, graduates attributed the effect they had on their workplace substantially to the MPH program; the highest rated variable ranged from 31% to 73% and the lowest ranged from 9% to 43%. Of the 10 impact variables on society, graduates attributed the effect they had on society substantially to the MPH program; for the highest rated variable (13% to 71%); for the lowest rated variable (4% to 42%). Candidates’ attribution of their application of acquired competencies as well as their impact at the workplace varied significantly according to institution of study and educational background. Conclusions This study concludes that these MPH programs contribute to improving graduates’ careers and to building leadership in public health. The MPH programs contribute to graduates’ application of competencies. MPH programs contribute substantially towards impact variables on the workplace, such as development of research proposals and reporting on population health needs, and less substantially to their impact on society, such as contributing equitable access to quality services. Differences reported between MPH programs merit further study. The results can be used for curriculum reform. PMID:25099707

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence

PubMed Central

Dürsteler, Kenneth M; Berger, Eva-Maria; Strasser, Johannes; Caflisch, Carlo; Mutschler, Jochen; Herdener, Marcus; Vogel, Marc

2015-01-01

Background Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. Aim To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. Methods We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. Results MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. Conclusion Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research. PMID:26124696

Perspectives of boron-neutron capture therapy of malignant brain tumors

NASA Astrophysics Data System (ADS)

Kanygin, V. V.; Kichigin, A. I.; Krivoshapkin, A. L.; Taskaev, S. Yu.

2017-09-01

Boron neutron capture therapy (BNCT) is characterized by a selective effect directly on the cells of malignant tumors. The carried out research showed the perspective of the given kind of therapy concerning malignant tumors of the brain. However, the introduction of BNCT into clinical practice is hampered by the lack of a single protocol for the treatment of patients and the difficulty in using nuclear reactors to produce a neutron beam. This problem can be solved by using a compact accelerator as a source of neutrons, with the possibility of installation in a medical institution. Such a neutron accelerator for BNCT was developed at Budker Institute of Nuclear Physics, Novosibirsk. A neutron beam was obtained on this accelerator, which fully complies with the requirements of BNCT, as confirmed by studies on cell cultures and experiments with laboratory animals. The conducted experiments showed the relative safety of the method with the absence of negative effects on cell cultures and living organisms, and also confirmed the effectiveness of BNCT for malignant brain tumors.

Influencing public health without authority.

PubMed

Suresh, K

2012-01-01

This paper analyzes the present processes, products and needs of post-graduate public health education for the health programming, implementation and oversight responsibilities at field level and suggests some solutions for the institutes to adopt or adapt for improving the quality of their scholars. Large number of institutions has cropped up in India in the recent years to meet the growing demand of public health specialists/practitioners in various national health projects, international development partners, national and international NGOs. Throwing open MPH courses to multi-disciplinary graduate's is a new phenomenon in India and may be a two edged sword. On one hand it is advantageous to produce multi-faceted Public health postgraduates to meet the multi tasking required, on the other hand getting all of them to a common basic understanding, demystifying technical teaching and churning out products that are acceptable to the traditional health system. These Institutions can and must influence public health in the country through producing professionals of MPH/ MD degree with right attitude and skill-mix. Engaging learners in experimentation, experience sharing projects, stepping into health professionals' roles and similar activities lead to development of relatively clear and permanent neural traces in the brain. The MPH institutes may not have all efficient faculties, for which they should try to achieve this by inviting veterans in public health and professionals from corporate health industry for interface with students on a regular basis. The corporate and public health stalwarts have the capacities to transmit the winning skills and knowledge and also inspire them to adopt or adapt in order to achieve the desired goals.

Attention-Deficit/Hyperactivity Disorder Drugs and Growth: An Italian Prospective Observational Study

PubMed Central

Germinario, Elena A.P.; Arcieri, Romano; Bonati, Maurizio; Zuddas, Alessandro; Masi, Gabriele; Vella, Stefano; Chiarotti, Flavia

2013-01-01

Abstract Objective This study was conducted to assess the long-term effect of methylphenidate (MPH) or atomoxetine (ATX) on growth in attention-deficit/hyperactivity disorder (ADHD) drug-naïve children. Design The study was an observational, post-marketing, fourth phase study. Methods Data on height and weight were collected at baseline and every 6 months up to 24 months. Results Both ATX and MPH lead to decreased height gain (assessed by means of z-scores); the effect was significantly higher for ATX than for MPH. At any time, height z-score decrease in the ATX group was higher than the corresponding decrease observed in the MPH group, but the difference was significantly relevant only during the first year of treatment. An increment of average weight was observed both in patients treated with MPH and in those treated with ATX. However, using Tanner's percentile, a subset of patients showed a degree of growth lower than expected. This negative effect was significantly higher for ATX than for MPH. Conclusions We conclude that ADHD drugs show a negative effect on linear growth in children in middle term. Such effect appears more evident for ATX than for MPH. PMID:24024538

Hurricane Darby off the Pacific Coast of Mexico

NASA Image and Video Library

2004-07-26

Hurricane Darby as observed by the Atmospheric Infrared Sounder AIRS onboard NASA Aqua in July, 2004. This daylight image of Hurricane Darby on July 28 was made with the visible sensor in the AIRS instrument suite. After reaching sustained winds on July 27 of 100 knots (115 mph) with gusts to 120 knots (138 mph), the intensity of the storm is now lowered to 75 knots (86 mph). Located in the eastern north Pacific Ocean located about 1,165 miles west-southwest of the southern tip of Baja California, the storm continues its west/northwest path at 14 knots (16mph). Figure 1 is a daylight snapshot from AIRS visible/near-infrared sensor before Darby became a tropical storm. Darby is in the upper right-hand corner. Circulation is not apparent because the storm was not organized sufficiently to allow the nascent eye to appear. At this time, winds were approximately 35 mph. Figure 2 is an AIRS infrared image. Darby falls on the edge of two AIRS data granules, which have been "stitched" together in this image. Storm intensity is lowered to 75 knots (86 mph), down from 100 knots (115 mph). http://photojournal.jpl.nasa.gov/catalog/PIA00439

Methylphenidate enhances cognitive performance in adults with poor baseline capacities regardless of attention-deficit/hyperactivity disorder diagnosis.

PubMed

Agay, Nirit; Yechiam, Eldad; Carmel, Ziv; Levkovitz, Yechiel

2014-04-01

We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.

Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.

PubMed

Lanctôt, Krista L; Chau, Sarah A; Herrmann, Nathan; Drye, Lea T; Rosenberg, Paul B; Scherer, Roberta W; Black, Sandra E; Vaidya, Vijay; Bachman, David L; Mintzer, Jacobo E

2014-02-01

Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses. MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline)). In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment. These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors.

PubMed

Furini, Cristiane R G; Behling, Jonny A K; Zinn, Carolina G; Zanini, Mara Lise; Assis Brasil, Eduardo; Pereira, Luiza Doro; Izquierdo, Ivan; de Carvalho Myskiw, Jociane

2017-05-30

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5μg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1μg/side) or MPH+SCH23390 (1.5μg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both β-adrenergic and D1/D5 dopaminergic receptors. Copyright © 2017 Elsevier B.V. All rights reserved.

Wind tunnel test of Teledyne Geotech model 1564B cup anemometer

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

Parker, M.J.; Addis, R.P.

1991-04-04

The Department of Energy (DOE) Environment, Safety and Health Compliance Assessment (Tiger Team) of the Savannah River Site (SRS) questioned the method by which wind speed sensors (cup anemometers) are calibrated by the Environmental Technology Section (ETS). The Tiger Team member was concerned that calibration data was generated by running the wind tunnel to only 26 miles per hour (mph) when speeds exceeding 50 mph are readily obtainable. A wind tunnel experiment was conducted and confirmed the validity of the practice. Wind speeds common to SRS (6 mph) were predicted more accurately by 0--25 mph regression equations than 0--50 mphmore » regression equations. Higher wind speeds were slightly overpredicted by the 0--25 mph regression equations when compared to 0--50 mph regression equations. However, the greater benefit of more accurate lower wind speed predictions accuracy outweight the benefit of slightly better high (extreme) wind speed predictions. Therefore, it is concluded that 0--25 mph regression equations should continue to be utilized by ETS at SRS. During the Department of Energy Tiger Team audit, concerns were raised about the calibration of SRS cup anemometers. Wind speed is measured by ETS with Teledyne Geotech model 1564B cup anemometers, which are calibrated in the ETS wind tunnel. Linear regression lines are fitted to data points of tunnel speed versus anemometer output voltages up to 25 mph. The regression coefficients are then implemented into the data acquisition computer software when an instrument is installed in the field. The concern raised was that since the wind tunnel at SRS is able to generate a maximum wind speed higher than 25 mph, errors may be introduced in not using the full range of the wind tunnel.« less

Impact of the 65 mph speed limit on Virginia's rural interstate highways, 1989-1992.

DOT National Transportation Integrated Search

1994-01-01

In April of 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA), which permitted states to raise their maximum speed limit on rural interstate highways to 65 mph. Virginia's 65 mph speed limit went into eff...

The impact of the 65 MPH speed limit on Virginia's rural interstate highways through 1990.

DOT National Transportation Integrated Search

1992-01-01

In April of 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA), which permitted states to raise their maximum speed limit on rural interstate highways (rural interstates) to 65 mph. Virginia's 65 mph speed...

Effects of methylphenidate on working memory components: influence of measurement.

PubMed

Bedard, Anne-Claude; Jain, Umesh; Johnson, Sheilah Hogg; Tannock, Rosemary

2007-09-01

To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in attention-deficit hyperactivity disorder (ADHD) and determine the responsiveness of WM measures to MPH. Participants were a clinical sample of 50 children and adolescents with ADHD, aged 6 to 16 years old, who participated in an acute randomized, double-blind, placebo-controlled, crossover trial with single challenges of three MPH doses. Four components of WM were investigated, which varied in processing demands (storage versus manipulation of information) and modality (auditory-verbal; visual-spatial), each of which was indexed by a minimum of two separate measures. MPH improved the ability to store visual-spatial information irrespective of instrument used, but had no effects on the storage of auditory-verbal information. By contrast, MPH enhanced the ability to manipulate both auditory-verbal and visual-spatial information, although effects were instrument specific in both cases. MPH effects on WM are selective: they vary as a function of WM component and measurement.

KSC-04pd1717

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Space Station Processing Facility, a worker wraps equipment in plastic in preparation for the expected impact of Hurricane Frances on Saturday. The various modules in the SSPF, such as the Japanese Experiment Module, U.S. Node 2 and Multi-Purpose Logistics Modules, are being covered as well. KSC workers also have powered down the Space Shuttle orbiters, closed their payload bay doors and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The SSPF can withstand sustained winds of 110 mph and wind gusts up to 132 mph. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies.

PubMed

da Fonseca, Anna Carolina Carvalho; Badie, Behnam

2013-01-01

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies.

Training stem cells for treatment of malignant brain tumors

PubMed Central

Li, Shengwen Calvin; Kabeer, Mustafa H; Vu, Long T; Keschrumrus, Vic; Yin, Hong Zhen; Dethlefs, Brent A; Zhong, Jiang F; Weiss, John H; Loudon, William G

2014-01-01

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system. PMID:25258664

Imaging of brain metastases.

PubMed

Fink, Kathleen R; Fink, James R

2013-01-01

Imaging plays a key role in the diagnosis of central nervous system (CNS) metastasis. Imaging is used to detect metastases in patients with known malignancies and new neurological signs or symptoms, as well as to screen for CNS involvement in patients with known cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) are the key imaging modalities used in the diagnosis of brain metastases. In difficult cases, such as newly diagnosed solitary enhancing brain lesions in patients without known malignancy, advanced imaging techniques including proton magnetic resonance spectroscopy (MRS), contrast enhanced magnetic resonance perfusion (MRP), diffusion weighted imaging (DWI), and diffusion tensor imaging (DTI) may aid in arriving at the correct diagnosis. This image-rich review discusses the imaging evaluation of patients with suspected intracranial involvement and malignancy, describes typical imaging findings of parenchymal brain metastasis on CT and MRI, and provides clues to specific histological diagnoses such as the presence of hemorrhage. Additionally, the role of advanced imaging techniques is reviewed, specifically in the context of differentiating metastasis from high-grade glioma and other solitary enhancing brain lesions. Extra-axial CNS involvement by metastases, including pachymeningeal and leptomeningeal metastases is also briefly reviewed.

Twin-arginine signal peptide of Bacillus subtilis YwbN can direct Tat-dependent secretion of methyl parathion hydrolase.

PubMed

Liu, Ruihua; Zuo, Zhenqiang; Xu, Yingming; Song, Cunjiang; Jiang, Hong; Qiao, Chuanling; Xu, Ping; Zhou, Qixing; Yang, Chao

2014-04-02

The twin-arginine translocation (Tat) pathway exports folded proteins across the cytoplasmic membranes of bacteria and archaea. Two parallel Tat pathways (TatAdCd and TatAyCy systems) with distinct substrate specificities have previously been discovered in Bacillus subtilis. In this study, to secrete methyl parathion hydrolase (MPH) into the growth medium, the twin-arginine signal peptide of B. subtilis YwbN was used to target MPH to the Tat pathway of B. subtilis. Western blot analysis and MPH assays demonstrated that active MPH was secreted into the culture supernatant of wild-type cells. No MPH secretion occurred in a total-tat2 mutant, indicating that the observed export in wild-type cells was mediated exclusively by the Tat pathway. Export was fully blocked in a tatAyCy mutant. In contrast, the tatAdCd mutant was still capable of secreting MPH. These results indicated that the MPH secretion directed by the YwbN signal peptide was specifically mediated by the TatAyCy system. The N-terminal sequence of secreted MPH was determined as AAPQVR, demonstrating that the YwbN signal peptide had been processed correctly. This is the first report of functional secretion of a heterologous protein via the B. subtilis TatAyCy system. This study highlights the potential of the TatAyCy system to be used for secretion of other heterologous proteins in B. subtilis.

Medical management of brain tumors and the sequelae of treatment

PubMed Central

Schiff, David; Lee, Eudocia Q.; Nayak, Lakshmi; Norden, Andrew D.; Reardon, David A.; Wen, Patrick Y.

2015-01-01

Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction. PMID:25358508

Childhood Brain Tumors

MedlinePlus

Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

MPH-M, AODV-M and DSR-M Performance Evaluation under Jamming Attacks.

PubMed

Del-Valle-Soto, Carolina; Mex-Perera, Carlos; Monroy, Raul; Nolazco-Flores, Juan A

2017-07-05

In this work, we present the design of a mitigation scheme for jamming attacks integrated to the routing protocols MPH, AODV, and DSR. The resulting protocols are named MPH-M (Multi-Parent Hierarchical - Modified), AODV-M (Ad hoc On Demand Distance Vector - Modified), and DSR-M (Dynamic Source Routing - Modified). For the mitigation algorithm, if the detection algorithm running locally in each node produces a positive result then the node is isolated; second, the routing protocol adapts their paths avoiding the isolated nodes. We evaluated how jamming attacks affect different metrics for all these modified protocols. The metrics we employ to detect jamming attack are number of packet retransmissions, number of CSMA/CA (Carrier Sense Multiple Access with Collision Avoidance) retries while waiting for an idle channel and the energy wasted by the node. The metrics to evaluate the performance of the modified routing protocols are the throughput and resilience of the system and the energy used by the nodes. We evaluated all the modified protocols when the attacker position was set near, middle and far of the collector node. The results of our evaluation show that performance for MPH-M is much better than AODV-M and DSR-M. For example, the node energy for MPH-M is 138.13% better than AODV-M and 126.07% better than DSR-M. Moreover, we also find that MPH-M benefits much more of the mitigation scheme than AODV-M and DSR-M. For example, the node energy consumption is 34.61% lower for MPH-M and only 3.92% and 3.42% for AODV-M and DSR-M, respectively. On throughput, the MPH protocol presents a packet reception efficiency at the collector node of 16.4% on to AODV and DSR when there is no mitigation mechanism. Moreover, MPH-M has an efficiency greater than 7.7% with respect to AODV-M and DSR-M when there is a mitigation scheme. In addition, we have that with the mitigation mechanism AODV-M and DSR-M do not present noticeable modification. However, MPH-M improves its efficiency by 8.4%. We also measure the resilience of these algorithms from the average packet re-transmissions perspective, and we find that MPH-M has around a 15% lower change rate than AODV-M and DSR-M. The MPH-M recovery time is 5 s faster than AODV-M and 2 s faster than DSR-M.

MPH-M, AODV-M and DSR-M Performance Evaluation under Jamming Attacks

PubMed Central

Del-Valle-Soto, Carolina

2017-01-01

In this work, we present the design of a mitigation scheme for jamming attacks integrated to the routing protocols MPH, AODV, and DSR. The resulting protocols are named MPH-M (Multi-Parent Hierarchical - Modified), AODV-M (Ad hoc On Demand Distance Vector - Modified), and DSR-M (Dynamic Source Routing - Modified). For the mitigation algorithm, if the detection algorithm running locally in each node produces a positive result then the node is isolated; second, the routing protocol adapts their paths avoiding the isolated nodes. We evaluated how jamming attacks affect different metrics for all these modified protocols. The metrics we employ to detect jamming attack are number of packet retransmissions, number of CSMA/CA (Carrier Sense Multiple Access with Collision Avoidance) retries while waiting for an idle channel and the energy wasted by the node. The metrics to evaluate the performance of the modified routing protocols are the throughput and resilience of the system and the energy used by the nodes. We evaluated all the modified protocols when the attacker position was set near, middle and far of the collector node. The results of our evaluation show that performance for MPH-M is much better than AODV-M and DSR-M. For example, the node energy for MPH-M is 138.13% better than AODV-M and 126.07% better than DSR-M. Moreover, we also find that MPH-M benefits much more of the mitigation scheme than AODV-M and DSR-M. For example, the node energy consumption is 34.61% lower for MPH-M and only 3.92% and 3.42% for AODV-M and DSR-M, respectively. On throughput, the MPH protocol presents a packet reception efficiency at the collector node of 16.4% on to AODV and DSR when there is no mitigation mechanism. Moreover, MPH-M has an efficiency greater than 7.7% with respect to AODV-M and DSR-M when there is a mitigation scheme. In addition, we have that with the mitigation mechanism AODV-M and DSR-M do not present noticeable modification. However, MPH-M improves its efficiency by 8.4%. We also measure the resilience of these algorithms from the average packet re-transmissions perspective, and we find that MPH-M has around a 15% lower change rate than AODV-M and DSR-M. The MPH-M recovery time is 5 s faster than AODV-M and 2 s faster than DSR-M. PMID:28678180

Methylphenidate Enhances Extinction of Contextual Fear

ERIC Educational Resources Information Center

Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show…

Small Arms - Hand and Shoulder Weapons and Machine Guns

DTIC Science & Technology

2016-06-24

temperature with a wind speed less than 8 kilometers per hour (km/hr) (5 miles per hour (mph)) with no sunlight on the barrel or receiver. e...the aiming of the mount/weapon system. d. Meteorological Conditions. (1) Ensure that the velocity of the transverse wind is no greater than 8...km/hr (5 mph) or varies by more than 4 km/hr (2.5 mph); wind parallel to the LOF should not exceed 16 km/hr (10 mph) or vary by more than 8 km/hr (5

Dream Chaser Rolls Through Tow Tests at NASA Armstrong

NASA Image and Video Library

2017-05-20

In this 2-minute, 41-second video, Sierra Nevada Corporation (SNC) puts its Dream Chaser engineering test vehicle through a series of ground tests at NASA's Armstrong Flight Research Center at Edwards Air Force Base, CA, to prepare for upcoming captive-carry and free-flight tests later this year. During this 60-mph tow test, a pickup truck pulled the Dream Chaser test vehicle on Edward’s runway to validate the performance of the spacecraft's nose skid, brakes, tires, and other systems. The company has performed the tests at 10 mph, 20 mph, and 40 mph over the last few months to lead up to the 60-mph runway test. Range and taxi tow tests are standard for winged vehicles that touchdown on a runway to prove the overall spacecraft handling post-landing.

Pooled analysis of two case-control studies on use of cellular and cordless telephones and the risk for malignant brain tumours diagnosed in 1997-2003.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2006-09-01

To study the use of cellular and cordless telephones and the risk for malignant brain tumours. Two case-control studies on malignant brain tumours diagnosed during 1997-2003 included answers from 905 (90%) cases and 2,162 (89%) controls aged 20-80 years. We present pooled analysis of the results in the two studies. Cumulative lifetime use for >2,000 h yielded for analogue cellular phones odds ratio (OR)=5.9, 95% confidence interval (CI)=2.5-14, digital cellular phones OR=3.7, 95% CI=1.7-7.7, and for cordless phones OR=2.3, 95% CI=1.5-3.6. Ipsilateral exposure increased the risk for malignant brain tumours; analogue OR=2.1, 95% CI=1.5-2.9, digital OR=1.8, 95% CI=1.4-2.4, and cordless OR=1.7, 95% CI=1.3-2.2. For high-grade astrocytoma using >10 year latency period analogue phones yielded OR=2.7, 95% CI=1.8-4.2, digital phones OR=3.8, 95% CI=1.8-8.1, and cordless phones OR=2.2, 95% CI=1.3-3.9. In the multivariate analysis all phone types increased the risk. Regarding digital phones OR=3.7, 95% CI=1.5-9.1 and cordless phones OR=2.1, 95% CI=0.97-4.6 were calculated for malignant brain tumours for subjects with first use use <20 years of age, higher than in older persons. Increased risk was obtained for both cellular and cordless phones, highest in the group with >10 years latency period.

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases.

PubMed

Wilhelm, Imola; Fazakas, Csilla; Molnár, Kinga; Végh, Attila G; Haskó, János; Krizbai, István A

2018-04-01

Despite the potential obstacle represented by the blood-brain barrier for extravasating malignant cells, metastases are more frequent than primary tumors in the central nervous system. Not only tightly interconnected endothelial cells can hinder metastasis formation, other cells of the brain microenvironment (like astrocytes and microglia) can also be very hostile, destroying the large majority of metastatic cells. However, malignant cells that are able to overcome these harmful mechanisms may benefit from the shielding and even support provided by cerebral endothelial cells, astrocytes and microglia, rendering the brain a sanctuary site against anti-tumor strategies. Thus, cells of the neurovascular unit have a Janus-faced attitude towards brain metastatic cells, being both destructive and protective. In this review, we present the main mechanisms of brain metastasis formation, including those involved in extravasation through the brain vasculature and survival in the cerebral environment.

Remission in children and adolescents diagnosed with attention-deficit/hyperactivity disorder via an effective and tolerable titration scheme for osmotic release oral system methylphenidate.

PubMed

Chou, Wen-Jiun; Chen, Shin-Jaw; Chen, Ying-Sheue; Liang, Hsin-Yi; Lin, Chih-Chien; Tang, Ching-Shu; Huang, Yu-Shu; Yeh, Chin-Bin; Chou, Miao-Chun; Lin, Dai-Yueh; Hou, Po-Hsun; Wu, Yu-Yu; Liu, Hung-Jen; Huang, Ya-Fen; Hwang, Kai-Ling; Chan, Chin-Hong; Pan, Chia-Ho; Chang, Hsueh-Ling; Huang, Chi-Fen; Hsu, Ju-Wei

2012-06-01

The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks. We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (<70 mg/day) for at least 1 month. The treatment, switched from IR-MPH to OROS-MPH according to a conversion scheme, started with a 6-week forced-titration phase of OROS-MPH to achieve symptomatic remission (defined as a score of 0 or 1 for each of the first 18 ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV [SNAP-IV]), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed. Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score < 40), no family history of ADHD, and an appropriate dosage of medication according to the patient's weight. The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme.

Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

PubMed

Vazana, Udi; Veksler, Ronel; Pell, Gaby S; Prager, Ofer; Fassler, Michael; Chassidim, Yoash; Roth, Yiftach; Shahar, Hamutal; Zangen, Abraham; Raccah, Ruggero; Onesti, Emanuela; Ceccanti, Marco; Colonnese, Claudio; Santoro, Antonio; Salvati, Maurizio; D'Elia, Alessandro; Nucciarelli, Valter; Inghilleri, Maurizio; Friedman, Alon

2016-07-20

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders. Copyright © 2016 the authors 0270-6474/16/367727-13$15.00/0.

Glutamate-Mediated Blood–Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery

PubMed Central

Vazana, Udi; Veksler, Ronel; Pell, Gaby S.; Prager, Ofer; Fassler, Michael; Chassidim, Yoash; Roth, Yiftach; Shahar, Hamutal; Zangen, Abraham; Raccah, Ruggero; Onesti, Emanuela; Ceccanti, Marco; Colonnese, Claudio; Santoro, Antonio; Salvati, Maurizio; D'Elia, Alessandro; Nucciarelli, Valter; Inghilleri, Maurizio

2016-01-01

The blood–brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood–brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood–brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood–brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood–brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT In this study, we reveal a new mechanism that governs blood–brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders. PMID:27445149

Using business plan development as a capstone project for MPH programs in Canada: validation through the student perspective.

PubMed

Papadopoulos, Andrew; Britten, Nicole; Hatcher, Meghan; Rainville, Keira

2013-10-01

Master of Public Health (MPH) programs have been developed across Canada as a response to the need for adequately trained individuals to work in the public health sector. Educational institutions that deliver MPH programs have a responsibility to ensure that graduates of their program have the essential knowledge, skills and attitudes to begin a successful career in public health. The Public Health Agency of Canada has created the core competencies for public health to guide the development, delivery and evaluation of MPH programs. In Canada, a capstone project is the recommended method of evaluating the MPH graduate's ability to demonstrate proficiency in the public health core competencies. A business plan that develops the framework for a public health program is an ideal capstone project currently used in practice within the University of Guelph MPH program. This group assignment incorporates all 36 of the public health core competencies while providing students with a real-world public health experience, and should be considered for inclusion within MPH programs across Canada. Business planning provides students the opportunity to engage in practice-based learning, applying theoretical knowledge to practice. Further, the ability to develop realistic but financially feasible public health problems is an invaluable skill for MPH graduates. As the development of programs becomes more restricted and the continuation of other programs are under constant threat, the ability to develop a sound business plan is a required skill for individuals entering the public health sector, and will ensure students are able to maximize outcomes given tight fiscal budgets and limited resources.

Disagreements with implications: diverging discourses on the ethics of non-medical use of methylphenidate for performance enhancement

PubMed Central

Forlini, Cynthia; Racine, Eric

2009-01-01

Background There is substantial evidence that methylphenidate (MPH; Ritalin), is being used by healthy university students for non-medical motives such as the improvement of concentration, alertness, and academic performance. The scope and potential consequences of the non-medical use of MPH upon healthcare and society bring about many points of view. Methods To gain insight into key ethical and social issues on the non-medical use of MPH, we examined discourses in the print media, bioethics literature, and public health literature. Results Our study identified three diverging paradigms with varying perspectives on the nature of performance enhancement. The beneficial effects of MPH on normal cognition were generally portrayed enthusiastically in the print media and bioethics discourses but supported by scant information on associated risks. Overall, we found a variety of perspectives regarding ethical, legal and social issues related to the non-medical use of MPH for performance enhancement and its impact upon social practices and institutions. The exception to this was public health discourse which took a strong stance against the non-medical use of MPH typically viewed as a form of prescription abuse or misuse. Wide-ranging recommendations for prevention of further non-medical use of MPH included legislation and increased public education. Conclusion Some positive portrayals of the non-medical use of MPH for performance enhancement in the print media and bioethics discourses could entice further uses. Medicine and society need to prepare for more prevalent non-medical uses of neuropharmaceuticals by fostering better informed public debates. PMID:19580661

Methylphenidate does not improve interference control during a working memory task in young patients with attention-deficit hyperactivity disorder.

PubMed

Prehn-Kristensen, Alexander; Krauel, Kerstin; Hinrichs, Hermann; Fischer, Jochen; Malecki, Ulrike; Schuetze, Hartmut; Wolff, Stephan; Jansen, Olav; Duezel, Emrah; Baving, Lioba

2011-05-04

Patients with attention-deficit/hyperactivity disorder (ADHD) show deficits in working memory (WM) which may be related to prefrontal dysfunction. Methylphenidate (MPH) can restore WM deficits in ADHD by enhancing prefrontal activity. At the same time, changes in striatal activation could cause ADHD patients to be more interference-sensitive during working memory tasks. However, it is unclear whether MPH reduces WM distractibility in ADHD. In this fMRI study, 12 ADHD patients and 12 healthy controls participated on two separate days in a delayed-match-to-sample test. During the delay interval, a distractor stimulus was presented in half of the trials. Children and adolescents with ADHD received MPH only on one of the two sessions. Behavioral data analyses revealed that MPH normalized WM in ADHD. However, MPH did not improve WM performance when a distractor was presented during the delay interval. Functional images showed that MPH enhanced prefrontal activity during the delay in ADHD patients when no distractor was present. If the delay was interrupted by a distractor, only healthy controls showed activation of the caudate. In patients with ADHD, however, in line with behavioral data, MPH did not enhance caudate activity. In healthy youth, caudate activity is involved in interference control allowing the successful maintenance of information in working memory even in the presence of distraction. Our findings suggest that interference control, linked to caudate activity, is not adequately enhanced by MPH in ADHD. Copyright © 2011 Elsevier B.V. All rights reserved.

Animal model of methylphenidate's long-term memory-enhancing effects.

PubMed

Carmack, Stephanie A; Howell, Kristin K; Rasaei, Kleou; Reas, Emilie T; Anagnostaras, Stephan G

2014-01-16

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

Animal model of methylphenidate's long-term memory-enhancing effects

PubMed Central

Carmack, Stephanie A.; Howell, Kristin K.; Rasaei, Kleou; Reas, Emilie T.; Anagnostaras, Stephan G.

2014-01-01

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01–10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1–10 mg/kg, i.p.), bupropion (0.5–20 mg/kg, i.p.), and citalopram (0.01–10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development. PMID:24434869

Methylphenidate and Cocaine Self-Administration Produce Distinct Dopamine Terminal Alterations

PubMed Central

Calipari, Erin S.; Ferris, Mark J.; Melchior, James R.; Bermejo, Kristel; Salahpour, Ali; Roberts, David C. S.; Jones, Sara R.

2012-01-01

Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a five-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates, and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase mRNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade. PMID:22458761

RNAi therapeutics for brain cancer: current advancements in RNAi delivery strategies.

PubMed

Malhotra, Meenakshi; Toulouse, André; Godinho, Bruno M D C; Mc Carthy, David John; Cryan, John F; O'Driscoll, Caitriona M

2015-10-01

Malignant primary brain tumors are aggressive cancerous cells that invade the surrounding tissues of the central nervous system. The current treatment options for malignant brain tumors are limited due to the inability to cross the blood-brain barrier. The advancements in current research has identified and characterized certain molecular markers that are essential for tumor survival, progression, metastasis and angiogenesis. These molecular markers have served as therapeutic targets for the RNAi based therapies, which enable site-specific silencing of the gene responsible for tumor proliferation. However, to bring about therapeutic success, an efficient delivery carrier that can cross the blood-brain barrier and reach the targeted site is essential. The current review focuses on the potential of targeted, non-viral and viral particles containing RNAi therapeutic molecules as delivery strategies specifically for brain tumors.

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

PubMed Central

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. PMID:28740389

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

PubMed

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Structure and Function of the Macrolide Biosensor Protein, MphR(A), with and without Erythromycin

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

Zheng, Jianting; Sagar, Vatsala; Smolinsky, Adam

2009-09-02

The regulatory protein MphR(A) has recently seen extensive use in synthetic biological applications, such as metabolite sensing and exogenous control of gene expression. This protein negatively regulates the expression of a macrolide 2{prime}-phosphotransferase I resistance gene (mphA) via binding to a 35-bp DNA operator upstream of the start codon and is de-repressed by the presence of erythromycin. Here, we present the refined crystal structure of the MphR(A) protein free of erythromycin and that of the MphR(A) protein with bound erythromycin at 2.00- and 1.76-{angstrom} resolutions, respectively. We also studied the DNA binding properties of the protein and identified mutants ofmore » MphR(A) that are defective in gene repression and ligand binding in a cell-based reporter assay. The combination of these two structures illustrates the molecular basis of erythromycin-induced gene expression and provides a framework for additional applied uses of this protein in the isolation and engineered biosynthesis of polyketide natural products.« less

Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

PubMed Central

Carvalho da Fonseca, Anna Carolina; Badie, Behnam

2013-01-01

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies. PMID:23864876

Cardiac mesothelial papillary hyperplasia in four dogs.

PubMed

Kirejczyk, Shannon G; Burnum, Anne L; Brown, Corrie C; Sakamoto, Kaori; Rissi, Daniel R

2018-05-01

Mesothelial papillary hyperplasia (MPH) has been described as an incidental finding on the epicardial surface of clinically normal laboratory Beagle dogs. We describe MPH in 4 dogs diagnosed with acute cardiac tamponade (1 case) or chronic cardiac disease (3 cases). Cardiac MPH appeared as distinct, soft, irregular villous plaques on the epicardial surface of the auricles and occasionally the ventricles. Histologically, areas of MPH were composed of multiple papillary fronds arising from the epicardial surface and projecting into the pericardial space. Fronds were covered by cuboidal and occasionally vacuolated mesothelial cells and were supported by loose fibrovascular stroma with various degrees of edema and inflammation. Although these may represent incidental findings with no clinical significance, the gross appearance warrants differentiation from other conditions. Additional insight into the pathogenesis of MPH is needed to fully understand its significance in the face of concurrent cardiac disease.

Miliary pattern of brain metastases - a case report of a hyperacute onset in a patient with malignant melanoma documented by magnetic resonance imaging.

PubMed

Reiter, Florian P; Giessen-Jung, Clemens; Dorostkar, Mario M; Ertl-Wagner, Birgit; Denk, Gerald U; Heck, Suzette; Rieger, Christina T; Pfister, Hans W; op den Winkel, Mark

2015-07-19

Miliary brain metastases are a rare condition but associated with an exceedingly poor prognosis. We present the case of a patient suffering from malignant melanoma with an acute progressively worsening of neurological symptoms up to the loss of consciousness. The magnetic resonance imaging (MRI) demonstrated a new onset of disseminated, miliary spread of central nervous system metastases from a malignant melanoma within 4 days. We report on a 57-year-old woman suffering from metastatic malignant melanoma positive for BRAF-V600E mutation who developed an acute onset of neurological symptoms. The patient received vemurafenib and dacarbacin as chemotherapeutic regime for treatment of malignant melanoma. After admission to our hospital due to progressive disturbance of memory and speech difficulty a magnetic resonance tomography (MRI) was performed. This showed no evidence of cerebral tumour manifestation. The symptoms progressed until a loss of consciousness occurred on day five after admission and the patient was admitted to our intensive care unit for orotracheal intubation. No evidence for infectious, metabolic or autoimmune cerebral disorders was found. Due to the inexplicable acute worsening of the neurological symptoms a second MRI was performed on day five. This revealed a new onset of innumerable contrast-enhancing miliary lesions, especially in the grey matter which was proven as metastases from malignant melanoma on histopathology. This case describes an unique hyperacute onset of tumour progression correlating with an acute deterioration of neurological symptoms in a patient suffering from miliary brain metastasis from BRAF positive malignant melanoma.

Flow cytometric detection of Pig-A mutant red blood cells using an erythroid-specific antibody: application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats.

PubMed

Dobrovolsky, Vasily N; Boctor, Sherin Y; Twaddle, Nathan C; Doerge, Daniel R; Bishop, Michelle E; Manjanatha, Mugimane G; Kimoto, Takafumi; Miura, Daishiro; Heflich, Robert H; Ferguson, Sherry A

2010-03-01

A modified flow cytometry assay for Pig-A mutant rat red blood cells (RBCs) was developed using an antibody that positively identifies rat RBCs (monoclonal antibody HIS49). The assay was used in conjunction with a flow cytometric micronucleus (MN) assay to evaluate gene mutation and clastogenicity/aneugenicity in adolescent male and female rats treated with methylphenidate hydrochloride (MPH). Sprague-Dawley rats were treated orally with 3 mg/kg MPH (70/sex) or water (40/sex) 3 x /day on postnatal days (PNDs) 29-50. Eight additional rats (4/sex) were injected i.p. with N-ethyl-N-nitrosourea (ENU) on PND 28. Blood was collected on PNDs 29, 50, and 90, and used for determining serum MPH levels and/or conducting genotoxicity assays. On the first and last days of MPH treatment (PNDs 29 and 50), serum MPH levels averaged 21 pg/microl, well within the clinical treatment range. Relative to our previously published method (Miura et al. [2008]; Environ Mol Mutagen 49: 614-629), the HIS49 Pig-A mutation assay significantly reduced the background RBC mutant frequency; in the experiments with ENU-treated rats, the modification increased the overall sensitivity of the assay 2-3 fold. Even with the increased assay sensitivity, the 21 consecutive days of MPH treatment produced no evidence of Pig-A mutation induction (measured at PND 90); in addition, MPH treatment did not increase MN frequency (measured at PND 50). These results support the consensus view that the genotoxicity of MPH in pediatric patients reported earlier (El-Zein et al. [2005]: Cancer Lett 230: 284-291) cannot be reproduced in animal models, suggesting that MPH at clinically relevant levels may be nongenotoxic in humans. Published 2009 by Wiley-Liss, Inc.

Development and validation of an UFLC-MS/MS method for enantioselectivity determination of d,l-thero-methylphenidate, d,l-thero-ethylphenidate and d,l-thero-ritalinic acid in rat plasma and its application to pharmacokinetic study.

PubMed

Zhang, Chenghao; Luo, Huafei; Wu, Yubo; Zhang, Junyun; Zhang, Furong; Lin, Guobei; Wang, Hao

2016-02-01

A chiral UFLC-MS/MS method was established and validated for quantifying d-threo-methylphenidate (d-threo-MPH), l-threo-methylphenidate (l-threo-MPH), d-threo-ethylphenidate (d-threo-EPH), l-threo-ethylphenidate (l-threo-EPH) and d,l-threo-ritalinic acid (d,l-threo-RA) in rat plasma over the linearity range of 1-500ng/mL. Chiral separation was performed on an Astec Chirobiotic V2 column (5μm, 250×2.1mm) with isocratic elution using methanol containing 0.003% ammonium acetate (w/v) and 0.003% trifluoroacetic acid (v/v) at a flow of 0.3mL/min. All analytes and IS were extracted from rat plasma by a one-step liquid-liquid extraction (LLE) method. The intra- and inter-run accuracies were within 85-115%, and the intra- and inter-run precision were <10% for all analytes. Extraction recoveries were 55-62% for d-threo-MPH, 54-60% for l-threo-MPH, 55-60% for d-threo-EPH, 53-57% for l-threo-EPH and 25-30% for d,l-threo-RA. The validated UFLC-MS/MS method successfully applied to the pharmacokinetic interaction study of oral d-threo-MPH and l-threo-MPH (alone or in combination) in female Sprague Dawley rats. The EPH was not detected in rat plasma following oral administrated MPH without EtOH. As far as it is known to the authors, this study is the first one step liquid-liquid extraction method to extract and UFLC-MS/MS method to quantify d-threo-MPH, l-threo-MPH, d-threo-EPH, l-threo-EPH and d,l-threo-RA simultaneously. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of Aptensio XR (Methylphenidate HCl Extended-Release) Capsules on Sleep in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Owens, Judith; Weiss, Margaret; Nordbrock, Earl; Mattingly, Greg; Wigal, Sharon; Greenhill, Laurence L; Chang, Wei-Wei; Childress, Ann; Kupper, Robert J; Adjei, Akwete

2016-12-01

To evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children. Study 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test. DB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p < 0.05); in Study 2 CSHQ total and Bedtime Resistance, Sleep Duration, Night Wakings, Parasomnias, and Daytime Sleepiness, and ASHQ total, Bedtime, Sleep Behavior, and Morning Waking all significantly improved (p < 0.05). In both studies, there was minimal negative impact of MPH-MLR on sleep during the brief DB phase and none during the longer duration OL phase. Some measures of sleep improved with optimized MPH-MLR dose.

Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate

PubMed Central

Engert, Veronika; Pruessner, Jens C

2008-01-01

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its precise neurochemical mechanisms of action are under debate. For the most part, MPH’s influence on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest for the task is thought to increase attention and improve performance. Recent animal studies have however shown that when administered at doses producing clinically relevant drug plasma levels and enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that allow integrating the different findings and models. PMID:19587853

The effect of methylphenidate on very low frequency electroencephalography oscillations in adult ADHD.

PubMed

Cooper, Ruth E; Skirrow, Caroline; Tye, Charlotte; McLoughlin, Grainne; Rijsdijk, Fruhling; Banaschweski, Tobias; Brandeis, Daniel; Kuntsi, Jonna; Asherson, Philip

2014-04-01

Altered very low-frequency electroencephalographic (VLF-EEG) activity is an endophenotype of ADHD in children and adolescents. We investigated VLF-EEG case-control differences in adult samples and the effects of methylphenidate (MPH). A longitudinal case-control study was conducted examining the effects of MPH on VLF-EEG (.02-0.2Hz) during a cued continuous performance task. 41 untreated adults with ADHD and 47 controls were assessed, and 21 cases followed up after MPH treatment, with a similar follow-up for 38 controls (mean follow-up=9.4months). Cases had enhanced frontal and parietal VLF-EEG and increased omission errors. In the whole sample, increased parietal VLF-EEG correlated with increased omission errors. After controlling for subthreshold comorbid symptoms, VLF-EEG case-control differences and treatment effects remained. Post-treatment, a time by group interaction emerged; VLF-EEG and omission errors reduced to the same level as controls, with decreased inattentive symptoms in cases. Reduced VLF-EEG following MPH treatment provides preliminary evidence that changes in VLF-EEG may relate to MPH treatment effects on ADHD symptoms; and that VLF-EEG may be an intermediate phenotype of ADHD. Further studies of the treatment effect of MPH in larger controlled studies are required to formally evaluate any causal link between MPH, VLF-EEG and ADHD symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

A Status report to the Superintendent of Public Instruction on a study of optimal school bus speed limits on Virginia highways.

DOT National Transportation Integrated Search

1988-01-01

The study was prompted by the fact that on Virginia's rural interstate highways there is a three-tiered speed limit: 45 mph for school buses, 55 mph for other buses and trucks, and 65 mph for passenger vehicles. On the urban interstate system, school...

A Randomized, Single-Blind, Substitution Study of OROS Methylphenidate (Concerta) in ADHD Adults Receiving Immediate Release Methylphenidate

ERIC Educational Resources Information Center

Spencer, Thomas J.; Mick, Eric; Surman, Craig B. H.; Hammerness, Paul; Doyle, Robert; Aleardi, Megan; Kotarski, Meghan; Williams, Courtney G.; Biederman, Joseph

2011-01-01

Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants…

A Preliminary Study on the Effect of Methylphenidate on Motor Performance in Children with Comorbid DCD and ADHD

ERIC Educational Resources Information Center

Bart, Orit; Podoly, Tamar; Bar-Haim, Yair

2010-01-01

Attention Deficit Hyperactive Disorder (ADHD) and Developmental Coordination Disorder (DCD) are two developmental disorders with considerable comorbidity. The impact of Methylphenidate (MPH) on ADHD symptoms is well documented. However, the effects of MPH on motor coordination are less studied. We assessed the influence of MPH on motor performance…

Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study.

PubMed

Liang, Sophie Hsin-Yi; Yang, Yao-Hsu; Kuo, Ting-Yu; Liao, Yin-To; Lin, Tzu-Chin; Lee, Yena; McIntyre, Roger S; Kelsen, Brent A; Wang, Tsu-Nai; Chen, Vincent Chin-Hung

2018-01-01

Attention-deficit/hyperactivity disorder (ADHD) youths have increased suicide risk. Nevertheless, the beneficial effects of methylphenidate (MPH) on suicide attempt have received relatively little attention. To investigate the MPH usage and the risk of suicide attempt among ADHD youths. We identified 84,898 youths less than 18 years old with ADHD diagnosis between 1997 and 2013 from National Health Insurance, and examined whether MPH use affected suicide attempt risk using Cox proportional-hazards models. Among ADHD youths, reduction of suicide risk was found in patients prescribed 90-180days of MPH after adjusting for confounding factors (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.19-0.90) and a greater reduction in those prescribed more than 180days of MPH (HR: 0.28, 95% CI: 0.17-0.48). We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180days and a 72% risk reduction in those prescribed more than 180days of MPH. The protective benefit observed by the group prescribed MPH for longer duration underscores the importance of psychoeducation and compliance enhancement as part of ADHD management. Indication bias is identified as a limitation of this study, and future self-case control study to investigate the association between suicide attempt and ADHD medication is suggested. This nationwide population-based cohort study showed that among ADHD youths, reduction of suicide risk was observed in patients prescribed MPH for duration 90days and longer, underscoring the importance of appropriate ADHD pharmacotherapy and enhancing drug compliance. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Randomized Controlled Trial of Osmotic-Release Methylphenidate with CBT in Adolescents with ADHD and Substance Use Disorders

PubMed Central

Riggs, Paula D.; Winhusen, Theresa; Davies, Robert D.; Leimberger, Jeffrey D.; Mikulich-Gilbertson, Susan; Klein, Constance; Macdonald, Marilyn; Lohman, Michelle; Bailey, Genie L.; Haynes, Louise; Jaffee, William B.; Hodgkins, Candace; Whitmore, Elizabeth; Trello-Rishel, Kathlene; Tamm, Leanne; Acosta, Michelle C.; Royer-Malvestuto, Charlotte; Subramaniam, Geetha; Fishman, Marc; Holmes, Beverly W.; Kaye, Mary Elyse; Vargo, Mark A.; Woody, George E.; Nunes, Edward V.; Liu, David

2011-01-01

Objective To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared to placebo for attention deficit hyperactivity disorder (ADHD) and impact on substance treatment outcomes in adolescents concurrently receiving cognitive behavioral therapy (CBT) for substance use disorders (SUD). Method 16-week randomized controlled multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13-18), meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcomes: (1) ADHD- clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; (2) Substance- adolescent reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). Results There were no group differences on reduction in ADHD-RS scores (OROS-MPH: −19.2, 95% confidence interval [CI], −17.1 to −21.2; placebo,−21.2, 95% CI, −19.1 to −23.2) or reduction in days of substance use (OROS-MPH: −5.7 days, 95% CI, 4.0-7.4; placebo: −5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH including lower parent ADHD-RS scores at 8 (mean difference [md]=4.4, 95% CI, 0.8-7.9) and 16 weeks (md=6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean=3.8) compared to placebo (mean=2.8; P=0.04). Conclusions OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. PMID:21871372

Switch in Therapy from Methylphenidate to Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: An Analysis of Patient Records.

PubMed

Warrer, Pernille; Thomsen, Per Hove; Dalsgaard, Søren; Hansen, Ebba Holme; Aagaard, Lise; Wallach Kildemoes, Helle; Rasmussen, Henrik Berg

2016-05-01

The purpose of this study was to investigate therapy switching from methylphenidate (MPH) to atomoxetine (ATX) in a clinical sample of Danish children and adolescents with attention-deficit/hyperactivity disorder (ADHD); specifically, to determine the duration of MPH treatment before switching to ATX, and the reasons leading to a switch in therapy. We included 55 patients with ADHD who switched from first-line MPH to second-line ATX during January 01, 2012 and May 15, 2014. Patient and treatment characteristics along with clinical reasons for switching therapy were extracted from individual patients' records. Mean duration of MPH treatment until switch to ATX was 11.2 months (range = 0.3-28.5 months); 36% of the patients switched within the first 6 months, 56% within the first year, and 76% within 1.5 years of initiating MPH; 24% continued MPH treatment for up to 2.5 years prior to switching. Most common reasons for switching were "adverse events" (AEs) (78%), "wish for more optimal day coverage" (24%), and "lack of efficacy" (16%). Other reasons for switching included "patient/parental request" (13%) and "noncompliance" (2%). Most common AEs leading to switch were psychiatric disorders (insomnia, aggression, tic, depression, anxiety) and decreased appetite. Our findings highlight the importance of continuous evaluation of the need for prescription switch to ATX in children and adolescents treated with MPH, taking into consideration various factors including potential AEs, non-optimal day coverage, lack of efficacy, patient/parental preferences, and noncompliance. These factors should be considered, not only at the initial stage of MPH treatment but throughout the whole treatment course.

Efficacy of hemostatic matrix and microporous polysaccharide hemospheres.

PubMed

Lewis, Kevin M; Atlee, Holly; Mannone, Angela; Lin, Lawrence; Goppelt, Andreas

2015-02-01

Microporous Polysaccharide Hemospheres (MPH) are a new plant-derived polysaccharide powder hemostat. Previous studies investigated MPH as a replacement to nonflowable hemostatic agents of different application techniques (e.g., oxidized cellulose, collagen); therefore, the purpose of this study was to determine if MPH is a surrogate for flowable hemostatic agents of similar handling and application techniques, specifically a flowable thrombin-gelatin hemostatic matrix. Hemostatic efficacy was compared using a heparinized porcine abrasion model mimicking a capsular tear of a parenchymal organ. MPH (ARISTA, 1 g) and hemostatic matrix (Floseal, 1 mL) were applied, according to a randomized scheme, to paired hepatic abrasions (40 lesions per group). Hemostatic success, control of bleeding, and blood loss were assessed 2, 5, and 10 min after treatment. Hemostatic success and control of bleeding were analyzed using odds ratios and blood loss using mean differences. Hemostatic matrix provided superior hemostatic success relative to MPH at 5 (odds ratio: 0.035, 95% confidence interval: 0.004-0.278) and 10 min (0.032, 0.007-0.150), provided superior control of bleeding at 5 (0.006, <0.001-0.037) and 10 min (0.009, 0.001-0.051), and had significantly less blood loss at 5 (mean difference: 0.3118 mL/min, 95% confidence interval: 0.0939-0.5296) and 10 min (0.5025, 0.2489-0.7561). These findings corroborate other MPH investigations regarding its low-level efficacy and suggest that MPH is not an appropriate surrogate for hemostatic matrix despite similar application techniques. The lack of a procoagulant within MPH may likely be the reason for its lower efficacy and need for multiple applications. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase.

PubMed

Ang, J Sidney; Duffy, Supipi; Segovia, Romulo; Stirling, Peter C; Hieter, Philip

2016-11-01

Mutations that cause genome instability are considered important predisposing events that contribute to initiation and progression of cancer. Genome instability arises either due to defects in genes that cause an increased mutation rate (mutator phenotype), or defects in genes that cause chromosome instability (CIN). To extend the catalog of genome instability genes, we systematically explored the effects of gene overexpression on mutation rate, using a forward-mutation screen in budding yeast. We screened ∼5100 plasmids, each overexpressing a unique single gene, and characterized the five strongest mutators, MPH1 (mutator phenotype 1), RRM3, UBP12, PIF1, and DNA2 We show that, for MPH1, the yeast homolog of Fanconi Anemia complementation group M (FANCM), the overexpression mutator phenotype is distinct from that of mph1Δ. Moreover, while four of our top hits encode DNA helicases, the overexpression of 48 other DNA helicases did not cause a mutator phenotype, suggesting this is not a general property of helicases. For Mph1 overexpression, helicase activity was not required for the mutator phenotype; in contrast Mph1 DEAH-box function was required for hypermutation. Mutagenesis by MPH1 overexpression was independent of translesion synthesis (TLS), but was suppressed by overexpression of RAD27, a conserved flap endonuclease. We propose that binding of DNA flap structures by excess Mph1 may block Rad27 action, creating a mutator phenotype that phenocopies rad27Δ. We believe this represents a novel mutator mode-of-action and opens up new prospects to understand how upregulation of DNA repair proteins may contribute to mutagenesis. Copyright © 2016 by the Genetics Society of America.

Methylphenidate in Adults with Attention Deficit Hyperactivity Disorder and Substance Use Disorders.

PubMed

Simon, Nicolas; Rolland, Benjamin; Karila, Laurent

2015-01-01

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopment disorder occurring during childhood. However, ADHD persists into adulthood in 45.7% of cases. The global prevalence of adult ADHD is estimated to 5.3%, with no difference between Europe and North America. ADHD is often comorbid with substance use disorder (SUD), with Odds Ratio ranges from 1.5 to 7.9, depending on the substance and the dependence level. Conversely, the prevalence of ADHD among patients with SUD is 10.8%, versus 3.8% for patients without SUD. Methylphenidate (MPH) alleviates ADHD symptoms and, as such, is currently considered as a first choice medication. MPH blocks the dopamine and norepinephrine transporters leading to an increase in extracellular dopamine. It should be noted that its subjective effects are highly dependent on the pharmacokinetic and especially on the rate of input, which highlights the importance of choosing a sustained-release formulation. Meanwhile, prescribing MPH to patients with comorbid SUD has always been challenging for clinicians. The aim of this review is to address the benefits and pitfalls of using MPH in adults with ADHD comorbid SUD, depending on each of the following types of SUD: amphetamine, cocaine, nicotine, alcohol, cannabis and opiates. Overall, due to the prevalence of ADHD in SUD and to the benefits of MPH observed in this population, and considering the mild or low side effects observed, the response to MPH treatment should be evaluated individually in adults with comorbid ADHD and SUD. The choice of the formulation should favor sustained- release MPH over immediate release MPH. Cardiovascular parameters also have to be monitored during long-term use.

Phase II Study of Intraventricular Methotrexate in Children With Recurrent or Progressive Malignant Brain Tumors

ClinicalTrials.gov

2018-03-01

Recurrent Childhood Medulloblastoma; Recurrent Childhood Ependymoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Embryonal Tumor With Abundant Neuropil and True Rosettes; Metastatic Malignant Neoplasm to the Leptomeninges

Effects of methylphenidate on acute math performance in children with attention-deficit hyperactivity disorder.

PubMed

Grizenko, Natalie; Cai, Emmy; Jolicoeur, Claude; Ter-Stepanian, Mariam; Joober, Ridha

2013-11-01

Examine the short-term (acute) effects of methylphenidate (MPH) on math performance in children with attention-deficit hyperactivity disorder (ADHD) and what factors predict improvement in math performance. One hundred ninety-eight children with ADHD participated in a double-blind, placebo-controlled, randomized crossover MPH trial. Math response to MPH was determined through administration of math problems adjusted to their academic level during the Restricted Academic Situation Scale (RASS). Student t tests were conducted to assess change in math performance with psychostimulants. Correlation between change on the RASS and change on the math performance was also examined. Linear regression was performed to determine predictor variables. Children with ADHD improved significantly in their math with MPH (P < 0.001). The degree of improvement on the RASS (which evaluates motor activity and orientation to task) and on math performance on MPH was highly correlated. A child's age at baseline and Wechsler Individual Achievement Test (WIAT)-Numerical Operations standard scores at baseline accounted for 15% of variances for acute math improvement. MPH improves acute math performance in children with ADHD. Younger children with lower math scores (as assessed by the WIAT) improved most on math scores when given psychostimulants. NCT00483106.

The dual DVM/MPH degree at the University of Wisconsin--Madison: a uniquely interdisciplinary collaboration.

PubMed

Olsen, Christopher W; Remington, Patrick L

2008-01-01

The University of Wisconsin-Madison (UWM) launched a new Master of Public Health (MPH) degree program in 2005. This 42-credit MPH degree consists of 18 core and 14 elective course credits, two seminar credits, and eight field project/culminating experience credits. Unique strengths of the program include its strongly interdisciplinary philosophy, encompassing both health science (human medicine, veterinary medicine, pharmacy, nursing) and social science units on campus, and its emphasis on service learning through instructional and field project ties to the public-health community of the state and beyond. To date, the program has admitted 87 students, including full-time students as well as part-time students who continue to work in the health care and/or public-health sectors. The program is currently proceeding with the process for accreditation through the Council for Education in Public Health. In 2007, a formal dual DVM/MPH program was approved to allow students to integrate DVM and MPH training and complete both degrees in a total of five years. Nine MPH students over the first three years of admissions have been individuals affiliated with veterinary medicine (five DVM students and four post-graduate veterinarians).

Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

ClinicalTrials.gov

2018-03-09

Central Nervous System Embryonal Tumor, Not Otherwise Specified; Malignant Glioma; Recurrent Atypical Teratoid/Rhabdoid Tumor; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Diffuse Intrinsic Pontine Glioma

Reinforcement and Stimulant Medication Ameliorate Deficient Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Rosch, Keri S; Fosco, Whitney D; Pelham, William E; Waxmonsky, James G; Bubnik, Michelle G; Hawk, Larry W

2016-02-01

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions.

Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Rosch, Keri S.; Fosco, Whitney D.; Pelham, William E.; Waxmonsky, James G.; Bubnik, Michelle G.; Hawk, Larry W.

2015-01-01

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n=111, 25 girls) and typically-developing (TD) controls (n=33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

Toward effective immunotherapy for the treatment of malignant brain tumors.

PubMed

Mitchell, Duane A; Sampson, John H

2009-07-01

The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.

Multifunctional Nanoparticles for Brain Tumor Diagnosis and Therapy

PubMed Central

Cheng, Yu; Morshed, Ramin; Auffinger, Brenda; Tobias, Alex L.; Lesniak, Maciej S.

2013-01-01

Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

Validation of the OMNI RPE Seven Day Exertional Recall Questionnaire

ERIC Educational Resources Information Center

Schafer, Mark A.; Robertson, Robert J.; Thekkada, Savitha J.; Gallagher, Michael, Jr.; Hunt, Sarah E.; Goss, Fredric L.; Aaron, Deborah J.

2013-01-01

Purpose: The present study examined the validity of the Seven Day Recall Questionnaire among recreationally active men and women. Method: Initially, participants completed a level walk (2.5 mph [4.0 kph]), hill walk (3.5 mph [5.6 kph], 5% grade), and run (5.0 mph [8.0 kph], 2.5% grade). Seven days later, participants were given the Seven Day…

PAIRED-CITY STUDY TO DETERMINE THE CONTRIBUTION OF SOURCE WATER TYPE TO THE ENDEMIC LEVEL OF MICROBIAL DISEASE

EPA Science Inventory

Paired-City Study to Determine the Contribution of Source Water Type to the Endemic Level of Microbial Disease

F Frost PhD, T Kunde MPH, L Harter PhD, T Muller MS, GF Craun PE MPH, RL Calderon MPH PhD

ABSTRACT

Context: The effectiveness of current drinking...

Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience.

PubMed

Madajewicz, S; Karakousis, C; West, C R; Caracandas, J; Avellanosa, A M

1984-06-01

One-hundred twenty five of 700 patients with malignant melanoma treated at Roswell Park Memorial Institute from 1972 to 1978 were found to have brain metastases. Seventy-three percent of the patients had multiple brain metastases. Male to female ratio was 1.9:1. The median survival of the untreated group of patients was 3 weeks as compared with that of 6 weeks for the patients maintained on steroids only, 9 weeks for those who received radiotherapy, 11 weeks for the patients treated with intraarterial chemotherapy, and 26 weeks for the patients who underwent successful surgical excision of a solitary lesion.

Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder.

PubMed

Cao, Ai-hua; Yu, Lin; Wang, Yu-wei; Wang, Jun-mei; Yang, Le-jin; Lei, Ge-Fei

2012-02-28

Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models. This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks. The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p < 0.001] and trials to criterion [F (2, 21) = 114.118, p < 0.001] were observed. The SHRs were found to have more perseverative and regressive errors than the control strains (p < 0.001). After MPH treatment, the two MPH treated groups exhibited significantly longer latency and fewer trials to reach criterion than the SHR-vehicle group and the MPH-L group exhibited fewer trials to reach criterion in more stages compared with the MPH-H group. Significant main effects of treatment [F (2, 21) = 52.174, p < 0.001] and error subtype [F (2, 42) = 221.635, p < 0.01] were found. The SHR may be impaired in discrimination learning, reversal learning and attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose.

Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder

PubMed Central

2012-01-01

Background Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models. Methods This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks. Results The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p < 0.001] and trials to criterion [F (2, 21) = 114.118, p < 0.001] were observed. The SHRs were found to have more perseverative and regressive errors than the control strains (p < 0.001). After MPH treatment, the two MPH treated groups exhibited significantly longer latency and fewer trials to reach criterion than the SHR-vehicle group and the MPH-L group exhibited fewer trials to reach criterion in more stages compared with the MPH-H group. Significant main effects of treatment [F (2, 21) = 52.174, p < 0.001] and error subtype [F (2, 42) = 221.635, p < 0.01] were found. Conclusions The SHR may be impaired in discrimination learning, reversal learning and attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose. PMID:22369105

Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

PubMed

Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

2017-03-01

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.

PubMed

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L; Park, John K

2008-07-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.

Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment.

PubMed

Cho, Soo-Churl; Kim, Bung-Nyun; Cummins, Tarrant D R; Kim, Jae-Won; Bellgrove, Mark A

2012-03-01

The purpose of this study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of the Osmotic Controlled-Release Oral Delivery System-methylphenidate (OROS-MPH) in Korean children with attention-deficit/hyperactivity disorder (ADHD). One hundred and one children with ADHD (8.7 ± 1.7 years) were recruited from child psychiatric centers at six university hospitals in South Korea. All participants were drug-naive ADHD children treated with OROS-MPH for 12 weeks. During the treatment period the investigators titrated the OROS-MPH dosage on the basis of symptom severity and side effects. Resting heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were examined before and after treatment. The percentage change score (post-treatment - pretreatment/pretreatment × 100) of each parameter was calculated. Genotyping of SLC6A2 -3081(A/T) and G1287A, and alpha-2A-adrenergic receptor (ADRA2A) MspI and DraI polymorphisms was performed. Clinically significant changes were not found in cardiovascular monitoring during the course of treatment. An increase of HR after OROS-MPH treatment was found to be statistically significant (t = 3.54, p = 0.001). Changes in SBP and DBP were not significant and no specific change was found in the ECGs. However, an additive regression analysis demonstrated a significant association between SLC6A2 -3081(A/T) and percentage change in HR post-treatment (p = 0.01) after controlling for age, gender, dosage of MPH and response and baseline pulse rate. Children with ADHD having the T/T genotype of SLC6A2 showed a 12.5% increase in HR compared to baseline, whereas children with the A/T or A/A genotype showed a 3.5% and 2.5% increase after OROS-MPH treatment, respectively. There was also a significant association between the ADRA2A MspI genotype and percentage change of DBP post-treatment after controlling for age, gender, dosage of MPH and response and baseline DBP (p = 0.009). Children with ADHD having the C/C genotype of ADRA2A MspI showed an 18.5% increase in DBP compared to baseline, but children with the G/G or G/C genotype showed a 0.2% decrease after OROS-MPH treatment. The overall cardiovascular effects of OROS-MPH were modest. However, our findings show a positive association between norepinephrine-related gene polymorphisms and cardiovascular response induced by MPH in Korean children with ADHD. Consideration must be given to such children or adults with specific norepinephrine-related genotypes, especially if they show significant changes in HR or DBP after OROS-MPH administration.

The Population Benefit of Radiotherapy for Malignant Brain Tumors: Local Control and Survival Estimates for Guideline-Based Use.

PubMed

Hanna, Timothy Paul; Delaney, Geoffrey Paul; Barton, Michael Bernard

2016-09-01

To estimate the population benefit of radiotherapy (RT) for primary malignant brain tumors if evidence-based guidelines were routinely followed. This study investigated 5-year local control (LC) and 2- and 5-year overall survival (OS) benefits. RT benefit was the absolute proportional benefit of RT alone over no RT for radical indications, and over surgery alone for adjuvant indications. Chemoradiotherapy (CRT) benefit was the absolute incremental benefit of concurrent chemotherapy and RT over RT alone. Decision tree models were adapted to define the incidence of each indication. Citation databases were systematically queried for the highest level of evidence defining indication benefits. Meta-analysis was performed if there were multiple sources of the same evidence level, and deterministic and probabilistic sensitivity analysis was also performed. Among all patients with malignant brain tumors, 82% had indications for curative- or adjuvant-intent RT. The magnitude of benefit was based on level I or II evidence in 44% of all patients. A total of 25 relevant studies were used to quantify indication benefits. All RT benefit included in the model was irreplaceable. For malignant brain tumors, the estimated population benefit for RT alone was 9% for 5-year LC (95% CI, 7%-10%), 9% for 2-year OS (95% CI, 8%-11%), and 5% for 5-year OS (95% CI, 4%-5%). The incremental benefit of CRT was 1% for 5-year LC (95% CI, 0%-2%), 7% for 2-year OS (95% CI, 4%-11%), and 3% for 5-year OS (95% CI, 1%-5%). The model was robust in sensitivity analysis. When optimally used, RT provides an important benefit for many patients with malignant brain tumors. The model provided a robust means for estimating the magnitude of this benefit. Copyright © 2016 by the National Comprehensive Cancer Network.

PROBABILISTIC HAZARD ASSESSMENT FOR TORNADOES, STRAIGHT-LINE WIND, AND EXTREME PRECIPITATION AT THE SAVANNAH RIVER SITE

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

Werth, D.; NOEMAIL), A.; Shine, G.

Recent data sets for three meteorological phenomena with the potential to inflict damage on SRS facilities - tornadoes, straight winds, and heavy precipitation - are analyzed using appropriate statistical techniques to estimate occurrence probabilities for these events in the future. Summaries of the results for DOE-mandated return periods and comparisons to similar calculations performed in 1998 by Weber, et al., are given. Using tornado statistics for the states of Georgia and South Carolina, we calculated the probability per year of any location within a 2⁰ square area surrounding SRS being struck by a tornado (the ‘strike’ probability) and the probabilitymore » that any point will experience winds above set thresholds. The strike probability was calculated to be 1.15E-3 (1 chance in 870) per year and wind speeds for DOE mandated return periods of 50,000 years, 125,000 years, and 1E+7 years (USDOE, 2012) were estimated to be 136 mph, 151 mph and 221 mph, respectively. In 1998 the strike probability for SRS was estimated to be 3.53 E-4 and the return period wind speeds were 148 mph every 50,000 years and 180 mph every 125,000 years. A 1E+7 year tornado wind speed was not calculated in 1998; however a 3E+6 year wind speed was 260 mph. The lower wind speeds resulting from this most recent analysis are largely due to new data since 1998, and to a lesser degree differences in the models used. By contrast, default tornado wind speeds taken from ANSI/ANS-2.3-2011 are somewhat higher: 161 mph for return periods of 50,000 years, 173 mph every 125,000 years, and 230 mph every 1E+7 years (ANS, 2011). Although the ANS model and the SRS models are very similar, the region defined in ANS 2.3 that encompasses the SRS also includes areas of the Great Plains and lower Midwest, regions with much higher occurrence frequencies of strong tornadoes. The SRS straight wind values associated with various return periods were calculated by fitting existing wind data to a Gumbel distribution, and extrapolating the values for any return period from the tail of that function. For the DOE mandated return periods, we expect straight winds of 123 mph every 2500 years, and 132mph every 6250 years at any point within the SRS. These values are similar to those from the W98 report (which also used the Gumbel distribution for wind speeds) which gave wind speeds of 115mph and 122 mph for return periods of 2500 years and 6250 years, respectively. For extreme precipitation accumulation periods, we compared the fits of three different theoretical extreme-value distributions, and in the end decided to maintain the use of the Gumbel distribution for each period. The DOE mandated 6-hr accumulated rainfall for return periods of 2500 years and 6250 years was estimated as 7.8 inches and 8.4 inches, respectively. For the 24- hr rainfall return periods of 10,000 years and 25,000 years, total rainfall estimates were 10.4 inches and 11.1 inches, respectively. These values are substantially lower than comparable values provided in the W98 report. This is largely a consequence of the W98 use of a different extreme value distribution with its corresponding higher extreme probabilities.« less

The effect of methylphenidate on postural stability under single and dual task conditions in children with attention deficit hyperactivity disorder - a double blind randomized control trial.

PubMed

Jacobi-Polishook, Talia; Shorer, Zamir; Melzer, Itshak

2009-05-15

To investigate the effects of Methylphenidate (MPH) on postural stability in attention deficit hyperactivity disorder (ADHD) children in single and dual task conditions. A randomized controlled double-blind study analyzing postural stability in 24 ADHD children before and after MPH vs. placebo treatments, in three task conditions: (1) Single task, standing still; (2) dual task, standing still performing a memory-attention demanding task; (3) standing still listening to music. MPH resulted in a significant improvement in postural stability during the dual task condition and while listening to music, with no equivalent improvement in placebo controls. MPH improves postural stability in ADHD, especially when an additional task is performed. This is probably due to enhanced attention abilities, thus contributing to improved balance control during performance of tasks that require attention. MPH remains to be studied as a potential drug treatment to improve balance control and physical functioning in other clinical populations.

Novelty-seeking trait predicts the effect of methylphenidate on creativity.

PubMed

Gvirts, Hila Z; Mayseless, Naama; Segev, Aviv; Lewis, D Yael; Feffer, Kfir; Barnea, Yael; Bloch, Yuval; Shamay-Tsoory, Simon G

2017-05-01

In recent years the use of psychostimulants for cognitive enhancement in healthy individuals with no psychiatric disorders has been on the rise. However, it is still unclear whether psychostimulants improve certain cognitive functions at the cost of others, and how these psychostimulants interact with individual personality differences. In the current study, we investigated whether the effect of one common stimulant, methylphenidate (MPH), on creativity is associated with novelty seeking. Thirty-six healthy adults, without attention-deficit hyperactivity disorder (ADHD) symptomology, were assigned randomly in a double-blind fashion to receive MPH or placebo. We found that the effect of MPH on creativity was dependent on novelty-seeking (NS) personality characteristics of the participants. MPH increased creativity in individuals with lower NS, while it reduced creativity levels in individuals with high NS. These findings highlight the role of the dopaminergic system in creativity, and indicate that among healthy individuals NS can be seen as a predictor of the effect of MPH on creativity.

Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

PubMed

Doolittle, N D; Anderson, C P; Bleyer, W A; Cairncross, J G; Cloughesy, T; Eck, S L; Guastadisegni, P; Hall, W A; Muldoon, L L; Patel, S J; Peereboom, D; Siegal, T; Neuwelt, E A

2001-01-01

Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.

A Double-Blind, Placebo-Controlled Trial of Dexmethylphenidate Hydrochloride and D,l-Threo-Methylphenidate Hydrochloride in Children with Attention-Deficit-Hyperactivity Disorder

ERIC Educational Resources Information Center

Wigal, Sharon; Swanson, James M.; Feifel, David; Sangal, R. Bart; Elia, Josephine; Casat, Charles D.; Zeldis, Jerome B.; Conners, C. Keith

2004-01-01

Objective: To evaluate the efficacy and safety of dexmethylphenidate hydrochloride (d-MPH, Focalin[TM]) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and to test an a priori hypothesis that d-MPH would have a longer duration of action than d,l-threo-methylphenidate (d,l-MPH). Method: This was a randomized, double-blind study…

Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study.

PubMed

Johnston, Blair A; Coghill, David; Matthews, Keith; Steele, J Douglas

2015-01-01

Methylphenidate (MPH) is established as the main pharmacological treatment for patients with attention deficit hyperactivity disorder (ADHD). Whilst MPH is generally a highly effective treatment, not all patients respond, and some experience adverse reactions. Currently, there is no reliable method to predict how patients will respond, other than by exposure to a trial of medication. In this preliminary study, we sought to investigate whether an accurate predictor of clinical response to methylphenidate could be developed for individual patients, using sociodemographic, clinical and neuropsychological measures. Of the 43 boys with ADHD included in this proof-of-concept study, 30 were classed as responders and 13 as non-responders to MPH, with no significant differences in age nor verbal intelligence quotient (IQ) between the groups. Here we report the application of a multivariate analysis approach to the prediction of clinical response to MPH, which achieved an accuracy of 77% (p = 0.005). The most important variables to the classifier were performance on a 'go/no go' task and comorbid conduct disorder. This preliminary study suggested that further investigation is merited. Achieving a highly significant accuracy of 77% for the prediction of MPH response is an encouraging step towards finding a reliable and clinically useful method that could minimise the number of children needlessly being exposed to MPH. © The Author(s) 2014.

Effectiveness of atomoxetine and methylphenidate for problematic online gaming in adolescents with attention deficit hyperactivity disorder.

PubMed

Park, Jeong Ha; Lee, Young Sik; Sohn, Ji Hyun; Han, Doug Hyun

2016-11-01

There is a high prevalence of problematic online gaming in adolescents with attention deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents with ADHD. We recruited 86 adolescents diagnosed with ADHD together with Internet gaming disorder. These participants were divided into two treatment groups: 44 participants were treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks. During the 3-month study period, the MPH group showed greater improvement in Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improvement in Child Depression Inventory scores than the MPH group. However, Young Internet Addiction Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales scores. Both MPH and ATM reduced the severity of Internet gaming disorder symptoms, and this reduction was correlated with impulsivity reduction, which also resulted from both ADHD medications. These findings suggest impulsivity plays a critical role in the development of problematic online gaming. Copyright © 2016 John Wiley & Sons, Ltd.

Malignant tumors of childhood

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

Brooks, B.J.

1986-01-01

This book contains 34 papers about malignant tumors. some of the titles are: Invasive Cogenital Mesoblastic Nephroma, Leukemia Update, Unusual Perinatal Neoplasms, Lymphoma Update, Gonadal Germ Cell Tumors in Children, Nutritional Status and Cancer of Childhood, and Chemotherapy of Brain tumors in Children.

Surgical management of patients with primary brain tumors.

PubMed

Bohan, Eileen; Glass-Macenka, Deanna

2004-11-01

To provide an overview of the diagnostic work-up, intraoperative technologies, postoperative treatment options, and investigational new therapies in patients with malignant brain tumors. Published textbooks and articles and other reference materials. Recent improvements in diagnostic and surgical equipment have influenced outcomes and overall quality of life for patients with central nervous system tumors. The ability to more accurately target and more safely remove brain tumors has enhanced the postoperative period and decreased hospital stays. However, malignant neoplasms continue to be refractory to current treatments, necessitating innovative surgical approaches at the time of initial diagnosis and at tumor recurrence. Nurses with an understanding of current diagnostic and surgical treatment modalities for brain tumors are able to provide accurate patient education and comprehensive care, enhancing the overall hospital and outpatient experience.

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed Central

Shah, Khalid

2016-01-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. PMID:27282399

Cross-validation of oxygen uptake prediction during walking in ambulatory persons with multiple sclerosis.

PubMed

Agiovlasitis, Stamatis; Motl, Robert W

2016-01-01

An equation for predicting the gross oxygen uptake (gross-VO2) during walking for persons with multiple sclerosis (MS) has been developed. Predictors included walking speed and total score from the 12-Item Multiple Sclerosis Walking Scale (MSWS-12). This study examined the validity of this prediction equation in another sample of persons with MS. Participants were 18 persons with MS with limited mobility problems (42 ± 13 years; 14 women). Participants completed the MSWS-12. Gross-VO2 was measured with open-circuit spirometry during treadmill walking at 2.0, 3.0, and 4.0 mph (0.89, 1.34, and 1.79 m·s(-1)). Absolute percent error was small: 8.3 ± 6.1% , 8.0 ± 5.6% , and 12.2 ± 9.0% at 2.0, 3.0, and 4.0 mph, respectively. Actual gross-VO2 did not differ significantly from predicted gross-VO2 at 2.0 and 3.0 mph, but was significantly higher than predicted gross-VO2 at 4.0 mph (p <  0.001). Bland-Altman plots indicated nearly zero mean difference between actual and predicted gross-VO2 with modest 95% confidence intervals at 2.0 and 3.0 mph, but there was some underestimation at 4.0 mph. Speed and MSWS-12 score provide valid prediction of gross-VO2 during treadmill walking at slow and moderate speeds in ambulatory persons with MS. However, there is a possibility of small underestimation for walking at 4.0 mph.

Assessment of potential cardiovascular risks of methylphenidate in comparison with sibutramine: do we need a SCOUT (trial)?

PubMed

Antel, Jochen; Albayrak, Özgür; Heusch, Gerd; Banaschewski, Tobias; Hebebrand, Johannes

2015-04-01

With the recent approval of methylphenidate (MPH) for treating attention-deficit/hyperactivity disorder (ADHD) in adults, the number of patients exposed will increase tremendously. The ongoing debate on the cardiovascular safety of MPH has triggered two large retrospective cohort studies in children and adolescents as well as in young to middle-aged adults. These studies looked into serious cardiovascular events (sudden cardiac death, acute myocardial infarction and stroke) as primary endpoints and concluded that MPH was safe after a mean duration of 2.1 years of follow-up in children and adolescents and mean duration of 0.33 years of current use in adults. The results are encouraging with respect to the short- and medium-term use of MPH. Without the inherent limitations of retrospective cohort studies, a prospective randomized, double-blind, placebo-controlled, multicenter trial in individuals stratified for cardiovascular risk factors would allow for an optimized risk assessment. With many millions of patients treated per year and drawing parallels to the lately discovered risks of sibutramine, another sympathomimetic with an overlapping mode of action and similar side effects on heart rate and blood pressure, we hypothesize that such a trial might be a dedicated risk mitigation strategy for public health. A critical assessment of cardiovascular side effects of MPH appears particularly warranted, because ADHD is associated with obesity, smoking and poor health in general. We summarize recent findings with the focus on cardiovascular risks of MPH in humans; we additionally analyze the limited number of rodent studies that have addressed cardiovascular risks of MPH.

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of Attention Deficit Hyperactivity Disorder

PubMed Central

Somkuwar, Sucharita S.; Kantak, Kathleen M.; Dwoskin, Linda P.

2015-01-01

Attention Deficit Hyperactivity Disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in Spontaneously Hypertensive Rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax) x first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD. PMID:25680322

Factors Associated With Adherence to Methylphenidate Treatment in Adult Patients With Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders.

PubMed

Skoglund, Charlotte; Brandt, Lena; Almqvist, Catarina; DʼOnofrio, Brian M; Konstenius, Maija; Franck, Johan; Larsson, Henrik

2016-06-01

Adherence to treatment is one of the most consistent factors associated with a favorable addiction treatment outcome. Little is known about factors associated with treatment adherence in individuals affected with comorbid attention-deficit/hyperactivity disorder and substance use disorders (SUD). This study aimed to explore whether treatment-associated factors, such as the prescribing physician's (sub)specialty and methylphenidate (MPH) dose, or patient-related factors, such as sex, age, SUD subtype, and psychiatric comorbidity, were associated with adherence to MPH treatment. Swedish national registers were used to identify adult individuals with prescriptions of MPH and medications specifically used in the treatment of SUD or a diagnosis of SUD and/or coexisting psychiatric diagnoses. Primary outcome measure was days in active MPH treatment in stratified dose groups (≤36 mg, ≥37 mg to ≤54 mg, ≥55 mg to ≤72 mg, ≥73 mg to ≤90 mg, ≥91 mg to ≤108 mg, and ≥109 mg). Lower MPH doses (ie, ≤36 mg day 100) were associated with treatment discontinuation between days 101 and 830 (HR≤36 mg, 1.67; HR37-54mg, 1.37; HR55-72mg, 1.36; HR73-90mg, 1.19; HR≥108mg, 1.09). The results showed a linear trend (P < 0.0001) toward decreased risk of treatment discontinuation along with increase of MPH doses. In conclusion, this study shows that higher MPH doses were associated with long-term treatment adherence in individuals with attention-deficit/hyperactivity disorder and SUD.

Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services?

PubMed

Chan, Vincy; Xiong, Chen; Colantonio, Angela

2015-01-01

Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting. Copyright © 2015 by the American Occupational Therapy Association, Inc.

Growth of Malignant Non-CNS Tumors Alters Brain Metabolome

PubMed Central

Kovalchuk, Anna; Nersisyan, Lilit; Mandal, Rupasri; Wishart, David; Mancini, Maria; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga

2018-01-01

Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as “tumor brain.” Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraft™ mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID:29515623

Methylphenidate alleviates manganese-induced impulsivity but not distractibility

PubMed Central

Beaudin, Stephane A.; Strupp, Barbara J.; Uribe, Walter; Ysais, Lauren; Strawderman, Myla; Smith, Donald R.

2017-01-01

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50 mg Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107 – 115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5 mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention. PMID:28363668

Methylphenidate alleviates manganese-induced impulsivity but not distractibility.

PubMed

Beaudin, Stephane A; Strupp, Barbara J; Uribe, Walter; Ysais, Lauren; Strawderman, Myla; Smith, Donald R

2017-05-01

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention. Copyright © 2017 Elsevier Inc. All rights reserved.

Subjective Effects, Misuse, and Adverse Effects of Osmotic-Release Methylphenidate Treatment in Adolescent Substance Abusers with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Lewis, Daniel F.; Riggs, Paula D.; Davies, Robert D.; Adler, Lenard A.; Sonne, Susan; Somoza, Eugene C.

2011-01-01

Abstract Objective Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non–substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD. Method Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13–18) with at least one non-nicotine SUD and one with 255 adult smokers (18–55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). Results Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults. Conclusions With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence. PMID:22040190

Subjective effects, misuse, and adverse effects of osmotic-release methylphenidate treatment in adolescent substance abusers with attention-deficit/hyperactivity disorder.

PubMed

Winhusen, Theresa M; Lewis, Daniel F; Riggs, Paula D; Davies, Robert D; Adler, Lenard A; Sonne, Susan; Somoza, Eugene C

2011-10-01

Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non-substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD. Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13-18) with at least one non-nicotine SUD and one with 255 adult smokers (18-55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults. With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence.

The hairpin region of Ndc80 is important for the kinetochore recruitment of Mph1/MPS1 in fission yeast.

PubMed

Chmielewska, Aldona Ewa; Tang, Ngang Heok; Toda, Takashi

2016-01-01

The establishment of proper kinetochore-microtubule attachments facilitates faithful chromosome segregation. Incorrect attachments activate the spindle assembly checkpoint (SAC), which blocks anaphase onset via recruitment of a cohort of SAC components (Mph1/MPS1, Mad1, Mad2, Mad3/BubR1, Bub1 and Bub3) to kinetochores. KNL1, a component of the outer kinetochore KMN network (KNL1/Mis12 complex/Ndc80 complex), acts as a platform for Bub1 and Bub3 localization upon its phosphorylation by Mph1/MPS1. The Ndc80 protein, a major microtubule-binding site, is critical for MPS1 localization to the kinetochores in mammalian cells. Here we characterized the newly isolated mutant ndc80-AK01 in fission yeast, which contains a single point mutation within the hairpin region. This hairpin connects the preceding calponin-homology domain with the coiled-coil region. ndc80-AK01 was hypersensitive to microtubule depolymerizing reagents with no apparent growth defects without drugs. Subsequent analyses indicated that ndc80-AK01 is defective in SAC signaling, as mutant cells proceeded into lethal cell division in the absence of microtubules. Under mitotic arrest conditions, all SAC components (Ark1/Aurora B, Mph1, Bub1, Bub3, Mad3, Mad2 and Mad1) did not localize to the kinetochore. Further genetic analyses indicated that the Ndc80 hairpin region might act as a platform for the kinetochore recruitment of Mph1, which is one of the most upstream SAC components in the hierarchy. Intriguingly, artificial tethering of Mph1 to the kinetochore fully restored checkpoint signaling in ndc80-AK01 cells, further substantiating the notion that Ndc80 is a kinetochore platform for Mph1. The hairpin region of Ndc80, therefore, plays a critical role in kinetochore recruitment of Mph1.

Components of a Fanconi-like pathway control Pso2-independent DNA interstrand crosslink repair in yeast.

PubMed

Ward, Thomas A; Dudášová, Zuzana; Sarkar, Sovan; Bhide, Mangesh R; Vlasáková, Danuša; Chovanec, Miroslav; McHugh, Peter J

2012-01-01

Fanconi anemia (FA) is a devastating genetic disease, associated with genomic instability and defects in DNA interstrand cross-link (ICL) repair. The FA repair pathway is not thought to be conserved in budding yeast, and although the yeast Mph1 helicase is a putative homolog of human FANCM, yeast cells disrupted for MPH1 are not sensitive to ICLs. Here, we reveal a key role for Mph1 in ICL repair when the Pso2 exonuclease is inactivated. We find that the yeast FANCM ortholog Mph1 physically and functionally interacts with Mgm101, a protein previously implicated in mitochondrial DNA repair, and the MutSα mismatch repair factor (Msh2-Msh6). Co-disruption of MPH1, MGM101, MSH6, or MSH2 with PSO2 produces a lesion-specific increase in ICL sensitivity, the elevation of ICL-induced chromosomal rearrangements, and persistence of ICL-associated DNA double-strand breaks. We find that Mph1-Mgm101-MutSα directs the ICL-induced recruitment of Exo1 to chromatin, and we propose that Exo1 is an alternative 5'-3' exonuclease utilised for ICL repair in the absence of Pso2. Moreover, ICL-induced Rad51 chromatin loading is delayed when both Pso2 and components of the Mph1-Mgm101-MutSα and Exo1 pathway are inactivated, demonstrating that the homologous recombination stages of ICL repair are inhibited. Finally, the FANCJ- and FANCP-related factors Chl1 and Slx4, respectively, are also components of the genetic pathway controlled by Mph1-Mgm101-MutSα. Together this suggests that a prototypical FA-related ICL repair pathway operates in budding yeast, which acts redundantly with the pathway controlled by Pso2, and is required for the targeting of Exo1 to chromatin to execute ICL repair.

The hairpin region of Ndc80 is important for the kinetochore recruitment of Mph1/MPS1 in fission yeast

PubMed Central

Chmielewska, Aldona Ewa; Tang, Ngang Heok; Toda, Takashi

2016-01-01

ABSTRACT The establishment of proper kinetochore-microtubule attachments facilitates faithful chromosome segregation. Incorrect attachments activate the spindle assembly checkpoint (SAC), which blocks anaphase onset via recruitment of a cohort of SAC components (Mph1/MPS1, Mad1, Mad2, Mad3/BubR1, Bub1 and Bub3) to kinetochores. KNL1, a component of the outer kinetochore KMN network (KNL1/Mis12 complex/Ndc80 complex), acts as a platform for Bub1 and Bub3 localization upon its phosphorylation by Mph1/MPS1. The Ndc80 protein, a major microtubule-binding site, is critical for MPS1 localization to the kinetochores in mammalian cells. Here we characterized the newly isolated mutant ndc80-AK01 in fission yeast, which contains a single point mutation within the hairpin region. This hairpin connects the preceding calponin-homology domain with the coiled-coil region. ndc80-AK01 was hypersensitive to microtubule depolymerizing reagents with no apparent growth defects without drugs. Subsequent analyses indicated that ndc80-AK01 is defective in SAC signaling, as mutant cells proceeded into lethal cell division in the absence of microtubules. Under mitotic arrest conditions, all SAC components (Ark1/Aurora B, Mph1, Bub1, Bub3, Mad3, Mad2 and Mad1) did not localize to the kinetochore. Further genetic analyses indicated that the Ndc80 hairpin region might act as a platform for the kinetochore recruitment of Mph1, which is one of the most upstream SAC components in the hierarchy. Intriguingly, artificial tethering of Mph1 to the kinetochore fully restored checkpoint signaling in ndc80-AK01 cells, further substantiating the notion that Ndc80 is a kinetochore platform for Mph1. The hairpin region of Ndc80, therefore, plays a critical role in kinetochore recruitment of Mph1. PMID:26900649

Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma.

PubMed

Asavarut, Paladd; O'Neill, Kevin; Syed, Nelofer; Hajitou, Amin

2014-01-01

The incipient development of gene therapy for cancer has fuelled its progression from bench to bedside in mere decades. Of all malignancies that exist, gliomas are the largest class of brain tumors, and are renowned for their aggressiveness and resistance to therapy. In order for gene therapy to achieve clinical success, a multitude of barriers ranging from glioma tumor physiology to vector biology must be overcome. Many viral gene delivery systems have been subjected to clinical investigation; however, with highly limited success. In this review, the current progress and challenges of gene therapy for malignant glioma are discussed. Moreover, we highlight the hybrid adeno-associated virus and bacteriophage vector as a potential candidate for targeted gene delivery to brain tumors.

[A case of pulmonary malignant melanoma mimicking lung abscess].

PubMed

Mochizuki, Hideaki; Chikui, Emiko; Tokumaru, Aya; Kato, Takayuki; Arai, Tomio; Takahashi, Hideki

2011-06-01

An 84-year-old man was admitted with paresis of the right lower limb. Hemorrhagic lesions were demonstrated in the left frontoparietal lobe and cerebellum by cranial computed tomography (CT) and magnetic resonance imaging (MRI). Chest CT revealed an ill-defined mass measuring 4 x 6 cm in the left lower lobe of the lung, although bronchoscopic examination failed to obtain pathological diagnosis. Clinical diagnosis of primary lung cancer with multiple brain metastases was made, and he underwent whole brain radiotherapy. The pulmonary and cerebral lesions mimicked abscesses during his clinical course, and he died of respiratory failure due to bilateral pneumonia three months after admission. Autopsy revealed that both the pulmonary and brain lesions were malignant melanomas, but no other melanoma lesions could be identified despite meticulous investigation. Although malignant melanoma with an unknown primary site is rare in Japan, careful evaluation of the CT and MRI findings might be the key to correct diagnosis in this case.

Stereotactic Radiosurgery in Treating Patients With Brain Tumors

ClinicalTrials.gov

2012-03-21

Adult Central Nervous System Germ Cell Tumor; Adult Malignant Meningioma; Adult Medulloblastoma; Adult Noninfiltrating Astrocytoma; Adult Oligodendroglioma; Adult Craniopharyngioma; Adult Meningioma; Brain Metastases; Adult Ependymoma; Adult Pineal Parenchymal Tumor; Adult Brain Stem Glioma; Adult Infiltrating Astrocytoma; Mixed Gliomas; Stage IV Peripheral Primitive Neuroectodermal Tumor

Grumman WS33 wind system: prototype construction and testing, Phase II technical report

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

Adler, F.M.; Henton, P.; King, P.W.

1980-11-01

The prototype fabrication and testing of the 8 kW small wind energy conversion system are reported. The turbine is a three-bladed, down-wind machine designed to interface directly with an electrical utility network. The machine as finally fabricated is rated at 15 kW at 24 mpH and peak power of 18 kW at 35 mph. Utility compatible electrical power is generated in winds between a cut-in speed of 9 mph and a cut-out speed of 35 mph by using the torque characteristics of the unit's induction generator combined with the rotor aerodynamics to maintain essentially constant speed. Inspection procedures, pre-delivery testing,more » and a cost analysis are included.« less

Hurricane Celia off the Pacific Coast of Mexico

NASA Image and Video Library

2004-07-23

Hurricane Celia as observed by NASA's spaceborne Atmospheric Infrared Sounder (AIRS). This image shows Celia on July 23 in visible light, as you would perceive it from space. Located in the eastern north Pacific Ocean off the coast of Mexico, Celia's winds have now dissipated to highs of 40 mph. Celia was the first hurricane of the eastern north Pacific season. Figure 1 is a daylight snapshot taken on July 19; Celia as tropical storm, winds at 50mph. Figure 2 is a daylight snapshot taken on July 21; Celia has a small eye with an 80-90% closed eyewall; sustained winds at 75mph with gusts reaching 92mph; Celia is upgraded to hurricane status. http://photojournal.jpl.nasa.gov/catalog/PIA00438

KSC-04pd1697

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, workers prepare to close the payload bay doors on Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1692

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare to stow the landing gear on the orbiter Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, and closing their payload bay doors. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1694

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare the wheel bay to stow Atlantis’ landing gear in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, and closing their payload bay doors. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1711

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility finish Hurricane preparations on the payload bay doors of Atlantis. Preparing for the expected impact of Hurricane Frances on Saturday, workers also powered down the Space Shuttle orbiters, and stowed the landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1691

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare to close the nose wheel doors on Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Preparations at KSC include powering down the Space Shuttle orbiters, closing their payload bay doors and stowing their landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1688

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare the orbiter Atlantis and related equipment for the expected impact of Hurricane Frances on Saturday. Preparations at KSC include powering down the Space Shuttle orbiters, closing their payload bay doors and stowing their landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1703

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the payload bay doors on Atlantis are being closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1710

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility cover up areas of Atlantis with plastic, preparing for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, closing the payload bay doors and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1693

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare to stow the landing gear on the orbiter Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, and closing their payload bay doors. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1699

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, Atlantis’ payload bay doors are being closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1698

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, workers prepare to close the payload bay doors on Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1690

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare to close the nose wheel doors on Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Preparations at KSC include powering down the Space Shuttle orbiters, closing their payload bay doors and stowing their landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1689

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility prepare to close the nose wheel doors on Atlantis in preparation for the expected impact of Hurricane Frances on Saturday. Preparations at KSC include powering down the Space Shuttle orbiters, closing their payload bay doors and stowing their landing gear. They are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1708

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility cover up areas of Atlantis, preparing for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, closing the payload bay doors and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1702

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the payload bay doors on Atlantis are being closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1700

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the payload bay doors on Atlantis are being closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1696

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, Atlantis’ wheels are raised into their wheel bays in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, and closing their payload bay doors. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1704

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the payload bay doors on Atlantis are being closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1701

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, a worker checks out part of Atlantis after payload bay doors were closed in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1695

NASA Image and Video Library

2004-08-31

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, Atlantis’ wheels are raised into their wheel bays in preparation for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, and closing their payload bay doors. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

KSC-04pd1709

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility cover up areas of Atlantis with plastic, preparing for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, closing the payload bay doors and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

Photodynamic Therapy for Malignant Brain Tumors.

PubMed

Akimoto, Jiro

2016-01-01

Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women's Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area.

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.

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

PubMed

Wigal, Sharon B; Childress, Ann; Berry, Sally A; Belden, Heidi W; Chappell, Phillip; Wajsbrot, Dalia B; Nagraj, Praneeta; Abbas, Richat; Palumbo, Donna

2018-06-01

To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

PubMed

McCracken, J T; Badashova, K K; Posey, D J; Aman, M G; Scahill, L; Tierney, E; Arnold, L E; Vitiello, B; Whelan, F; Chuang, S Z; Davies, M; Shah, B; McDougle, C J; Nurmi, E L

2014-06-01

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Methylphenidate treatment of attention deficit hyperactivity disorder in young people with learning disability and difficult-to-treat epilepsy: evidence of clinical benefit.

PubMed

Fosi, Tangunu; Lax-Pericall, Maria T; Scott, Rod C; Neville, Brian G; Aylett, Sarah E

2013-12-01

To establish the efficacy and safety of methylphenidate (MPH) treatment for attention deficit hyperactivity disorder (ADHD) in a group of children and young people with learning disability and severe epilepsy. This retrospective study systematically reviewed the case notes of all patients treated with methylphenidate (MPH) for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD at a specialist epilepsy center between 1998 and 2005. Treatment efficacy was ascertained using clinical global impressions (CGI) scores, and safety was indexed by instances of >25% increase in monthly seizure count within 3 months of starting MPH. Eighteen (18) patients were identified with refractory epilepsies (14 generalized, 4 focal), IQ <70, and ADHD. Male patients predominated (13:5) and ADHD was diagnosed at a median age of 11.5 years (range 6–18 years). With use of a combination of a behavioral management program and MPH 0.3–1 mg/kg/day, ADHD symptoms improved in 61% of patients (11/18; type A intraclass correlation coefficient of CGI 0.85, 95% confidence interval [CI] 0.69–0.94). Daily MPH dose, epilepsy variables, and psychiatric comorbidity did not relate to treatment response across the sample. MPH adverse effects led to treatment cessation in three patients (dysphoria in two, anxiety in one). There was no statistical evidence for a deterioration of seizure control in this group with the use of MPH. Methylphenidate with behavioral management was associated with benefit in the management of ADHD in more than half of a group of children with severe epilepsy and additional cognitive impairments. Eighteen percent had significant side effects but no attributable increase in seizures. Methylphenidate is useful in this group and is likely to be under employed.

Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials.

PubMed

Liu, Qiang; Zhang, Hong; Fang, Qingqing; Qin, Lili

2017-11-01

Comparative efficacy and safety are important issues for appropriate drug selection for attention-deficit hyperactivity disorder (ADHD) treatment. Therefore we conducted a meta-analysis, where we compared atomoxetine (ATX) and methylphenidate (MPH) for ADHD treatment in children and adolescents. Literature retrieval was conducted in relevant databases from their inception to April 2016 to select head-to-head trials that compared ATX and MPH in children and adolescents. Outcomes like response rate, ADHD Rating Scale (ADHD-RS) score, and adverse events were compared between ATX and MPH treatments. The standardized mean difference (SMD) and risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were used as the effect size for continuous data or dichotomous data, respectively. Eleven eligible randomized-controlled trials were included, and two of them were double-blind, while the remaining were open-label. Compared to ATX, MPH showed a higher response rate (RR = 1.14, 95% CI [1. 09, 1.20]), decreased inattention (SMD = -0.13, 95% CI [-0.25, -0.01]) and lower risk of adverse events (drowsiness: RR = 0.17, 95% CI [0.11, 0.26; nausea: RR = 0.49; 95% CI [0.29, 0.85; vomiting: RR = 0.41, 95% CI [0.27, 0.63]). However, MPH presented a higher risk of insomnia than ATX (RR = 2.27, 95% CI [1.63, 3.15], p < .01). Results of the meta-analysis add additional evidence of the effectiveness of both ATX and MPH and suggest that MPH should be a first treatment option in most patients with ADHD.

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

PubMed Central

Izquierdo, Alicia; Pozos, Hilda; De La Torre, Adrianna; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

2016-01-01

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. PMID:27091300

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats.

PubMed

Izquierdo, Alicia; Pozos, Hilda; Torre, Adrianna De La; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

2016-07-15

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. Copyright © 2016 Elsevier B.V. All rights reserved.

SLC6A3 polymorphism and response to methylphenidate in children with ADHD: A systematic review and meta-analysis.

PubMed

Soleimani, Robabeh; Salehi, Zivar; Soltanipour, Soheil; Hasandokht, Tolou; Jalali, Mir Mohammad

2018-04-01

Methylphenidate (MPH) is the most commonly used treatment for attention-deficit hyperactivity disorder (ADHD) in children. However, the response to MPH is not similar in all patients. This meta-analysis investigated the potential role of SLC6A3 polymorphisms in response to MPH in children with ADHD. Clinical trials or naturalistic studies were selected from electronic databases. A meta-analysis was conducted using a random-effects model. Cohen's d effect size and 95% confidence intervals (CIs) were determined. Sensitivity analysis and meta-regression were performed. Q-statistic and Egger's tests were conducted to evaluate heterogeneity and publication bias, respectively. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Sixteen studies with follow-up periods of 1-28 weeks were eligible. The mean treatment acceptability of MPH was 97.2%. In contrast to clinical trials, the meta-analysis of naturalistic studies indicated that children without 10/10 repeat carriers had better response to MPH (Cohen's d: -0.09 and 0.44, respectively). The 9/9 repeat polymorphism had no effect on the response rate (Cohen's d: -0.43). In the meta-regression, a significant association was observed between baseline severity of ADHD, MPH dosage, and combined type of ADHD in some genetic models. Sensitivity analysis indicated the robustness of our findings. No publication bias was observed in our meta-analysis. The GRADE evaluations revealed very low levels of confidence for each outcome of response to MPH. The results of clinical trials and naturalistic studies regarding the effect size between different polymorphisms of SLC6A3 were contradictory. Therefore, further research is recommended. © 2017 Wiley Periodicals, Inc.

[Primary culture of human malignant meningioma cells and its intracranial orthotopic transplantation in nude mice].

PubMed

Hu, Mei-Xin; Liu, Jia-le; Chen, Xuan-Bo; Xu, An-Qi; Shu, Song-Ren; Wang, Chao-Hu; Liu, Yi

2018-03-20

To obtain stable primary cultures of human malignant meningioma cells and establish an intracranial in-situ tumor model in nude mice. Ten surgical specimens of highly suspected malignant meningioma were obtained with postoperative pathological confirmation. Primary malignant meningioma cells were cultured from the tissues using a modified method and passaged. After identification with cell immunofluorescence, the cultured cells were inoculated into the right parietal lobe of 6 nude mice using stereotaxic apparatus and also transplanted subcutaneously in another 6 nude mice. The nude mice were executed after 6 weeks, and HE staining and immunohistochmistry were used to detect tumor growth and the invasion of the adjacent brain tissues. The primary malignant meningioma cells were cultured successfully, and postoperative pathology reported anaplastic malignant meningioma. Cell immunofluorescence revealed positivity for vimentin and EMA in the cells, which showed a S-shaped growth curve in culture. Flow cytometry revealed a cell percentage in the Q3 area of (95.99∓2.58)%. Six weeks after transplantation, tumor nodules occurred in the subcutaneous tumor group, and the nude mice bearing the in situ tumor showed obvious body weight loss. The xenografts in both groups contained a mean of (36∓5.35)% cells expressing Ki-67, and the intracranial in situ tumor showed obvious invasion of the adjacent peripheral brain tissues. We obtained stable primary cultures of malignant meningioma cells and successfully established a nude mouse model bearing in situ human malignant meningioma.

Nitrosoureas Inhibit the Stathmin Mediated Migration and Invasion of Malignant Glioma Cells

PubMed Central

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L.; Park, John K.

2008-01-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement related processes. Scratch-wound healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down regulation of cellular stathmin levels and in the absence and presence of sub-lethal nitrosourea (CCNU; [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]) concentrations. We demonstrate that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μM, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain and that nitrosoureas may have therapeutic benefits in addition to their anti-proliferative effects. PMID:18593927

Exposure to methylphenidate during peri-adolescence affects endocrine functioning and sexual behavior in female Long-Evans rats.

PubMed

Guarraci, Fay A; Holifield, Caroline; Morales-Valenzuela, Jessica; Greene, Kasera; Brown, Jeanette; Lopez, Rebecca; Crandall, Christina; Gibbs, Nicole; Vela, Rebekah; Delgado, Melissa Y; Frohardt, Russell J

2016-03-01

The present study was designed to test the effects of methylphenidate (MPH) exposure on the maturation of endocrine functioning and sexual behavior. Female rat pups received either MPH (2.0mg/kg, i.p.) or saline twice daily between postnatal days 20-35. This period of exposure represents the time just prior to puberty as well as puberty onset. Approximately five weeks after the last injection of MPH or saline, female subjects were hormone-primed and tested during their first sexual experience. Subjects were given the choice to interact with a sexually active male or a sexually receptive female rat (i.e., the partner-preference test). The partner-preference paradigm allows us to assess multiple aspects of female sexual behavior. MPH exposure during peri-adolescence delayed puberty and, when mated for the first time, affected sexual behavior (e.g., increased time spent with the male stimulus and decreased the likelihood of leaving after mounts) during the test of partner preference. When monitoring estrous cyclicity, female subjects treated with MPH during peri-adolescence frequently experienced irregular estrous cycles. The results of the present study suggest that chronic exposure to a therapeutic dose of MPH around the onset of puberty alters long-term endocrine functioning, but with hormone priming, increases sensitivity to sexual stimuli. Copyright © 2015 Elsevier Inc. All rights reserved.

Anti-Melanogenic Activity and Cytotoxicity of Pistacia vera Hull on Human Melanoma SKMEL-3 Cells.

PubMed

Sarkhail, Parisa; Salimi, Mona; Sarkheil, Pantea; Mostafapour Kandelous, Hirsa

2017-07-01

Pistacia vera seed is a common food and medicinal seed in Iran. It's hull (outer skin) as a significant byproduct of pistachio, is traditionally used as tonic, sedative and antidiarrheal and has been shown to be a rich source of antioxidants. The aim of the present study is to evaluate the anti-melanogenic activity of the pistachio hulls in order to discover a new alternative herbal agent to treat skin hyperpigmentation disorders. In this work, antioxidant and anti-tyrosinase activity of MeOH extract from Pistacia vera hull (MPH) were evaluated in vitro, respectively, by DPPH radical scavenging and mushroom tyrosinase activity assays. Then the effect of MPH on the melanin content, cellular tyrosinase activity and cytotoxicity (MTT assay) on human melanoma SKMEL-3 cell were determined followed by 72 h incubation. The results indicated that MPH had valuable DPPH radical scavenging effect and weak anti-tyrosinase activity when compared to the well-known antioxidant (BHT) and tyrosinase inhibitor (kojic acid), respectively. MPH, at a high dose (0.5 mg/mL), showed significant cytotoxic activity (~63%) and strong anti-melanogenic effect (~57%) on SKMEL-3 cells. The effect of MPH in the reduction of melanin content may be related to its cytotoxicity. The results obtained suggest that MPH can be used as an effective agent in the treatment of some skin hyperpigmentation disorders such as melanoma.

The effect of methylphenidate on decision making in patients with borderline personality disorder and attention-deficit/hyperactivity disorder.

PubMed

Gvirts, Hila Z; Lewis, Yael D; Dvora, Shira; Feffer, Kfir; Nitzan, Uriel; Carmel, Ziv; Levkovitz, Yechiel; Maoz, Hagai

2018-07-01

Impaired decision making in patients with borderline personality disorder (BPD) has been reported in several studies. Although methylphenidate (MPH) is known to ameliorate impaired decision making in patients with attention-deficit/hyperactivity disorder (ADHD), it has not yet been examined in patients with BPD. We therefore assessed the efficacy of a single dose of MPH on cognitive functions and decision making in patients with BPD. Twenty-two patients diagnosed with BPD participated in the study. The study was a randomized, double-blind placebo-controlled, random block order cross-over trial. Patients participated in two sessions and performed the Test of Variables of Attention, a digit-span test, and the computerized Iowa Gambling Task, after they had been administered either the MPH or a placebo. ADHD symptoms were assessed using the Adult ADHD Self-Report Scale-18. Lower scores on the inattention symptoms scale were associated with a greater improvement in decision making following the administration of MPH when compared with improvements in patients with higher ADHD scores [F(1,17)=5.63, P=0.030]. We conclude that MPH may improve decision making in patients with BPD, although this effect is mediated by the level of ADHD symptoms. Further studies are needed to assess whether a prolonged beneficial effect of MPH on decision making in patients with BPD might also be present in 'real life'.

Influence of Methylphenidate on the Frequency of Stuttering: A Randomized Controlled Trial.

PubMed

Rabaeys, Henk; Bijleveld, Henny-Annie; Devroey, Dirk

2015-10-01

Recently, a case report described a decrease in frequency of stuttering after intake of methylphenidate (MPH). This study was undertaken to investigate if this effect could again be reproduced in a population of young healthy male adult persons with developmental stuttering. A double-blind randomized crossover trial, with a 2-week washout period, including 15 Dutch-speaking young healthy persons with developmental stuttering, assessed the effects of a single dose of 20 mg MPH compared with placebo on stuttering. Dependent and 1-sample t tests were used to detect significant differences. The end point was the number of stutter moments and self-perceived improvement. MPH yielded a significant decrease in the number of stutter moments when reading and speaking (P = 0.002), which was not the case with placebo (P = 0.090). There was a significant improvement from baseline after intake of MPH as compared with placebo (P = 0.003). Self-perceived improvement with MPH was not significantly better as compared with placebo (P = 0.28). This study showed that the participants had an objective statistically significant decrease in the frequency of stuttering with MPH, and this was not the case with placebo. This was also the case for a reduction in stutter moments when reading out loud and speaking spontaneously. However, this result was not subjectively perceived by the participants. © The Author(s) 2015.

Methylphenidate treatment in children with attention deficit hyperactivity disorder and comorbid social phobia.

PubMed

Golubchik, Pavel; Sever, Jonathan; Weizman, Abraham

2014-07-01

The aim of this study was to assess the response of social phobia (SP) symptoms to methylphenidate (MPH) treatment in children with attention deficit hyperactivity disorder (ADHD). Twenty-one ADHD patients with SP, aged between 8 and 18 years, received 12 weeks of MPH treatment. The severity of SP symptoms were assessed by the Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA), and the severity of ADHD symptoms was assessed by the ADHD Rating Scale at baseline and at endpoint. MPH treatment was associated with a significant decrease in the ADHD Rating Scale scores (P<0.0001) and in the total LSAS-CA scores (P=0.013), as well as the school-related items of LSAS-CA (P=0.011). A significant correlation was found between the reductions in ADHD score and total LSAS-CA score (P=0.038), especially in school-related SP. The improvement in ADHD symptoms because of MPH treatment correlates with a parallel improvement in SP. MPH treatment appears to be safe and effective in ADHD/SP children.

Cytogenetic Effects of Chronic Methylphenidate Treatment and Chronic Social Stress in Adults with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kittel-Schneider, S; Spiegel, S; Renner, T; Romanos, M; Reif, A; Reichert, S; Heupel, J; Schnetzler, L; Stopper, H; Jacob, C

2016-07-01

Methylphenidate (MPH) is widely used to treat childhood and adult attention-deficit/hyperactivity disorder (ADHD). However, there are still safety concerns about side effects in long-term treatment. The aim of this study was to assess cytogenetic effects of chronic MPH treatment in adult ADHD and to find out if chronic social stress is attenuated by medication and to investigate whether chronic psychosocial stress leads to mutagenic effects by itself. Lymphocytes for micronucleus assay and saliva samples for cortisol measurement were collected from adult ADHD patients and healthy controls. Stress exposure of the last 3 months was assessed by TICS (Trier Inventory for Chronic Stress). We could not detect an influence of MPH treatment on cytogenetic markers. ADHD patients displayed significantly higher chronic stress levels measured by TICS compared to healthy controls which were influenced by duration of MPH treatment. ADHD patients also showed significantly lower basal cortisol levels. We could corroborate that there are neither cytogenetic effects of chronic stress nor of chronic MPH intake even after several years of treatment. © Georg Thieme Verlag KG Stuttgart · New York.

Inferring the 1985-2014 impact of mobile phone use on selected brain cancer subtypes using Bayesian structural time series and synthetic controls.

PubMed

de Vocht, Frank

2016-12-01

Mobile phone use has been increasing rapidly in the past decades and, in parallel, so has the annual incidence of certain types of brain cancers. However, it remains unclear whether this correlation is coincidental or whether use of mobile phones may cause the development, promotion or progression of specific cancers. The 1985-2014 incidence of selected brain cancer subtypes in England were analyzed and compared to counterfactual 'synthetic control' timeseries. Annual 1985-2014 incidence of malignant glioma, glioblastoma multiforme, and malignant neoplasms of the temporal and parietal lobes in England were modelled based on population-level covariates using Bayesian structural time series models assuming 5,10 and 15year minimal latency periods. Post-latency counterfactual 'synthetic England' timeseries were nowcast based on covariate trends. The impact of mobile phone use was inferred from differences between measured and modelled time series. There is no evidence of an increase in malignant glioma, glioblastoma multiforme, or malignant neoplasms of the parietal lobe not predicted in the 'synthetic England' time series. Malignant neoplasms of the temporal lobe however, have increased faster than expected. A latency period of 10years reflected the earliest latency period when this was measurable and related to mobile phone penetration rates, and indicated an additional increase of 35% (95% Credible Interval 9%:59%) during 2005-2014; corresponding to an additional 188 (95%CI 48-324) cases annually. A causal factor, of which mobile phone use (and possibly other wireless equipment) is in agreement with the hypothesized temporal association, is related to an increased risk of developing malignant neoplasms in the temporal lobe. Copyright © 2016 The Author. Published by Elsevier Ltd.. All rights reserved.

ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis.

PubMed

Anderson, Joshua C; Grammer, J Robert; Wang, Wenquan; Nabors, L Burton; Henkin, Jack; Stewart, Jerry E; Gladson, Candece L

2007-03-01

Anti-angiogenic therapies would be particularly beneficial in the treatment of malignant gliomas. Peptides derived from the second type 1 repeat (TSR) of thrombospondin-1 (TSP-1) have been shown to inhibit angiogenesis in non-glioma tumor models and a modified TSR peptide, ABT-510, has now entered into Phase II clinical trials of its efficacy in non-glioma tumors. As microvascular endothelial cells (MvEC) exhibit heterogeneity, we evaluated the ability of the modified TSR peptide (NAcSarGlyValDallolleThrNvalleArgProNHE, ABT-510) to inhibit malignant glioma growth in vivo and to induce apoptosis of brain microvessel endothelial cells (MvEC) propagated in vitro. We found that daily administration of ABT-510 until euthanasia (days 7 to 19), significantly inhibited the growth of human malignant astrocytoma tumors established in the brain of athymic nude mice. The microvessel density was significantly lower and the number of apoptotic MvEC was significantly higher (3-fold) in the tumors of the ABT-510-treated animals. Similar results were found using a model in which the established tumor is an intracerebral malignant glioma propagated in a syngeneic mouse model. ABT-510 treatment of primary human brain MvEC propagated as a monolayer resulted in induction of apoptosis in a dose- and time-dependent manner through a caspase-8-dependent mechanism. It also inhibited tubular morphogenesis of MvEC propagated in collagen gels in a dose- and caspase-8 dependent manner through a mechanism that requires the TSP-1 receptor (CD36) on the MvEC. These findings indicate that ABT-510 should be evaluated as a therapeutic option for patients with malignant glioma.

Everything is connected: social determinants of pediatric health and disease.

PubMed

Tarazi, Carine; Skeer, Margie; Fiscella, Kevin; Dean, Stephanie; Dammann, Olaf

2016-01-01

Carine Tarazi, MA, is an Assistant Editor for Pediatric Research in Boston, Massachusetts, USA. Margie Skeer, ScD, MPH, MSW, served as a Guest Editor for this special issue. Dr. Skeer is Assistant Professor of Public Health and Community Medicine at Tufts University. Her research focuses on adolescent substance misuse and sexual risk prevention, both from epidemiologic and intervention-development perspectives. Kevin Fiscella, MD, MPH, served as a Guest Editor for this special issue. Dr. Fiscella is Tenured Professor of Family Medicine, Public Health Sciences and Community Health at the University of Rochester Medical Center. Dr. Fiscella's research focuses on health and health care disparities, particularly practical strategies to improve health equity. Stephanie Dean, MBA, is Managing Editor of Pediatric Research and is based out of editorial office in The Woodlands, Texas. Olaf Dammann, MD, served as a Guest Editor for this special issue. Dr. Dammann is a Professor of Public Health and Community Medicine, Pediatrics, and Ophthalmology at Tufts University School of Medicine in Boston, Massachusetts, USA, as well as Professor of Perinatal Neuroepidemiology at Hannover Medical School, Hannover, Germany. His research interests include the elucidation of risk factors for brain damage and retinopathy in preterm newborns, the theory of risk and causation in biomedical and public health research, and the development of computational chronic disease models.

Dynamic Alignment Models for Neural Coding

PubMed Central

Kollmorgen, Sepp; Hahnloser, Richard H. R.

2014-01-01

Recently, there have been remarkable advances in modeling the relationships between the sensory environment, neuronal responses, and behavior. However, most models cannot encompass variable stimulus-response relationships such as varying response latencies and state or context dependence of the neural code. Here, we consider response modeling as a dynamic alignment problem and model stimulus and response jointly by a mixed pair hidden Markov model (MPH). In MPHs, multiple stimulus-response relationships (e.g., receptive fields) are represented by different states or groups of states in a Markov chain. Each stimulus-response relationship features temporal flexibility, allowing modeling of variable response latencies, including noisy ones. We derive algorithms for learning of MPH parameters and for inference of spike response probabilities. We show that some linear-nonlinear Poisson cascade (LNP) models are a special case of MPHs. We demonstrate the efficiency and usefulness of MPHs in simulations of both jittered and switching spike responses to white noise and natural stimuli. Furthermore, we apply MPHs to extracellular single and multi-unit data recorded in cortical brain areas of singing birds to showcase a novel method for estimating response lag distributions. MPHs allow simultaneous estimation of receptive fields, latency statistics, and hidden state dynamics and so can help to uncover complex stimulus response relationships that are subject to variable timing and involve diverse neural codes. PMID:24625448

Grantee Spotlight: Katherine Briant, MPH, CHES

Cancer.gov

Katherine Briant, MPH, CHES, is Community Health Educator in NCI’s National Outreach Network links NCI-supported outreach and community education efforts and cancer health disparities research and training programs.

KSC-04pd1707

NASA Image and Video Library

2004-09-01

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility unwrap plastic for use in covering equipment as part of preparations for the expected impact of Hurricane Frances on Saturday. Other preparations at KSC include powering down the Space Shuttle orbiters, closing the payload bay doors and stowing the landing gear. Workers are also taking precautions against flooding by moving spacecraft hardware off the ground and sandbagging facilities. The Orbiter Processing Facility is constructed of concrete and steel and was designed to withstand winds of 105 mph. The Vehicle Assembly Building is constructed of concrete and steel and was designed to withstand winds of 125 mph. Other payload and flight hardware support facilities can endure winds of 110 mph. Launch pads and the Payload Hazardous Servicing Facility can withstand 125-mph winds.

Childhood Brain and Spinal Cord Tumors Treatment Overview (PDQ®)—Patient Version

Cancer.gov

Brain and spinal cord tumors may be benign (not cancer) or malignant (cancer). Both types cause signs or symptoms and need treatment. Get information about the many kinds of brain and spinal cord tumors, signs and symptoms, tests to diagnose, and treatment in this expert-reviewed summary.

The effect of using different competence frameworks to audit the content of a masters program in public health.

PubMed

Harrison, Roger A; Gemmell, Isla; Reed, Katie

2015-01-01

(1) To quantify the effect of using different public health competence frameworks to audit the curriculum of an online distance learning MPH program, and (2) to measure variation in the outcomes of the audit depending on which competence framework is used. Retrospective audit. We compared the teaching content of an online distance learning MPH program against each competence listed in different public health competence frameworks relevant to an MPH. We then compared the number of competences covered in each module in the program's teaching curriculum and in the program overall, for each of the competence frameworks used in this audit. A comprehensive search of the literature identified two competence frameworks specific to MPH programs and two for public health professional/specialty training. The number of individual competences in each framework were 32 for the taught aspects of the UK Faculty of Public Health Specialist Training Program, 117 for the American Association of Public Health, 282 for the exam curriculum of the UK Faculty of Public Health Part A exam, and 393 for the European Core Competencies for MPH Education. This gave a total of 824 competences included in the audit. Overall, the online MPH program covered 88-96% of the competences depending on the specific framework used. This fell when the audit focused on just the three mandatory modules in the program, and the variation between the different competence frameworks was much larger. Using different competence frameworks to audit the curriculum of an MPH program can give different indications of its quality, especially as it fails to capture teaching considered to be relevant, yet not included in an existing competence framework. The strengths and weaknesses of using competence frameworks to audit the content of an MPH program have largely been ignored. These debates are vital given that external organizations responsible for accreditation specify a particular competence framework to be used. Our study found that each of four different competence frameworks suggested different levels of quality in our teaching program, at least in terms of the competences included in the curriculum. Relying on just one established framework missed some aspects of the curriculum included in other frameworks used in this study. Conversely, each framework included items not covered by the others. Thus, levels of agreement with the content of our MPH and established areas of competence were, in part, dependent on the competence framework used to compare its' content. While not entirely a surprising finding, this study makes an important point and makes explicit the challenges of selecting an appropriate competence framework to inform MPH programs, and especially one which recruits students from around the world.

Passive antibody-mediated immunotherapy for the treatment of malignant gliomas.

PubMed

Mitra, Siddhartha; Li, Gordon; Harsh, Griffith R

2010-01-01

Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

Studying the MicroRNA role as a survival predictor and revealing its part in malignancy level determination in patients with supratentorial gliomas of brain

NASA Astrophysics Data System (ADS)

Stupak, E. V.; Veryaskina, Yu. A.; Titov, S. E.; Achmerova, L. G.; Stupak, V. V.; Dolzhenko, D. A.; Rabinovich, S. S.; Narodov, A. A.; Ivanov, M. K.; Zhimulev, I. F.; Kolesnikov, N. N.

2017-09-01

The numerous data show, that microRNA (miRNA) are direct participants of carcinogenesis. Also miRNA plays the role of a diagnostic and prognostic marker for different types of cancer, including gliomas. The aim of this research is to make the comparative analysis of 10 micro RNA (miR-124, -125b, -16, -181b, -191, -21, -221, -223, -31 and -451) expression profiles. The analysis was made for gliomas with different malignancy degree, then compared with the samples of the adjacent not changed tissues (n = 90). During the study the specific profiles of miRNA expression for various histotypes of tumors were revealed. It was determined, that miRNA acts as a predictor of patient survival in the cases with malignant supratentorial brain tumors. The diagnostic approaches based on miRNA expression profile were designed. It will help to determine the malignancy level and to predict the course of the disease.

Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts1

PubMed Central

Yamashita, Yoji; Krauze, Michal T.; Kawaguchi, Tomohiro; Noble, Charles O.; Drummond, Daryl C.; Park, John W.; Bankiewicz, Krystof S.

2007-01-01

Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in single-agent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas. PMID:17018695

Drug Treatment Patterns of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents in Germany: Results from a Large Population-Based Cohort Study

PubMed Central

Mikolajczyk, Rafael T.; Banaschewski, Tobias; Petermann, Ulrike; Petermann, Franz; Kraut, Angela A.; Langner, Ingo

2012-01-01

Abstract Objective Despite a substantial increase in total methylphenidate (MPH) prescriptions in Germany over the last 20 years, and the introduction of modified release MPH (MR MPH) and atomoxetine (ATX), remarkably little is known about treatment patterns of attention- deficit/hyperactivity disorder (ADHD) in individual patients. Methods Usage patterns of ADHD drugs in children and adolescents in Germany were analyzed using data from one large German health insurance including >7,200,000 members. Of those, 6210 ADHD patients newly diagnosed in 2005 were followed for a maximum of 4 years. Kaplan–Meier estimates were calculated for onset and discontinuation of ADHD drug treatment. Predictors of time until drug treatment initiation were assessed by Cox regression. Results During follow-up, 52.0% of ADHD subjects (53.4% of boys, 47.5% of girls) received ADHD drug treatment. The majority of them (91.6%) were started on MPH, with immediate release MPH (IR MPH) being the initial treatment choice in 75.3%. In these subjects, change to drug treatment with MR MPH in the first year occurred in 48% by switch or addition. Significant predictors of drug treatment were behavioral and emotional disorders (HR=1.13; 95% CI 1.03–1.24) and a diagnosis of ADHD with conduct disorder (HR=1.21, 95% CI 1.12–1.32), whereas young age showed a protective effect. After 6, 12, and 24 months of treatment initiation, 22.4%, 43.4%, and 66.3% of treated girls, and 17.8%, 36.1%, and 54.1% of treated boys had discontinued ADHD treatment. Conclusion Drug treatment of ADHD was relatively common in Germany and more frequent in boys than in girls. IR MPH was the predominant treatment choice at treatment initiation. Approximately 20% of treated subjects discontinued drug treatment within the first 6 months, with girls stopping drug treatment earlier than boys. The reasons for early drug discontinuation need to be further explored. PMID:23234588

Inter- and Intraindividual Variation of Methylphenidate Concentrations in Serum and Saliva of Patients with Attention-Deficit/Hyperactivity Disorder.

PubMed

Preiskorn, Joshua; Studer, Sophie; Rauh, Reinhold; Lukačin, Richard; Geffert, Christoph; Fleischhaker, Christian; Clement, Hans-Willi; Schulz, Eberhard; Biscaldi, Monica

2018-05-03

BackgroundTherapeutic drug monitoring (TDM) is becoming increasingly important in psychiatric therapy; especially in children. However, for several reasons, it cannot yet be implemented as a daily routine in clinical or outpatient settings. To evaluate new, non-invasive procedures; blood and saliva (oral fluid) samples were collected from patients with attention-deficit/hyperactivity disorder (ADHD) who were also being administered methylphenidate (MPH). The study's main purposes were to correlate MPH concentrations in serum and saliva between subjects; and to analyze intraindividual variation of serum concentration.MethodsThirty-six ADHD patients (27 children and 9 adults) on methylphenidate medication were included for drug analysis. MPH and its major metabolite ritalinic acid (RA) were quantified using LC-MS/MS measurements. The following correlations were investigated: 1) between drug concentrations in serum and saliva, and 2) between pH value and saliva to serum concentration ratio. Furthermore, the mean intraindividual MPH-concentration fluctuation in saliva under constant frame conditions was analyzed.ResultsAfter quantification, MPH concentrations were approximately 5 times higher in the saliva than in the serum, while the concentrations of RA were much lower in saliva. We found significant correlations between concentrations of MPH in serum and saliva (r=0.51, p<0.05). Saliva MPH measures, compared to serum, were pH-dependent(r=-0.56, p<0.01). Daily coefficient of variance of saliva concentration in children taking constant medication was 27.3% (11%-42 %), while the coefficient of variance for the ratio of saliva to serum was 122% (2%-2060%).ConclusionsOur data indicates that the interindividual variation in saliva to serum concentrations is rather high, while the intraindividual variation is fairly low, as already shown in the literature for repeated citalopram serum measurements. Saliva may well serve as an alternative matrix for TDM of MPH in ADHD patients, especially for follow-up examinations. Future research should focus on analyzing the relationship between drug levels in saliva and clinical effects; as well as on understanding the mechanisms that generate saliva drug concentrations. These are essential steps prior to potential clinical use.

The effect of economic status on height, insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in healthy Turkish children.

PubMed

Turan, S; Bereket, A; Furman, A; Omar, A; Berber, M; Ozen, A; Akbenlioglu, C; Haklar, G

2007-06-01

The effect of economic status (ES) on growth, insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in healthy children is not well characterized. We aimed to study the interrelationship between height, weight, IGF-I, IGFBP-3, mid-parental height (MPH) and ES. Eight hundred and fourteen healthy children (428 boys, 386 girls; age 3-18 years) were classified according to income of the families as low, middle and high. Standard deviation scores (SDSs) of height, weight, MPH, IGF-I and IGFBP-3 were compared between the groups. The combined effect of these parameters and ES on height SDS was investigated with complex statistical models. There was a significant trend for height and weight SDSs to increase with higher income levels in boys, but not in girls. Body mass index (BMI) SDSs were similar in three groups. There was a general trend for MPH SDS to increase with income levels in both sexes. In boys, IGF-I SDS was significantly higher in high ES group than low ES. In girls, IGFBP-3 SDSs were significantly higher in high ES group than in middle ES group. For both genders, height SDS was highly correlated with weight SDS and moderately correlated with BMI SDS, MPH SDS and IGF-1 SDS. All correlations were significant and positive. Complex models showed that MPH (19%), IGF-I (13%) and ES (3%) in boys, and MPH (16%) and IGF-I (7%) in girls have significant contribution to height SDSs. ES per se, independent of overt malnutrition, affects height, weight, IGF-I and IGFBP-3 with some gender differences in healthy children. Influence of income on height and weight show sexual dimorphism, a slight but significant effect is observed only in boys. MPH is the most prominent variable effecting height in healthy children. Higher height and MPH SDSs observed in higher income groups suggest that secular trend in growth still exists, at least in boys, in a country of favorable economic development.

Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting.

PubMed

Childress, Ann C; Kollins, Scott H; Cutler, Andrew J; Marraffino, Andrea; Sikes, Carolyn R

2017-02-01

Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. Children aged 6-12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract infection, affect lability, irritability, cough, and vomiting. MPH XR-ODT was effective and well tolerated for the treatment of children with ADHD in a laboratory classroom setting. Clinical Trial Registry: NCT01835548 ( ClinicalTrials.gov ).

Pediatric Brain Tumors: Genomics and Epigenomics Pave the Way.

PubMed

Fontebasso, Adam M; Jabado, Nada

2015-01-01

Primary malignant brain tumors remain a disproportionate cause of morbidity and mortality in humans. A number of studies exploring the cancer genome of brain tumors across ages using integrated genetics and epigenetics and next-generation sequencing technologies have recently emerged. This has led to considerable advances in the understanding of the basic biology and pathogenesis of brain tumors, including the most malignant and common variants in children: gliomas and medulloblastoma. Notably, studies of pediatric brain tumors have identified unexpected oncogenic pathways implicated in tumorigenesis. These range from a single pathway/molecule defect such as abnormalities of the mitogen-activated protein kinase pathway, considered to be a hallmark of pilocytic astrocytomas, to alterations in the epigenome as a critical component altered in many subgroups of high-grade brain tumors. Importantly, the type, timing, and spatial clustering of these molecular alterations provide a better understanding of the pathogenesis of the respective brain tumor they target and critical markers for therapy that will help refine pathological grading. We summarize these novel findings in pediatric brain tumors, which also are put in the context of the evolving notion of molecular pathology, now a mandated tool for proper classification and therapy assignment in the clinical setting.

Improving Care in Pediatric Neuro-oncology Patients: An Overview of the Unique Needs of Children With Brain Tumors.

PubMed

Fischer, Cheryl; Petriccione, Mary; Donzelli, Maria; Pottenger, Elaine

2016-03-01

Brain tumors represent the most common solid tumors in childhood, accounting for almost 25% of all childhood cancer, second only to leukemia. Pediatric central nervous system tumors encompass a wide variety of diagnoses, from benign to malignant. Any brain tumor can be associated with significant morbidity, even when low grade, and mortality from pediatric central nervous system tumors is disproportionately high compared to other childhood malignancies. Management of children with central nervous system tumors requires knowledge of the unique aspects of care associated with this particular patient population, beyond general oncology care. Pediatric brain tumor patients have unique needs during treatment, as cancer survivors, and at end of life. A multidisciplinary team approach, including advanced practice nurses with a specialty in neuro-oncology, allows for better supportive care. Knowledge of the unique aspects of care for children with brain tumors, and the appropriate interventions required, allows for improved quality of life. © The Author(s) 2015.

[Therapeutic strategies targeting brain tumor stem cells].

PubMed

Toda, Masahiro

2009-07-01

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Cancer Data and Statistics Tools

MedlinePlus

... Joseph Jacqueline W. Miller Mona Saraiya Judith Lee Smith Sherri L. Stewart Mary C. White Debra Younginer ... MD, MPH Simple Singh, MD, MPH Judith Lee Smith, PhD Sherri L. Stewart, PhD Eric Tai, MD, ...

Ashley Felix, Ph.D., M.P.H.

Cancer.gov

NCI Cancer Prevention Fellowship Program (CPFP) alumna, Ashley Felix, Ph.D., M.P.H., details her transition from pre-med student to an epidemiologist who focuses on studying the causes and prevention of disease.

Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan.

PubMed

Bruce, Jeffrey N; Fine, Robert L; Canoll, Peter; Yun, Jonathan; Kennedy, Benjamin C; Rosenfeld, Steven S; Sands, Stephen A; Surapaneni, Krishna; Lai, Rose; Yanes, Candix L; Bagiella, Emilia; DeLaPaz, Robert L

2011-12-01

Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival. We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas. Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.

Assessing the interplay between the shoulders and low back during manual patient handling techniques in a nursing setting.

PubMed

Belbeck, Alicia; Cudlip, Alan C; Dickerson, Clark R

2014-01-01

The purpose of this research was to quantify shoulder demands during freestyle manual patient handling (MPH) tasks and determine whether approaches intended to prevent low back injury increased shoulder demands. Twenty females completed 5 MPH tasks found commonly in hospital settings before and after a training session using current workplace MPH guidelines. Most normalized muscle activity indices and ratings of perceived exertion decreased following training at both the low back and shoulders, but were more pronounced at the low back. There was little evidence to suggest that mechanical demands were transferred from the low back to the shoulders following the training session. The study generally supports continued use of the recommended MPH techniques, but indicates that several tasks generate high muscular demands and should be avoided if possible.

Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

PubMed Central

Stage, C; Bergmann, TK; Ferrero‐Milliani, L; Bjerre, D; Thomsen, R; Dalhoff, KP; Rasmussen, HB; Jürgens, G

2016-01-01

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure. PMID:27754602

The Africanization of poverty: a retrospective on "Make Poverty History".

PubMed

Harrison, Graham

2010-01-01

This article explores the ways in which the British campaign coalition Make Poverty History represented Africa throughout 2005. Focusing particularly on the G8 Gleneagles summit, Make Poverty History (MPH) asserted a series of justice claims which had no geographical reference. Nevertheless, as a result of internal tensions within the coalition, and especially as a result of the ways in which MPH interacted with other political agencies as the summit approached, MPH's messages became increasingly interpolated by references to Africa as a result of the emergence of government, media, and celebrity involvement. The result of this was that global poverty increasingly became an African issue. As 2005 became the "Year of Africa," the justice messages that constituted MPH were largely effaced by the more familiar imperial legacy which represents Africa as a place of indigence in need of outside assistance.

Methylphenidate Induced Lip and Tongue Biting.

PubMed

Gokcen, Cem; Karadag, Mehmet; Aksoy, Ihsan

2018-05-31

Attention deficit hyperactivity disorder (ADHD) is a life-long neurodevelopmental disorder and treatment depends on pharmacotherapy because of its biological origin. Stimulant drugs are the most commonly used treatment for ADHD and they have various side effects. Herein, we report a case who bit off the tip of her tongue with Osmotic Release Oral System methylphenidate (OROS MPH) 36 mg/day, bit the tip of her lower lip with immediate release (IR) MPH 10 mg/day and lateral part of her tongue with IR MPH 20 mg/day. A diagnosis of epilepsy was unlikely because of the normal neurological examination and electroencephalography findings. This case was considered as an atypical side effect of MPH such as perseverative/compulsive behaviours and movement disorders. Clinicians should be aware of that stimulant medications may cause lip and tongue biting behavior and this may effect treatment compliance tremendously.

The role of gender in MPH graduates' salaries.

PubMed

Bradley, E H; White, W; Anderson, E; Mattocks, K; Pistell, A

2000-01-01

Several studies have demonstrated that workforce roles and salaries differ substantially between men and women in administrative positions within the health care industry. Recent studies of graduates with masters of business administration (MBA) and masters of health administration (MHA) degrees have indicated that women tend to experience lower salaries, given like responsibilities. However, the impact of gender on salary has been less studied among masters of public health (MPH) graduates in the health care field. Our objective was to assess the impact of gender on salary among MPH degree graduates. Using a cross-sectional survey of all graduates from the MPH program at Yale University between 1991-1997 (n = 201, response rate = 51%), we ascertained graduates' reported salary in the first job post-graduation and reported salary in their current position. Bivariate and multivariate analyses were used to assess the unadjusted and adjusted associations between gender and salary. Salaries in both the first job post-graduation and in the current job differed significantly by gender, with women earning less than men (p-values < .05). Moreover, these differences persisted after controlling for a set of human capital measures including pre-MPH work experience, age at graduation, years since graduation, area of specialization within the MPH degree, and type of work site (governmental or nonprofit versus for-profit). Unlike studies of MBA and MHA graduates, however, this study did not find evidence that the gender-related salary gap widened as the years since graduation increased, although the sample size did not allow comprehensive testing of this trend.

Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder.

PubMed

Tucha, O; Mecklinger, L; Laufkötter, R; Klein, H E; Walitza, S; Lange, K W

2006-10-01

The present study examined the effect of the stimulant medication methylphenidate (MPH) on attentional functioning of adults with ADHD. Sixteen adults with a diagnosed ADHD without comorbidity were assessed twice, at baseline off MPH and following MPH treatment. The assessment battery consisted of reaction time tasks of low complexity, including measures of alertness--subdivided into tonic and phasic alertness, vigilance, divided attention, flexibility and such aspects of selective attention as including focused attention, inhibition and integration of sensory information. In addition, 16 healthy participants who were matched to adults with ADHD according to sex, age, education level and intellectual functions were also assessed twice using the same test battery. The results of the present study suggest that adults with ADHD off stimulant medication are seriously impaired in various components of attention including vigilance, divided attention, selective attention and flexibility. These impairments of attention were observed primarily in regard to reaction time and its variability. Treatment of adults with ADHD using individually tailored doses of MPH has a positive effect on measures of alertness, vigilance, selective attention, divided attention and flexibility. However, even on MPH adults with ADHD displayed considerable deficits in vigilance and integration of sensory information. The present findings indicate that adults with ADHD are not differentially impaired in attentional processes but may suffer from a more global deficit of attention. Although MPH treatment has been found to be effective in the treatment of the attention deficit of adults with ADHD, additional treatment appears to be necessary.

Exploring longitudinal course and treatment-baseline severity interactions in secondary outcomes of smoking cessation treatment in individuals with attention-deficit hyperactivity disorder.

PubMed

Luo, Sean X; Wall, Melanie; Covey, Lirio; Hu, Mei-Chen; Scodes, Jennifer M; Levin, Frances R; Nunes, Edward V; Winhusen, Theresa

2018-01-25

A double blind, placebo-controlled randomized trial (NCT00253747) evaluating osmotic-release oral system methylphenidate (OROS-MPH) for smoking-cessation revealed a significant interaction effect in which participants with higher baseline ADHD severity had better abstinence outcomes with OROS-MPH while participants with lower baseline ADHD severity had worse outcomes. This current report examines secondary outcomes that might bear on the mechanism for this differential treatment effect. Longitudinal analyses were conducted to evaluate the effect of OROS-MPH on three secondary outcomes (ADHD symptom severity, nicotine craving, and withdrawal) in the total sample (N = 255, 56% Male), and in the high (N = 134) and low (N = 121) baseline ADHD severity groups. OROS-MPH significantly improved ADHD symptoms and nicotine withdrawal symptoms in the total sample, and exploratory analyses showed that in both higher and lower baseline severity groups, OROS-MPH statistically significantly improved these two outcomes. No effect on craving overall was detected, though exploratory analyses showed statistically significantly decreased craving in the high ADHD severity participants on OROS-MPH. No treatment by ADHD baseline severity interaction was detected for the outcomes. Methylphenidate improved secondary outcomes during smoking cessation independent of baseline ADHD severity, with no evident treatment-baseline severity interaction. Our results suggest divergent responses to smoking cessation treatment in the higher and lower severity groups cannot be explained by concordant divergence in craving, withdrawal and ADHD symptom severity, and alternative hypotheses may need to be identified.

COMPARING STIMULANT EFFECTS IN YOUTH WITH ADHD SYMPTOMS AND EPILEPSY

PubMed Central

Gonzalez-Heydrich, Joseph; Hsin, Olivia; Gumlak, Sarah; Kimball, Kara; Rober, Ashley; Azeem, Muhammad W.; Hickory, Meredith; Mrakotsky, Christine; Torres, Alcy; Mezzacappa, Enrico; Bourgeois, Blaise; Biederman, Joseph

2014-01-01

To retrospectively examine response to stimulant treatment in patients with epilepsy and ADHD symptoms as predicted by seizure freedom for six months, use of methylphenidate (MPH) versus amphetamine (AMP) preparations, and cognitive level, medical records were searched for patients under age 18 with epilepsy and ADHD symptoms treated with MPH or AMP (n = 36, age 10.4±3.5; 67% male). “Responders” had a CGI-Improvement score of ≤2 and did not stop medication due to adverse effects. “Worsened” patients discontinued medication due to agitation/emotional lability. Seizure freedom did not predict treatment response. Lower cognitive level was associated with increased rate of worsening (p=0.048). No patients who were seizure-free at start of the medication trial experienced an increase in seizures. Of the patients having seizures at the start of trial, one patient on MPH and two on AMP had increased seizures during the trial. Seizures returned to baseline frequency or less after stimulant discontinuation or anticonvulsant adjustment. MPH was associated with a higher response rate, with 12 of 19 given MPH 0.62±0.28mg/kg/day compared to 4 of 17 given AMP 0.37±0.26mg/kg/day responding (p=0.03). MPH treatment and higher cognitive level were associated with improved treatment outcome while seizure freedom had no clear effect. Confidence in these findings is limited by the study’s small, open label, and uncontrolled nature. PMID:24907495

Multiple Primary and Histology Coding Rules - SEER

Cancer.gov

Download the coding manual and training resources for cases diagnosed from 2007 to 2017. Sites included are lung, breast, colon, melanoma of the skin, head and neck, kidney, renal pelvis/ureter/bladder, benign brain, and malignant brain.

Medulloblastoma | Office of Cancer Genomics

Cancer.gov

The Medulloblastoma Project was developed to apply newly emerging genomic methods towards the discovery of novel genetic alterations in medulloblastoma (MB). MB is the most common malignant brain tumor in children, accounting for approximately 20% of all pediatric brain tumors.

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

ClinicalTrials.gov

2018-06-28

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy.

PubMed

Lobel, J; MacDonald, I J; Ciesielski, M J; Barone, T; Potter, W R; Pollina, J; Plunkett, R J; Fenstermaker, R A; Dougherty, T J

2001-01-01

In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

The role of Homer 1a in increasing locomotor activity and non-selective attention, and impairing learning and memory abilities.

PubMed

Yang, Lei; Hong, Qin; Zhang, Min; Liu, Xiao; Pan, Xiao-Qin; Guo, Mei; Fei, Li; Guo, Xi-Rong; Tong, Mei-Ling; Chi, Xia

2013-06-17

The current study aimed to investigate the possible role of Homer 1a in the etiology and pathogenesis of attention deficit hyperactivity disorder (ADHD). We divided 32 rats into four groups. The rats in the RNAi-MPH group were given the lentiviral vector containing Homer 1a-specific miRNA (Homer 1a-RNAi-LV) by intracerebroventricular injection, and 7 days later they were given three daily doses of methylphenidate (MPH) by intragastric gavage. The RNAi-SAL group was given Homer 1a-RNAi-LV and saline later. The NC-MPH group was given the negative control lentiviral vector (NC-LV) and MPH later. The NC-SAL group was given NC-LV and saline later. Rats that were given Homer 1a RNAi exhibited increased locomotor activity and non-selective attention, and impaired learning and memory abilities, which is in line with the behavioral findings of animal models of ADHD. However, MPH ameliorated these abnormal behaviors. All findings indicated that Homer 1a may play an important role in the etiology and pathogenesis of ADHD. Copyright © 2013 Elsevier B.V. All rights reserved.

Factors influencing publication of scientific articles derived from masters theses in public health.

PubMed

Hollmann, Malen; Borrell, Carme; Garin, Olatz; Fernández, Esteve; Alonso, Jordi

2015-05-01

To evaluate theses of a Masters program in Public Health (MPH), in terms of the students' and theses' characteristics that influence publication of the thesis as a scientific article. Longitudinal study of students who successfully completed the MPH at Universitat Pompeu Fabra and Universitat Autònoma de Barcelona (Spain) from 2006 to 2010. Participants completed an electronic survey and additional data were gathered from university files. 162 students participated in the study (83 % response rate). 60.5 % had already published an article derived from their thesis at the time of the study or were in process of publishing it. The likelihood of publishing in a peer-reviewed journal was greater among women (aRR = 1.41), among those who had a bachelor's degree in sciences other than health (aRR = 1.40), had completed the MPH on time (aRR = 2.10), had enrolled in a doctoral program after the MPH (aRR = 1.44) or had a masters thesis score of ≥7 (aRR = 1.61). The majority of MPH students published their thesis in a peer-reviewed journal. The strongest predictors of successful publication were related to academic performance.

The Possible Effect of Methylphenidate Treatment on Empathy in Children Diagnosed with Attention-Deficit/Hyperactivity Disorder, Both With and Without Comorbid Oppositional Defiant Disorder.

PubMed

Golubchik, Pavel; Weizman, Abraham

2017-06-01

To assess the Empathizing Quotient (EQ) of patients diagnosed with attention-deficit/hyperactivity disorder (ADHD) only or comorbid with oppositional defiant disorder (ODD) and compare the two groups' responses to methylphenidate (MPH) treatment. Fifty-two children (8-18 years) diagnosed with ADHD, 26 of whom were also diagnosed with comorbid ODD (ADHD/ODD), were treated with MPH for 12 weeks. The level of EQ was assessed with the Children's version of the Empathizing Quotient (EQ-C) and the severity of ADHD symptoms with the ADHD Rating Scale (ADHD-RS). Assessments were done at baseline and at end point. A significant increase in EQ scores was obtained in both groups following MPH treatment (p = 0.003 for ADHD/ODD; p = 0.002 for ADHD). Significant correlation was found in the ADHD group between the changes in ADHD-RS and those in EQ, following MPH treatment (p = 0.015), but not in the ADHD/ODD group (p = 0.48). A correlation exists between MPH-related improvement in ADHD symptoms and between more empathy in children with ADHD not comorbid with ODD.

75 FR 10867 - Determinations Concerning Illnesses Discussed in the Institute of Medicine Report on Gulf War and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-09

... cancer; nervous system disease; reproductive or developmental dysfunction; non-malignant respiratory... nervous system cancers, stomach cancer, prostatic cancer and testicular cancer. The non-malignant diseases... and bladder cancer exists. G. Brain and Other Central Nervous System Cancers Of the 20 published...

Brain invasion assessability in meningiomas is related to meningioma size and grade, and can be improved by extensive sampling of the surgically removed meningioma specimen.

PubMed

Pizem, Joze; Velnar, Tomaz; Prestor, Borut; Mlakar, Jernej; Popovic, Mara

2014-01-01

Despite the important prognostic value of brain invasion in meningiomas, little attention has been paid to its massessment, and the parameters associated with brain invasion assessability (identification of brain tissue in the surgical specimen) are not well characterized. The aim of our study was to determine the parameters that are associated with brain invasion assessability and brain invasion in meningiomas. By binary logistic regression analysis, we studied the association of various clinical and pathologic parameters with brain invasion assessabilitym and brain invasion in 294 meningiomas: 149 unselected consecutive meningiomas with extensive sampling, diagnosed in 2009 and 2010, collected prospectively, and 145 meningiomas diagnosed in 1999 and 2000 when little attention was paid to brain invasion assessment. Meningioma grade, size and number of tissue blocks were independent predictors of brain invasion assessability. Brain tissue was identified in 78 of 233 (33%) benign, 33 of 51 (65%) atypical, and 10 of 10 (100%) malignant meningiomas. In univariate analysis, group (prospective vs.retrospective), type (recurrent vs. primary), cleavability, meningioma grade and mitotic count were predictors of brain invasion, while only meningioma grade, and group retained predictive value in multivariate analysis. Brain invasion, when assessable, was identified in 22 of 78 (28%) benign, 21 of 33 (64%) atypical, and 10 of 10 (100%) malignant meningiomas. Brain invasion assessability is related to meningioma grade and size and can be improved by extensive sampling of meningioma surgical.

Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system.

PubMed

Kohler, Betsy A; Ward, Elizabeth; McCarthy, Bridget J; Schymura, Maria J; Ries, Lynn A G; Eheman, Christie; Jemal, Ahmedin; Anderson, Robert N; Ajani, Umed A; Edwards, Brenda K

2011-05-04

The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information on cancer occurrence and trends in the United States. This year's report highlights brain and other nervous system (ONS) tumors, including nonmalignant brain tumors, which became reportable on a national level in 2004. Cancer incidence data were obtained from the National Cancer Institute, CDC, and NAACCR, and information on deaths was obtained from the CDC's National Center for Health Statistics. The annual percentage changes in age-standardized incidence and death rates (2000 US population standard) for all cancers combined and for the top 15 cancers for men and for women were estimated by joinpoint analysis of long-term (1992-2007 for incidence; 1975-2007 for mortality) trends and short-term fixed interval (1998-2007) trends. Analyses of malignant neuroepithelial brain and ONS tumors were based on data from 1980-2007; data on nonmalignant tumors were available for 2004-2007. All statistical tests were two-sided. Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence. The death rates continued to decrease for both sexes. Childhood cancer incidence rates continued to increase, whereas death rates continued to decrease. Lung cancer death rates decreased in women for the first time during 2003-2007, more than a decade after decreasing in men. During 2004-2007, more than 213 500 primary brain and ONS tumors were diagnosed, and 35.8% were malignant. From 1987-2007, the incidence of neuroepithelial malignant brain and ONS tumors decreased by 0.4% per year in men and women combined. The decrease in cancer incidence and mortality reflects progress in cancer prevention, early detection, and treatment. However, major challenges remain, including increasing incidence rates and continued low survival for some cancers. Malignant and nonmalignant brain tumors demonstrate differing patterns of occurrence by sex, age, and race, and exhibit considerable biologic diversity. Inclusion of nonmalignant brain tumors in cancer registries provides a fuller assessment of disease burden and medical resource needs associated with these unique tumors.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.

PubMed

Newton, Herbert B

2003-10-01

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.

Methylphenidate treatment of attention deficit hyperactivity disorder in young people with learning disability and difficult-to-treat epilepsy: Evidence of clinical benefit

PubMed Central

Fosi, Tangunu; Lax-Pericall, Maria T; Scott, Rod C; Neville, Brian G; Aylett, Sarah E

2013-01-01

Purpose To establish the efficacy and safety of methylphenidate (MPH) treatment for attention deficit hyperactivity disorder (ADHD) in a group of children and young people with learning disability and severe epilepsy. Methods This retrospective study systematically reviewed the case notes of all patients treated with methylphenidate (MPH) for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD at a specialist epilepsy center between 1998 and 2005. Treatment efficacy was ascertained using clinical global impressions (CGI) scores, and safety was indexed by instances of >25% increase in monthly seizure count within 3 months of starting MPH. Key Findings Eighteen (18) patients were identified with refractory epilepsies (14 generalized, 4 focal), IQ <70, and ADHD. Male patients predominated (13:5) and ADHD was diagnosed at a median age of 11.5 years (range 6–18 years). With use of a combination of a behavioral management program and MPH 0.3–1 mg/kg/day, ADHD symptoms improved in 61% of patients (11/18; type A intraclass correlation coefficient of CGI 0.85, 95% confidence interval [CI] 0.69–0.94). Daily MPH dose, epilepsy variables, and psychiatric comorbidity did not relate to treatment response across the sample. MPH adverse effects led to treatment cessation in three patients (dysphoria in two, anxiety in one). There was no statistical evidence for a deterioration of seizure control in this group with the use of MPH. Significance Methylphenidate with behavioral management was associated with benefit in the management of ADHD in more than half of a group of children with severe epilepsy and additional cognitive impairments. Eighteen percent had significant side effects but no attributable increase in seizures. Methylphenidate is useful in this group and is likely to be under employed. PMID:24304474

Comparative treatment patterns, healthcare resource utilization and costs of atomoxetine and long-acting methylphenidate among children and adolescents with attention-deficit/hyperactivity disorder in Germany.

PubMed

Greven, Peter; Sikirica, Vanja; Chen, Yaozhu J; Curtice, Tammy G; Makin, Charles

2017-09-01

Attention-deficit/hyperactivity disorder (ADHD) imposes a substantial burden on patients and their families. A retrospective, propensity score-matched cohort study compared treatment patterns, healthcare resource utilization (HRU) and costs among children/adolescents with ADHD aged 6-17 years at treatment initiation (index) in Germany who received atomoxetine (ATX) or long-acting methylphenidate (LA-MPH) monotherapy. Patients received at least one prescription for their index medication (ATX/LA-MPH) during 2006-2010; the first prescription marked the index date. ATX- and LA-MPH-indexed cohorts were matched 1:1 (n = 737); a patient subset was identified that had not received ADHD-indicated medications in 12 months prior to index (novel initiators: ATX, n = 486; LA-MPH, n = 488). Treatment patterns were evaluated among novel initiators, and HRU and costs among the matched cohorts in the 12 months after index. No significant differences in baseline characteristics were found between the novel initiator patient subsets. ATX-indexed novel initiators had significantly longer persistence to index medication [mean (standard deviation; SD) days: 222.0 (133.9) vs 203.2 (135.0), P = 0.029) but higher switching rates (8.8 vs 5.5 %, P = 0.045) than LA-MPH-indexed novel initiators. The total ATX-indexed cohort required more prescriptions [any medication; mean (SD): 20.9 (11.5) vs 15.7 (9.0), P < 0.001] and outpatient visits [mean (SD): 10.1 (6.3) vs 8.3 (5.3), P < 0.001], and incurred significantly higher total median healthcare costs (€1144 vs €541, P < 0.001) versus matched LA-MPH patients. These real-world data indicate that, among children/adolescents with ADHD in Germany, ATX-indexed patients may require more prescriptions and physician visits, and incur higher total healthcare costs, than matched LA-MPH patients.

Alumni survey of Masters of Public Health (MPH) training at the Hanoi School of Public Health

PubMed Central

Le, Linh Cu; Bui, Quyen Tu; Nguyen, Ha Thanh; Rotem, Arie

2007-01-01

Background 1) To elicit the opinions of the Public Health alumni of the MPH program; 2) To assess the applicability of the knowledge and skills acquired; 3) To identify the frequency of the public health competencies that the alumni performed. Methods We requested 187 graduates to complete a self-administered questionnaire and conducted in-depth interviews with 8 alumni as well as a focus group discussion with 14 alumni. Results In total 79.1% (148) of the MPH graduates completed and returned the questionnaire. Most alumni (91%) agreed that the MPH curriculum corresponded with the working requirements of public health professionals; and nearly all were satisfied with what they have learnt (96%). Most respondents said that the MPH program enabled them to develop relevant professional skills (95%) and that they were satisfied with the curriculum (90%). Notably fewer respondents (73%) felt that the MPH program structure was balanced and well designed. Most alumni (64.3%) were satisfied with Hanoi School of Public Health (HSPH) full-time lecturers; but even more (83%) were satisfied with visiting lecturers. The most commonly selected of the 34 pre-identified public health competencies were: applying computer skills (66.4%), planning and managing health programs (47.9%), communicating with the community and/or mobilizing the community to participate in health care (43.2%). Overall, the MPH alumni felt that HSPH emphasized research methods at the expense of some management and operational competencies. The most important challenges at work identified by the alumni were insufficient skills in: data analysis, decision making, inter-sectoral cooperation development, English language and training. Conclusion The training program should be reviewed and revised to meet the needs of its graduates who enter diverse situations and positions. English language skills were identified as top priority for further emphasis. The training program should comply with a more advanced accreditation system and standards. PMID:17949491

The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone.

PubMed

Spencer, Thomas J; Bhide, Pradeep; Zhu, Jinmin; Faraone, Stephen V; Fitzgerald, Maura; Yule, Amy M; Uchida, Mai; Spencer, Andrea E; Hall, Anna M; Koster, Ariana J; Feinberg, Leah; Kassabian, Sarah; Storch, Barbara; Biederman, Joseph

Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. ClinicalTrials.gov identifier: NCT01673594. © Copyright 2018 Physicians Postgraduate Press, Inc.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma

PubMed Central

Anai, Shigeo; Hide, Takuichiro; Takezaki, Tatsuya; Kuroda, Jun-ichiro; Shinojima, Naoki; Makino, Keishi; Nakamura, Hideo; Yano, Shigetoshi; Kuratsu, Jun-ichi

2014-01-01

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma. PMID:24673719

76 FR 62423 - National Institute on Deafness and Other Communication Disorders; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

...., Rockville, MD 20852, (Telephone Conference Call). Contact Person: Melissa Stick, PhD, MPH, Chief, Scientific...., Rockville, MD 20852, (Telephone Conference Call). Contact Person: Melissa Stick, PhD, MPH, Chief, Scientific...

Acute Effects of MPH on the Parent-Teen Interactions of Adolescents With ADHD.

PubMed

Pelham, William E; Meichenbaum, David L; Smith, Bradley H; Sibley, Margaret H; Gnagy, Elizabeth M; Bukstein, Oscar

2017-01-01

This study explored the nature of interactions between adolescent males with ADHD and their mothers, and the effects of methylphenidate (MPH) on an analogue parent-teen interaction task. Twenty-five adolescent males with ADHD ( M = 13.6 years) and their mothers and 14 non-ADHD adolescent males ( M = 13.4 years) and their mothers completed ratings of perceived dyadic conflict. Behavioral observations of dyads during 10-min conflict-resolution tasks were also collected. The ADHD dyads completed these tasks twice, with adolescents receiving either 0.3 mg/kg MPH or placebo. Videotaped sessions were coded using the Parent-Adolescent Interaction Rating Scale. Following the conflict-resolution task, participants rated their perceived conflict and affect during the interaction. Findings indicated higher conflict in the ADHD dyads, and minimal MPH effects on parent-teen interactions during the analogue task. Results suggest that stimulant medication does not produce meaningful acute effects on parent-teen interactions.

Music and video as distractors for boys with ADHD in the classroom: comparison with controls, individual differences, and medication effects.

PubMed

Pelham, William E; Waschbusch, Daniel A; Hoza, Betsy; Gnagy, Elizabeth M; Greiner, Andrew R; Sams, Susan E; Vallano, Gary; Majumdar, Antara; Carter, Randy L

2011-11-01

This study examined the effects of music and video on the classroom behavior and performance of boys with and without attention deficit hyperactivity disorder (ADHD) and examined the effects of 0.3 mg/kg methylphenidate (MPH). In one study, 41 boys with ADHD and 26 controls worked in the presence of no distractor, music, or video. Video produced significant distraction, particularly for the boys with ADHD, and MPH improved the performance of boys with ADHD across distractor conditions.There were individual differences in response to the music such that some boys were adversely affected and others benefited relative to no-distractor.In a second study, music and MPH were assessed in an additional 86 boys with ADHD to examine further the music results. In the presence or absence of music, MPH improved performance relative to placebo. Similar individual differences were found as in Experiment 1.

KSC-06pd1980

NASA Image and Video Library

2006-08-29

KENNEDY SPACE CENTER, FLA. - A serene scene surrounds Space Shuttle Atlantis as it begins rolling off Launch Pad 39B to return to the Vehicle Assembly Building. First motion off the pad was at 10:04 a.m. EDT. The crawler is 131 feet long, 113 feet wide and 20 feet high. It weights 5.5 million pounds unloaded. The combined weight of crawler, mobile launcher platform and a space shuttle is 12 million pounds. Unloaded, the crawler moves at 2 mph. Loaded, the snail's pace slows to 1 mph. The rollback is a safety precaution as the area waits for the arrival of Tropical Storm Ernesto. The storm is forecast to be bringing 58-mph to 70-mph winds in the next 24 hours. The shuttle will be moved into high bay 2, on the southwest side of the VAB, for protection from the storm. Photo credit: NASA/Ken Thornsley

Characterizing and Targeting Bone Marrow-Derived Inflammatory Cells in Driving the Malignancy and Progression of Childhood Astrocytic Brain Tumors

DTIC Science & Technology

2016-11-01

importance of myeloid derived ID2/VEGFR2 signaling in low-grade to high-grade glioma transformation . 15. SUBJECT TERMS Glioma, Pediatric, bone-marrow...derived-cells, endothelial, mesenchymal, myeloid, hematopoietic, differentiation, malignant, transformation , VEGFR2, ID2. 16. SECURITY CLASSIFICATION OF...subsequent recruitment, in order to suppress the malignant transformation of gliomas. In this project, we have initiated the study of BMDCs with RCAS and

Resonant Raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588 cm-1 mode

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhou, Lixin; Zhu, Ke; Liu, Yulong; Zhang, Lin; Boydston-White, Susie; Cheng, Gangge; Pu, Yang; Bidyut, Das; Alfano, Robert R.

2015-03-01

RR spectra of brain normal tissue, gliomas in low grade I and II, and malignant glioma tumors in grade III and IV were measured using a confocal micro Raman spectrometer. This report focus on the relative contents of tryptophan (W) in various grades of brain glioma tumors by the intrinsic molecular resonance Raman (RR) spectroscopy method using the 1588cm-1 of tryptophan mode by 532 nm excitation. The RR spectra of key fingerprints of tryptophan, with a main vibrational mode at 1588cm-1 (W8b), were observed. It was found that tryptophan contribution was accumulated in grade I to IV gliomas and the mode of 1588cm-1 in grade III and IV malignant gliomas were enhanced by resonance.

Children with ADHD and symptoms of oppositional defiant disorder improved in behavior when treated with methylphenidate and adjuvant risperidone, though weight gain was also observed - Results from a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Jahangard, Leila; Akbarian, Shahrokh; Haghighi, Mohammad; Ahmadpanah, Mohammad; Keshavarzi, Amir; Bajoghli, Hafez; Sadeghi Bahmani, Dena; Holsboer-Trachsler, Edith; Brand, Serge

2017-05-01

Children with ADHD often show symptoms of oppositional defiant disorders (ODD). We investigated the impact of adjuvant risperidone (RISP) to a standard treatment with methylphenidate (MPH) in children with ADHD and symptoms of ODD. Eighty-four children with ADHD and ODD (age: M=8.55; range: 7.28-9.95 years; 73.8% males) took part in a double-blind, randomized, placebo-controlled, clinical trial lasting eight weeks. Participants were randomly assigned either to the MPH+RISP (1mg/kg/d+0.5mg/d) or to the MPH+PLCO (1mg/kg/d+placebo) condition. Symptoms of ADHD, weight, height, and blood pressure were assessed at baseline, and at weeks 2, 4, 6 and 8. Symptoms of ADHD decreased over time, but more so in the MPH+RISP than in the MPH only condition. In the MPH+RISP condition weight, waist circumference and prolactine levels increased over time. Data suggest that adjuvant RISP improved symptoms in children with ADHD and ODD, but weight gain and higher prolactine levels were also observed, which are two alarming side effects. This may become an issue, once children become adolescents, a period of life in which body shape and body self-image are closely linked to self-confidence and peer acceptance. Health care professionals should carefully balance the short-term and long-term costs and benefits of administration of RISP. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PubMed

Wang, Liang-Jen; Lee, Sheng-Yu; Yuan, Shin-Sheng; Yang, Chun-Ju; Yang, Kang-Chung; Lee, Tung-Liang; Shyu, Yu-Chiau

2016-01-01

This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment. Copyright © 2015 John Wiley & Sons, Ltd.

Depression in adult patients with primary brain tumours: a review of independent risk factors.

PubMed

Pidani, Anum Sadruddin; Rao, Aaida Mumtaz; Shamim, Muhammad Shahzad

2018-04-01

Depression is considered an under-diagnosed problem, especially in patients with malignancies. Patients with brain tumours in particular, have a relatively higher risk of developing depression, which is multifactorial. Herein, the authors review the recent literature on the prevalence of depression in patients with brain tumours, and explore the various risk factors involved. .

70 mph study : final report.

DOT National Transportation Integrated Search

2016-06-30

In July and August 2014, the Pennsylvania Department of Transportation (PennDOT) and Pennsylvania Turnpike Commission : (PTC) raised the posted speed limit on rural sections of Interstates 80, 380, and 76 from 65 to 70 mph. The purpose of this study ...

Speed limit recommendation in vicinity of signalized, high-speed intersection.

DOT National Transportation Integrated Search

2012-04-01

We evaluated the traffic operations and safety effects of 5 mph and 10 mph speed limit reductions in the vicinity of highspeed, : signalized intersections with advance warning flashers (AWF). Traffic operational effects of the reduced speed : limits ...

Alternative Fuels Data Center

Science.gov Websites

a maximum speed of 35 miles per hour (mph) and that must comply with the safety standards in Title have a posted speed limit of 45 mph or less except to cross at an intersection. A county, municipality

Brain cancer and pesticide relationship in orchard farmers of Kashmir.

PubMed

Bhat, Abdul Rashid; Wani, Muhammed Afzal; Kirmani, A R

2010-09-01

The increasing trend in the incidence of primary malignant brain tumors in orchard farmers and their families in Kashmir. To determine the relationship between the patients of primary malignant brain tumors and their occupation. Retrospectively, case files along with death certificates of 432 patients of primary malignant brain tumors and 457 controls (non-tumor neurologic diseases), admitted for treatment simultaneously over a period of 4 years from January 2005 to December 2008, to the Neurosurgery, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Kashmir, were studied. Follow-up and family interaction was established. Analysis revealed that 90.04% (389 out of 432) patients were orchard farm workers, orchard residents and orchard playing children exposed to the high levels of multiple types of neurotoxic and carcinogenic (chlorpyriphos, dimethoate, mancozeb and captan) chemicals for more than 10 years [relative risk (RR) = 10.6; odds ratio (OR) = >10; 95% confidence interval (CI) = >25-40]. The 9.96% (43 out of 432) patients were not exposed to pesticides. On the other hand, only 19 patients out of 457 controls had recorded history of pesticide exposure and 438 were unrelated to pesticides. Out of 389 patients, 71.7% (279 out of 389) were males and 28.3% (110 out of 389), including six members of three families, were females (one male child). All orchard-related 389 patients had high-grade tumors as compared to the non-pesticide tumors. Mortality in pesticide-exposed tumors was 12%. The higher or upper-normal levels of serum cholinesterase (AChE) were observed in 54.7% (213 out of 389) patients and decreased levels were found in only 45.3% (176 out of 389) orchard-related patients (RR = 19.4; OR = >5; 95% CI = >1-10). Although serum AChE levels were a routine investigation in malignant brain tumors, this was not a routine in other neurological conditions (hospitalized controls). The familial gliomas have shown an emerging trend in the orchard residents of valley of Kashmir.

NI-16INTRA-OPERATIVE USE OF FLUORESCEIN FOR MALIGNANT GLIOMA RESECTION DIFFERENTIATES TUMOR FROM NORMAL BRAIN TISSUE BASED ON HISTOPATHOLOGIC ANALYSIS

PubMed Central

Decker, Matthew; Kresak, Jesse; Yachnis, Anthony; Bova, Frank; Rahman, Maryam

2014-01-01

OBJECTIVES: To determine whether the use of IV fluorescein during surgery for malignant glioma can reliably be used to differentiate between infiltrative tumor and normal brain tissue. BACKGROUND: Fluorescein sodium is a molecular compound with fluorescent capabilities between light wavelengths of 520-530nm, appearing yellow-green (1). Neurosurgical application of fluorescein has been studied primarily for increasing intra-operative visibility of malignant gliomas (1). The mechanism of action has been hypothesized to involve disruption of the blood brain barrier (BBB) (2). Cells in areas with disrupted BBB take up fluorescein with a sensitivity of 94% and specificity of 89% for high-grade gliomas (2). We performed histopathologic analysis on tissue obtained during fluorescein-guided tumor resections to evaluate the differences between fluorescent and non-fluorescent tissue. METHODS: Two adult patients with suspected high-grade gliomas underwent surgical resection. Prior to opening of the dura 3mg/kg of IV fluorescein was given. A Zeiss OPMI Pentero microscope (Carl Zeiss Meditech Inc.) with a yellow 560nm filter was used to visualize the tumor. At the tumor margins, tissue was identified as "bright" and "dark" and sent as separate specimens for histopathological analysis. RESULTS: Histological sections of specimens labeled "bright" contained infiltrating glioma with focal microvascular proliferation. Histological sections of specimens labeled "dark" contained gray matter and focal subcortical white matter with no high-grade glioma identified. Final grading for both patients was WHO Grade IV, glioblastoma. CONCLUSION: Intra-operative use of fluorescein in surgical resection of malignant gliomas can help to distinguish between infiltrating tumor and normal brain tissue based on histopathological analysis. Further evaluation of the utility of flurorescein during high and low-grade glioma surgery is necessary.

Windthrow a hazard in Virginia pine strip cuttings

Treesearch

Richard H. Fenton

1955-01-01

The eye of Hurricane Hazel passed to the west of the Beltsville Experimental Forest in Maryland on the afternoon of October 15, 1954. Sustained wind velocities of 66 mph (from the SE), with maximum gusts of 98 mph, were recorded nearby.

Reducing Carbon Dioxide Emissions: Using the Mole Concept.

ERIC Educational Resources Information Center

Myers, Alan

2002-01-01

Provides an application of quantitative chemistry concepts in the context of motor vehicle emissions. Shows how carbon dioxide emissions from cars may be reduced by up to 25% by reducing motorway speeds from 70-75 mph to 60 mph. (Author/MM)

Executive Impairment Determines ADHD Medication Response: Implications for Academic Achievement

ERIC Educational Resources Information Center

Hale, James B.; Reddy, Linda A.; Semrud-Clikeman, Margaret; Hain, Lisa A.; Whitaker, James; Morley, Jessica; Lawrence, Kyle; Smith, Alex; Jones, Nicole

2011-01-01

Methylphenidate (MPH) often ameliorates attention-deficit/hyperactivity disorder (ADHD) behavioral dysfunction according to "indirect" informant reports and rating scales. The standard of care behavioral MPH titration approach seldom includes "direct" neuropsychological or academic assessment data to determine treatment…

Alternative Fuels Data Center

Science.gov Websites

Low-Speed Vehicle Definition A low-speed vehicle is defined as a four wheeled vehicle that has a maximum speed greater than 20 miles per hour (mph) but not more than 25 mph and has a gross vehicle weight

A Comparison of 2 Current-Issue Army Boots, 5 Prototype Military Boots, and 5 Commercial Hiking Boots: Performance, Efficiency, Biomechanics, Comfort and Injury

DTIC Science & Technology

1999-11-01

Maximum force (N) on the ankle, knee and hip while walking at 3.5 mph 51 23. Maximum heel- strike force (N) while walking at 3.5 mph ^.ർ 24...to first force peak while running at 6.5 mph ’.""."..62 34. Variables relating to force low point between the heel- strike and push-off peak...was lower peak deceleration and lower peak pressure at the heel than at the forefoot . In the second phase of their research, Hamill and Bensel (7, 8

Strain actuated aeroelastic control

NASA Technical Reports Server (NTRS)

Lazarus, Kenneth B.

1992-01-01

Viewgraphs on strain actuated aeroelastic control are presented. Topics covered include: structural and aerodynamic modeling; control law design methodology; system block diagram; adaptive wing test article; bench-top experiments; bench-top disturbance rejection: open and closed loop response; bench-top disturbance rejection: state cost versus control cost; wind tunnel experiments; wind tunnel gust alleviation: open and closed loop response at 60 mph; wind tunnel gust alleviation: state cost versus control cost at 60 mph; wind tunnel command following: open and closed loop error at 60 mph; wind tunnel flutter suppression: open loop flutter speed; and wind tunnel flutter suppression: closed loop state cost curves.

Prophylactic cranial irradiation: recent outcomes and innovations.

PubMed

Snider, James W; Gondi, Vinai; Brown, Paul D; Tome, Wolfgang; Mehta, Minesh P

2014-05-01

Brain metastases represent a frequent problem in several malignancies. They can shorten survival while causing significant morbidity and impairment in the patient's quality of life. Prophylactic cranial irradiation (PCI) has become an integral part of the standard of care in small cell lung cancer (SCLC), yet its role in other malignancies remains the subject of significant discussion. Its role has been extensively investigated in non-small cell lung cancer and less so for breast cancer and other malignancies. Improvements in medical care as well as in whole brain radiotherapy (WBRT) techniques may improve the risk-benefit ratio of this therapy so as to expand its role in cancer care. The use of memantine in WBRT patients as well as the use of hippocampal avoidance techniques are of particular interest in this effort. Herein, we review the history of PCI, its current use, and areas of investigation in the application of PCI.

Mathematical modeling of the malignancy of cancer using graph evolution.

PubMed

Gunduz-Demir, Cigdem

2007-10-01

We report a novel computational method based on graph evolution process to model the malignancy of brain cancer called glioma. In this work, we analyze the phases that a graph passes through during its evolution and demonstrate strong relation between the malignancy of cancer and the phase of its graph. From the photomicrographs of tissues, which are diagnosed as normal, low-grade cancerous and high-grade cancerous, we construct cell-graphs based on the locations of cells; we probabilistically generate an edge between every pair of cells depending on the Euclidean distance between them. For a cell-graph, we extract connectivity information including the properties of its connected components in order to analyze the phase of the cell-graph. Working with brain tissue samples surgically removed from 12 patients, we demonstrate that cell-graphs generated for different tissue types evolve differently and that they exhibit different phase properties, which distinguish a tissue type from another.

Neural Stem Cells: Implications for the Conventional Radiotherapy of Central Nervous System Malignancies

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

Barani, Igor J.; Benedict, Stanley H.; Lin, Peck-Sun

Advances in basic neuroscience related to neural stem cells and their malignant counterparts are challenging traditional models of central nervous system tumorigenesis and intrinsic brain repair. Neurogenesis persists into adulthood predominantly in two neurogenic centers: subventricular zone and subgranular zone. Subventricular zone is situated adjacent to lateral ventricles and subgranular zone is confined to the dentate gyrus of the hippocampus. Neural stem cells not only self-renew and differentiate along multiple lineages in these regions, but also contribute to intrinsic brain plasticity and repair. Ionizing radiation can depopulate these exquisitely sensitive regions directly or impair in situ neurogenesis by indirect, dose-dependentmore » and inflammation-mediated mechanisms, even at doses <2 Gy. This review discusses the fundamental neural stem cell concepts within the framework of cumulative clinical experience with the treatment of central nervous system malignancies using conventional radiotherapy.« less

Comparison of analytical methods for calculation of wind loads

NASA Technical Reports Server (NTRS)

Minderman, Donald J.; Schultz, Larry L.

1989-01-01

The following analysis is a comparison of analytical methods for calculation of wind load pressures. The analytical methods specified in ASCE Paper No. 3269, ANSI A58.1-1982, the Standard Building Code, and the Uniform Building Code were analyzed using various hurricane speeds to determine the differences in the calculated results. The winds used for the analysis ranged from 100 mph to 125 mph and applied inland from the shoreline of a large open body of water (i.e., an enormous lake or the ocean) a distance of 1500 feet or ten times the height of the building or structure considered. For a building or structure less than or equal to 250 feet in height acted upon by a wind greater than or equal to 115 mph, it was determined that the method specified in ANSI A58.1-1982 calculates a larger wind load pressure than the other methods. For a building or structure between 250 feet and 500 feet tall acted upon by a wind rangind from 100 mph to 110 mph, there is no clear choice of which method to use; for these cases, factors that must be considered are the steady-state or peak wind velocity, the geographic location, the distance from a large open body of water, and the expected design life and its risk factor.

Accuracy of an infrared LED device to measure heart rate and energy expenditure during rest and exercise.

PubMed

Lee, C Matthew; Gorelick, Mark; Mendoza, Albert

2011-12-01

The purpose of this study was to examine the accuracy of the ePulse Personal Fitness Assistant, a forearm-worn device that provides measures of heart rate and estimates energy expenditure. Forty-six participants engaged in 4-minute periods of standing, 2.0 mph walking, 3.5 mph walking, 4.5 mph jogging, and 6.0 mph running. Heart rate and energy expenditure were simultaneously recorded at 60-second intervals using the ePulse, an electrocardiogram (EKG), and indirect calorimetry. The heart rates obtained from the ePulse were highly correlated (intraclass correlation coefficients [ICCs] ≥0.85) with those from the EKG during all conditions. The typical errors progressively increased with increasing exercise intensity but were <5 bpm only during rest and 2.0 mph. Energy expenditure from the ePulse was poorly correlated with indirect calorimetry (ICCs: 0.01-0.36) and the typical errors for energy expenditure ranged from 0.69-2.97 kcal · min(-1), progressively increasing with exercise intensity. These data suggest that the ePulse Personal Fitness Assistant is a valid device for monitoring heart rate at rest and low-intensity exercise, but becomes less accurate as exercise intensity increases. However, it does not appear to be a valid device to estimate energy expenditure during exercise.

Sex differences in attentional performance and their modulation by methylphenidate in children with attention-deficit/hyperactivity disorder.

PubMed

Günther, Thomas; Herpertz-Dahlmann, Beate; Konrad, Kerstin

2010-06-01

Still little is known about neuropsychological differences between boys and girls with attention-deficit/hyperactivity disorder (ADHD) and whether there are sex-specific differences in the modulation of attentional performance by methylphenidate (MPH). In this study, 27 males and 27 females between 8-12 years old and with ADHD were investigated in a double-blind, placebo-controlled trial on five computerized attention tests (0.25 vs. 0.5 mg/kg MPH as a single dose, versus placebo). Boys and girls with ADHD did not differ with respect to age, intelligence quotient (IQ), symptom severity, co-morbidity patterns, and ADHD subtype. However, ADHD boys were more impulsive on a sustained attention task, whereas girls with ADHD had more deficits on tasks measuring selective attention. Attentional performance increased differentially as a function of MPH dose, with some tasks showing linear improvement with higher dosage whereas more complex tasks in particular showed inverse U-shaped patterns of MPH effects. However, these effects were comparable between girls and boys. Our data suggest that there are some gender differences in attentional performance in subjects with ADHD in a clinical sample, even if symptom severity and co-morbidity are controlled; however, modulation of attention by MPH does not seem to differ between sexes.

Long non-coding RNA DANCR facilitates glioma malignancy by sponging miR-33a-5p.

PubMed

Yang, J X; Sun, Y; Gao, L; Meng, Q; Yang, B Y

2018-06-26

Glioma is among the most fatal brain tumors characterized by a highly malignancy and rapid progression and early metastasis. Dysregulation of long non-coding RNA differentiation antagonizing non-protein coding RNA (LncRNA DANCR) is associated with the development, progression and metastasis of various cancers. In the present study, we investigated functional role of LncRNA DANCR in the malignancy of glioma. The results showed that LncRNA DANCR was increased in glioma tissues and cells compared with normal brain tissues and cells. DANCR expression was positively correlated with the malignancy and poor prognosis of glioma patients. DANCR contained a binding site of miR-33a-5p. miR-33a-5p was decreased in glioma tissues and cells compared with normal brain tissues and cells. Downregulation of miR-33a-5p was positively correlated with the malignancy and poor prognosis of glioma patients. In glioma tissues, the expression of DANCR was negatively correlated with the expression of miR-33a-5p. Downregulation of DANCR increased miR-33a-5p expression. miR-33a-5p mimic reduced the luciferase of DANCR-WT but not DANCR-MUT. DANCR pull-down showed the expression of miR-33a-5p. miR-33a-5p mimic enhanced knockdown of DANCR -induced inhibition of cell proliferation, migration, and EMT, and increase of apoptosis. Anti-miR-33a-5p reversed the effects of si- DANCR on cell malignancy. Knockdown of DANCR remarkably reduced the increase of tumor volumes in xenograft mouse models. In tumor tissues, knockdown of DANCR increased the expression of miR-33a-5p, reduced EMT and increased apoptosis. Our study provides novel insights in the functions of LncRNA DANCR-miR-33a-5p axis in tumorigenesis of glioma.

De novo malignancy after pancreas transplantation in Japan.

PubMed

Tomimaru, Y; Ito, T; Marubashi, S; Kawamoto, K; Tomokuni, A; Asaoka, T; Wada, H; Eguchi, H; Mori, M; Doki, Y; Nagano, H

2015-04-01

Long-term immunosuppression is associated with an increased risk of cancer. Especially, the immunosuppression in pancreas transplantation is more intensive than that in other organ transplantation because of its strong immunogenicity. Therefore, it suggests that the risk of post-transplant de novo malignancy might increase in pancreas transplantation. However, there have been few studies of de novo malignancy after pancreas transplantation. The aim of this study was to analyze the incidence of de novo malignancy after pancreas transplantation in Japan. Post-transplant patients with de novo malignancy were surveyed and characterized in Japan. Among 107 cases receiving pancreas transplantation in Japan between 2001 and 2010, de novo malignancy developed in 9 cases (8.4%): post-transplant lymphoproliferative disorders in 6 cases, colon cancer in 1 case, renal cancer in 1 case, and brain tumor in 1 case. We clarified the incidence of de novo malignancy after pancreas transplantation in Japan. Copyright © 2015 Elsevier Inc. All rights reserved.

Examination of media coverage of increasing the speed limit to 65 mph

DOT National Transportation Integrated Search

1988-09-01

Heightened newspaper and television coverage of the proposed 65 mph limit may have encouraged increased travel speeds which in turn could have produced an increase in fatalities prior to passage of the national legislation. To pursue this further, NH...

Evaluating the impacts of proposed speed limit increases in Michigan : research spotlight.

DOT National Transportation Integrated Search

2014-07-01

Recent proposed speed limit legislation led MDOT to evaluate the : states current speed limit policies and potential alternatives. Currently, : Michigan freeways have a maximum speed limit of 70 mph for passenger : vehicles and 60 mph for trucks a...

High-speed rail aerodynamic assessment and mitigation report : final report.

DOT National Transportation Integrated Search

2015-12-01

This report advances the current state of knowledge, as well as shared understanding and evaluation of present procedures used to : mitigate the impacts effects from high-speed trains (HST) operating at speeds between 110 mph and 250 mph. This work g...

Engineering studies in support of the development of high-speed track geometry specifications

DOT National Transportation Integrated Search

1997-03-01

The Federal Railroad Administration has been directing engineering studies to support the development of high speed track geometry standards. These standards are intended to cover train operating speeds from 110 mph to 200 mph. The studies conducted ...

65 mph speed limit : analysis of fatal accident injury severity

DOT National Transportation Integrated Search

1989-11-01

Several studies of the fatality experience in the 38 states that implemented a65 mph speed : limit on Rural Interstate highways in 1987 concluded that the higher speed limit has : caused fatalities to increase. This relationship between the speed lim...

Passenger vehicles sustain huge damage in 5 Mph tests

DOT National Transportation Integrated Search

2000-04-15

Seventeen new cars, all 1999 and 2000 models, turned in mostly disappointing results in 5 mph crash tests conducted to assess how well the bumpers resist costly damage in the kinds of impacts that frequently occur in commuter traffic and parking lots...

Delineating Normal from Diseased Brain by Aminolevulinic Acid-Induced Fluorescence

NASA Astrophysics Data System (ADS)

Stepp, Herbert; Stummer, Walter

5-Aminolevulinic acid (5-ALA) as a precursor of protoporphyrin IX (PpIX) has been established as an orally applied drug to guide surgical resection of malignant brain tumors by exciting the red fluorescence of PpIX. The accumulation of PpIX in glioblastoma multiforme (GBM) is highly selective and provides excellent contrast to normal brain when using surgical microscopes with appropriately filtered light sources and cameras. The positive predictive value of fluorescent tissue is very high, enabling safe gross total resection of GBM and other brain tumors and improving prognosis of patients. Compared to other intraoperative techniques that have been developed with the aim of increasing the rate of safe gross total resections of malignant gliomas, PpIX fluorescence is considerably simpler, more cost effective, and comparably reliable. We present the basics of 5-ALA-based fluorescence-guided resection, and discuss the clinical results obtained for GBM and the experience with the fluorescence staining of other primary brain tumors and metastases as well as the results for spinal cord tumors. The phototoxicity of PpIX, increasingly used for photodynamic therapy of brain tumors, is mentioned briefly in this chapter.

Convection-enhanced delivery for the treatment of brain tumors

PubMed Central

Debinski, Waldemar; Tatter, Stephen B

2013-01-01

The brain is highly accessible for nutrients and oxygen, however delivery of drugs to malignant brain tumors is a very challenging task. Convection-enhanced delivery (CED) has been designed to overcome some of the difficulties so that pharmacological agents that would not normally cross the BBB can be used for treatment. Drugs are delivered through one to several catheters placed stereotactically directly within the tumor mass or around the tumor or the resection cavity. Several classes of drugs are amenable to this technology including standard chemotherapeutics or novel experimental targeted drugs. The first Phase III trial for CED-delivered, molecularly targeted cytotoxin in the treatment of recurrent glioblastoma multiforme has been accomplished and demonstrated objective clinical efficacy. The lessons learned from more than a decade of attempts at exploiting CED for brain cancer treatment weigh critically for its future clinical applications. The main issues center around the type of catheters used, number of catheters and their exact placement; pharmacological formulation of drugs, prescreening patients undergoing treatment and monitoring the distribution of drugs in tumors and the tumor-infiltrated brain. It is expected that optimizing CED will make this technology a permanent addition to clinical management of brain malignancies. PMID:19831841

ABERRANT SPLICING OF A BRAIN-ENRICHED ALTERNATIVE EXON ELIMINATES TUMOR SUPPRESSOR FUNCTION AND PROMOTES ONCOGENE FUNCTION DURING BRAIN TUMORIGENESIS

PubMed Central

Bredel, Markus; Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; Elverfeldt, Dominik v.; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.

2014-01-01

BACKGROUND: Tissue-specific alternative splicing is known to be critical to emergence of tissue identity during development, yet its role in malignant transformation is undefined. Tissue-specific splicing involves evolutionary-conserved, alternative exons, which represent only a minority of total alternative exons. Many, however, have functional features that influence activity in signaling pathways to profound biological effect. Given that tissue-specific splicing has a determinative role in brain development and the enrichment of genes containing tissue-specific exons for proteins with roles in signaling and development, it is thus plausible that changes in such exons could rewire normal neurogenesis towards malignant transformation. METHODS: We used integrated molecular genetic and cell biology analyses, computational biology, animal modeling, and clinical patient profiles to characterize the effect of aberrant splicing of a brain-enriched alternative exon in the membrane-binding tumor suppressor Annexin A7 (ANXA7) on oncogene regulation and brain tumorigenesis. RESULTS: We show that aberrant splicing of a tissue-specific cassette exon in ANXA7 diminishes endosomal targeting and consequent termination of the signal of the EGFR oncoprotein during brain tumorigenesis. Splicing of this exon is mediated by the ribonucleoprotein Polypyrimidine Tract-Binding Protein 1 (PTBP1), which is normally repressed during brain development but, we find, is excessively expressed in glioblastomas through either gene amplification or loss of a neuron-specific microRNA, miR-124. Silencing of PTBP1 attenuates both malignancy and angiogenesis in a stem cell-derived glioblastoma animal model characterized by a high native propensity to generate tumor endothelium or vascular pericytes to support tumor growth. We show that EGFR amplification and PTBP1 overexpression portend a similarly poor clinical outcome, further highlighting the importance of PTBP1-mediated activation of EGFR. CONCLUSIONS: Our data illustrate how anomalous splicing of a tissue-regulated exon in a constituent of an oncogenic signaling pathway eliminates its tumor suppressor function and promotes tumorigenesis. This paradigm of malignant glial transformation as a consequence of tissue-specific alternative exon splicing in a tumor suppressor, may have widespread applicability in explaining how changes in critical tissue-specific regulatory mechanisms reprogram normal development to oncogenesis. SECONDARY CATEGORY: n/a.

Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

PubMed

Kriström, Berit; Aronson, A Stefan; Dahlgren, Jovanna; Gustafsson, Jan; Halldin, Maria; Ivarsson, Sten A; Nilsson, Nils-Osten; Svensson, Johan; Tuvemo, Torsten; Albertsson-Wikland, Kerstin

2009-02-01

Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

Aboriginal and Torres Strait Islander Public Health: Online and Integrated into Core Master of Public Health Subjects

PubMed Central

Angus, Lynnell; Ewen, Shaun; Coombe, Leanne

2016-01-01

The Master of Public Health (MPH) is an internationally recognised post-graduate qualification for building the public health workforce. In Australia, MPH graduate attributes include six Indigenous public health (IPH) competencies. The University of Melbourne MPH program includes five core subjects and ten specialisation streams, of which one is Indigenous health. Unless students complete this specialisation or electives in Indigenous health, it is possible for students to graduate without attaining the IPH competencies. To address this issue in a crowded and competitive curriculum an innovative approach to integrating the IPH competencies in core MPH subjects was developed. Five online modules that corresponded with the learning outcomes of the core public health subjects were developed, implemented and evaluated in 2015. This brief report outlines the conceptualisation, development, and description of the curriculum content; it also provides preliminary student evaluation and staff feedback on the integration project. Significance for public health This approach to a comprehensive, online, integrated Indigenous public health (IPH) curriculum is significant, as it ensures that all University of Melbourne Master of Public Health (MPH) graduates will have the competencies to positively contribute to Indigenous health status. A workforce that is attuned not only to the challenges of IPH, but also to the principles of self-determination, Indigenous agency and collaboration is better equipped to be comprised of ethical and judgment-safe practitioners. Additionally, the outlined approach of utilizing IPH content and examples into core MPH subjects ensures both the Australian relevance for an Australian-based health professional course and international appeal through the modules inclusion of International Indigenous case-studies and content. Furthermore, approaches learned in a challenging Indigenous Australian context are transferable and applicable to other IPH challenges in a local, national and global context. PMID:27190981

OROS-methylphenidate efficacy on specific executive functioning deficits in adults with ADHD: a randomized, placebo-controlled cross-over study.

PubMed

Bron, Tannetje I; Bijlenga, Denise; Boonstra, A Marije; Breuk, Minda; Pardoen, Willem F H; Beekman, Aartjan T F; Kooij, J J Sandra

2014-04-01

Attention-deficit/hyperactivity disorder (ADHD) is linked to impaired executive functioning (EF). This is the first study to objectively investigate the effects of a long-acting methylphenidate on neurocognitive test performance of adults with ADHD. Twenty-two adults with ADHD participated in a 6-weeks study examining the effect of osmotic-release oral system methylphenidate (OROS-mph) on continuous performance tests (CPTs; objective measures), and on the self-reported ADHD rating scale (subjective measure) using a randomized, double-blind, placebo-controlled cross-over design. OROS-mph significantly improved reaction time variability (RTV), commission errors (CE) and d-prime (DP) as compared to baseline (Cohen's d>.50), but did not affect hit reaction time (HRT) or omission errors (OE). Compared to placebo, OROS-mph only significantly influenced RTV on one of two CPTs (p<.050). Linear regression analyses showed predictive ability of more beneficial OROS-mph effects in ADHD patients with higher EF severity (RTV: β=.670, t=2.097, p=.042; omission errors (OE): β=-.098, t=-4.759, p<.001), and with more severe ADHD symptoms (RTV: F=6.363, p=.019; HRT: F=3.914, p=.061). Side effects rates were substantially but non-significantly greater for OROS-mph compared to placebo (77% vs. 46%, p=.063). OROS-mph effects indicated RTV as the most sensitive parameter for measuring both neuropsychological and behavioral deficits in adults with ADHD. These findings suggest RTV as an endophenotypic parameter for ADHD symptomatology, and propose CPTs as an objective method for monitoring methylphenidate titration. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Park, Seo Yeon; Kim, Eun Joo; Cheon, Keun-Ah

2015-10-01

The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.

Treatment with a Clinically-Relevant Dose of Methylphenidate Alters NMDA Receptor Composition and Synaptic Plasticity in the Juvenile Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Li, Yan-Chun; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning. PMID:23333502

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Park, Seo Yeon; Kim, Eun Joo

2015-01-01

Abstract Objectives: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. Results: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). Conclusions: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting. PMID:26402385

Designing the framework for competency-based master of public health programs in India.

PubMed

Sharma, Kavya; Zodpey, Sanjay; Morgan, Alison; Gaidhane, Abhay; Syed, Zahiruddin Quazi; Kumar, Rajeev

2013-01-01

Competency in the practice of public health is the implicit goal of education institutions that offer master of public health (MPH) programs. With the expanding number of institutions offering courses in public health in India, it is timely to develop a common framework to ensure that graduates are proficient in critical public health. Steps such as situation assessment, survey of public health care professionals in India, and national consultation were undertaken to develop a proposed competency-based framework for MPH programs in India. The existing curricula of all 23 Indian MPH courses vary significantly in content with regard to core, concentration, and crosscutting discipline areas and course durations. The competency or learning outcome is not well defined. The findings of the survey suggest that MPH graduates in India should have competencies ranging from monitoring of health problems and epidemics in the community, applying biostatistics in public health, conducting action research, understanding social and community influence on public health developing indicators and instruments to monitor and evaluate community health programs, developing proposals, and involving community in planning, delivery, and monitoring of health programs. Competency statements were framed and mapped with domains including epidemiology, biostatistics, social and behavioral sciences, health care system, policy, planning, and financing, and environmental health sciences and a crosscutting domain that include health communication and informatics, health management and leadership, professionalism, systems thinking, and public health biology. The proposed competency-based framework for Indian MPH programs can be adapted to meet the needs of diverse, unique programs. The framework ensures the uniqueness and diversity of individual MPH programs in India while contributing to measures of overall program success.

Development and Validation of a Monte Carlo Simulation Tool for Multi-Pinhole SPECT

PubMed Central

Mok, Greta S. P.; Du, Yong; Wang, Yuchuan; Frey, Eric C.; Tsui, Benjamin M. W.

2011-01-01

Purpose In this work, we developed and validated a Monte Carlo simulation (MCS) tool for investigation and evaluation of multi-pinhole (MPH) SPECT imaging. Procedures This tool was based on a combination of the SimSET and MCNP codes. Photon attenuation and scatter in the object, as well as penetration and scatter through the collimator detector, are modeled in this tool. It allows accurate and efficient simulation of MPH SPECT with focused pinhole apertures and user-specified photon energy, aperture material, and imaging geometry. The MCS method was validated by comparing the point response function (PRF), detection efficiency (DE), and image profiles obtained from point sources and phantom experiments. A prototype single-pinhole collimator and focused four- and five-pinhole collimators fitted on a small animal imager were used for the experimental validations. We have also compared computational speed among various simulation tools for MPH SPECT, including SimSET-MCNP, MCNP, SimSET-GATE, and GATE for simulating projections of a hot sphere phantom. Results We found good agreement between the MCS and experimental results for PRF, DE, and image profiles, indicating the validity of the simulation method. The relative computational speeds for SimSET-MCNP, MCNP, SimSET-GATE, and GATE are 1: 2.73: 3.54: 7.34, respectively, for 120-view simulations. We also demonstrated the application of this MCS tool in small animal imaging by generating a set of low-noise MPH projection data of a 3D digital mouse whole body phantom. Conclusions The new method is useful for studying MPH collimator designs, data acquisition protocols, image reconstructions, and compensation techniques. It also has great potential to be applied for modeling the collimator-detector response with penetration and scatter effects for MPH in the quantitative reconstruction method. PMID:19779896

Effects of wind speed on aerosol spray penetration in adult mosquito bioassay cages.

PubMed

Hoffmann, W Clint; Fritz, Bradley K; Farooq, Muhammad; Cooperband, Miriam F

2008-09-01

Bioassay cages are commonly used to assess efficacy of insecticides against adult mosquitoes in the field. To correlate adult mortality readings to insecticidal efficacy and/or spray application parameters properly, it is important to know how the cage used in the bioassay interacts with the spray cloud containing the applied insecticide. This study compared the size of droplets, wind speed, and amount of spray material penetrating cages and outside of cages in a wind tunnel at different wind speeds. Two bioassay cages, Center for Medical, Agricultural and Veterinary Entomology (CMAVE) and Circle, were evaluated. The screen materials used on these cages reduced the size of droplets, wind speed, and amount of spray material inside the cages as compared to the spray cloud and wind velocity outside of the cages. When the wind speed in the dispersion tunnel was set at 0.6 m/sec (1.3 mph), the mean wind speed inside of the CMAVE Bioassay Cage and Circle Cage was 0.045 m/sec (0.10 mph) and 0.075 m/sec (0.17 mph), respectively. At air velocities of 2.2 m/sec (4.9 mph) in the dispersion tunnel, the mean wind speed inside of the CMAVE Bioassay Cage and Circle Cage was 0.83 m/sec (1.86 mph) and 0.71 m/sec (1.59 mph), respectively. Consequently, there was a consistent 50-70% reduction of spray material penetrating the cages compared to the spray cloud that approached the cages. These results provide a better understanding of the impact of wind speed, cage design, and construction on ultra-low-volume spray droplets.

Early long-term exposure with caffeine induces cross-sensitization to methylphenidate with involvement of DARPP-32 in adulthood of rats.

PubMed

Boeck, Carina R; Marques, Virgínia B; Valvassori, Samira S; Constantino, Leandra C; Rosa, Daniela V F; Lima, Fabrício F; Romano-Silva, Marco A; Quevedo, João

2009-09-01

Chronic ingestion of caffeine causes dependence and sleep disturbance in children and adolescents. In rodents, the administration of caffeine may produce behavioral cross-sensitization to some psychostimulants, such as dopaminergic psychoactive drugs. Methylphenidate (MPH; Ritalin) is a psychostimulant used in pediatric- and adult human populations to manage the symptoms associated with attention-deficit hyperactivity disorder (ADHD). Previous studies have suggested that dopamine- and cAMP-regulated phosphoproteins of 32 kDa (DARPP-32) participate in the manifestation of behavioral activity following ingestion of caffeine or MPH. The aim of the present study was to evaluate whether long-term administration of low doses of caffeine in rodents during their adolescence induces cross-sensitization to MPH challenge in their adulthood and investigate the involvement of DARPP-32 in this model. Young rats (P25) consumed water or caffeine (0.3 g/L; mean consumption was 7.5 mg/day/kg) for 28 days. The caffeine consumption was then suspended for 14 days (washout period) when the animals received saline solution or MPH (1, 2, or 10 mg/kg) (P67) intraperitoneally. The locomotor activity of these rats was assessed using the open-field test, following which the immunocontent of DARPP-32 was evaluated in samples of their prefrontal cortex, striatum, or hippocampus. Rats chronically exposed to caffeine in their adolescent period and to inactive doses of MPH (1mg/kg) in adulthood showed augmented locomotor activity. The behavioral effect observed was accompanied by increased levels of DARPP-32 in the striatum and prefrontal cortex compared to control groups (saline or caffeine). However, no alteration caused by these treatments was noted in the hippocampus. In conclusion, chronic caffeine exposure induces likely long-term cross-sensitization to MPH in a DARPP-32-dependent pathway.

[Possibilities of boron neutron capture therapy in the treatment of malignant brain tumors].

PubMed

Kanygin, V V; Kichigin, A I; Gubanova, N V; Taskaev, S Yu

2015-01-01

Boron neutron capture therapy (BNCT) that is of the highest attractiveness due to its selective action directly on malignant tumor cells is a promising approach to treating cancers. Clinical interest in BNCT focuses in neuro-oncology on therapy for gliomas, glioblastoma in particular, and BNCT may be used in brain metastatic involvement. This needs an epithermal neutron source that complies with the requirements for BNCT, as well as a 10B-containing agent that will selectively accumulate in tumor tissue. The introduction of BNCT into clinical practice to treat patients with glial tumors will be able to enhance therapeutic efficiency.

Multiple cutaneous melanomas associated with gastric and brain metastases*

PubMed Central

Grander, Lara Caroline; Cabral, Fernanda; Lisboa, Alice Paixão; Vale, Gabrielle; Barcaui, Carlos Baptista; Maceira, Juan Manuel Pineiro

2016-01-01

The occurrence of multiple primary melanomas in a single individual is rare. Most commonly, malignant melanocytic lesions subsequent to the initial diagnosis of melanoma are secondary cutaneous metastases. We report a patient with gastrointestinal bleeding from gastric metastasis of cutaneous melanoma. During clinical evaluation and staging, we discovered a brain metastasis associated with 3 synchronous primary cutaneous melanomas. We suggest the research on the mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) (INK4a) in such cases. We also emphasize the importance of clinical examination and dermoscopy of the entire tegument, even after a malignant melanocytic lesion is identified. PMID:28300909

Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas

PubMed Central

Chaichana, Kaisorn L; Pinheiro, Leon; Brem, Henry

2015-01-01

Malignant gliomas, including glioblastoma and anaplastic astrocytomas, are characterized by their propensity to invade surrounding brain parenchyma, making curative resection difficult. These tumors typically recur within two centimeters of the resection cavity even after gross total removal. As a result, there has been an emphasis on developing therapeutics aimed at achieving local disease control. In this review, we will summarize the current developments in the delivery of local therapeutics, namely direct injection, convection-enhanced delivery and implantation of drug-loaded polymers, as well as the application of these therapeutics in future methods including microchip drug delivery and local gene therapy. PMID:25853310

Delivery of local therapeutics to the brain: working toward advancing treatment for malignant gliomas.

PubMed

Chaichana, Kaisorn L; Pinheiro, Leon; Brem, Henry

2015-03-01

Malignant gliomas, including glioblastoma and anaplastic astrocytomas, are characterized by their propensity to invade surrounding brain parenchyma, making curative resection difficult. These tumors typically recur within two centimeters of the resection cavity even after gross total removal. As a result, there has been an emphasis on developing therapeutics aimed at achieving local disease control. In this review, we will summarize the current developments in the delivery of local therapeutics, namely direct injection, convection-enhanced delivery and implantation of drug-loaded polymers, as well as the application of these therapeutics in future methods including microchip drug delivery and local gene therapy.

Neurosurgery contact handheld probe based on sapphire shaped crystal

NASA Astrophysics Data System (ADS)

Shikunova, I. A.; Stryukov, D. O.; Rossolenko, S. N.; Kiselev, A. M.; Kurlov, V. N.

2017-01-01

A handheld contact probe based on sapphire shaped crystal is developed for intraoperative spectrally-resolved optical diagnostics, laser coagulation and aspiration of malignant brain tissue. The technology was integrated into the neurosurgical workflow for intraoperative real-time identification and removing of invasive brain cancer.

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed

Shah, Khalid

2016-08-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib.

PubMed

Messina, Julia A; Maziarz, Eileen K; Spec, Andrej; Kontoyiannis, Dimitrios P; Perfect, John R

2017-01-01

We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.

Enhancing the discrimination accuracy between metastases, gliomas and meningiomas on brain MRI by volumetric textural features and ensemble pattern recognition methods.

PubMed

Georgiadis, Pantelis; Cavouras, Dionisis; Kalatzis, Ioannis; Glotsos, Dimitris; Athanasiadis, Emmanouil; Kostopoulos, Spiros; Sifaki, Koralia; Malamas, Menelaos; Nikiforidis, George; Solomou, Ekaterini

2009-01-01

Three-dimensional (3D) texture analysis of volumetric brain magnetic resonance (MR) images has been identified as an important indicator for discriminating among different brain pathologies. The purpose of this study was to evaluate the efficiency of 3D textural features using a pattern recognition system in the task of discriminating benign, malignant and metastatic brain tissues on T1 postcontrast MR imaging (MRI) series. The dataset consisted of 67 brain MRI series obtained from patients with verified and untreated intracranial tumors. The pattern recognition system was designed as an ensemble classification scheme employing a support vector machine classifier, specially modified in order to integrate the least squares features transformation logic in its kernel function. The latter, in conjunction with using 3D textural features, enabled boosting up the performance of the system in discriminating metastatic, malignant and benign brain tumors with 77.14%, 89.19% and 93.33% accuracy, respectively. The method was evaluated using an external cross-validation process; thus, results might be considered indicative of the generalization performance of the system to "unseen" cases. The proposed system might be used as an assisting tool for brain tumor characterization on volumetric MRI series.

Effects of Raising Speed Limits on Motor Vehicle Emissions

DOT National Transportation Integrated Search

1997-03-01

In 1974 the Federal government introduced a national speed limit of 55 miles per hour (mph) in response to the Arab oil embargo and subsequent energy crisis. This limit was raised to 65 mph for rural interstate freeways in 1987. In November of 1995, ...

The impact of the 65 mph speed limit on Virginia's rural interstate highways through 1989.

DOT National Transportation Integrated Search

1990-01-01

In April 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA) which permitted states to raise their maximum speed limit on rural interstate highways (rural interstates) to 65 mph. Since then, 40 states, incl...

Evaluating the impacts of speed limit policy alternatives.

DOT National Transportation Integrated Search

2014-07-01

As of June 2014, Michigan is one of eight states with a differential speed limit in place on its rural : freeways, which sets a maximum speed of 70 mph for passenger vehicles and 60 mph for trucks and : buses. In select urban environments, these spee...

Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

PubMed

Tseng, Yuan-Yun; Su, Chen-Hsing; Yang, Shun-Tai; Huang, Yin-Chen; Lee, Wei-Hwa; Wang, Yi-Chuan; Liu, Shou-Cheng; Liu, Shih-Jung

2016-09-13

Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.

Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.

PubMed

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A; Fournier, Michelle; Vrionis, Frank D; Tran, Nam; Chan, Jennifer A; Kenchappa, Rajappa S; Forsyth, Peter A

2015-02-06

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Neurotrophin Signaling via TrkB and TrkC Receptors Promotes the Growth of Brain Tumor-initiating Cells*

PubMed Central

Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A.; Fournier, Michelle; Vrionis, Frank D.; Tran, Nam; Chan, Jennifer A.; Kenchappa, Rajappa S.; Forsyth, Peter A.

2015-01-01

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. PMID:25538243

A flexible approach to training veterinarians in public health: an overview and early assessment of the DVM/MPH dual-degree program at the University of Minnesota.

PubMed

Minicucci, Larissa A; Hanson, Kate A; Olson, Debra K; Hueston, William D

2008-01-01

As a result of the growing need for public-health veterinarians, novel educational programs are essential to train future public-health professionals. The University of Minnesota School of Public Health, in collaboration with the College of Veterinary Medicine, initiated a dual DVM/MPH program in 2002. This program provides flexibility by combining distance learning and on-campus courses offered through a summer public-health institute. MPH requirements are completed through core courses, elective courses in a focus area, and an MPH project and field experience. Currently, more than 100 students representing 13 veterinary schools are enrolled in the program. The majority of initial program graduates have pursued public-practice careers upon completion of the program. Strengths of the Minnesota program design include accessibility and an environment to support multidisciplinary training. Continued assessment of program graduates will allow for evaluation and adjustment of the program in the coming years.

Physicochemical and flavor characteristics of flavoring agent from mungbean protein hydrolyzed by bromelain.

PubMed

Sonklin, Chanikan; Laohakunjit, Natta; Kerdchoechuen, Orapin

2011-08-10

Enzymatic bromelain mungbean meal protein hydrolysate (eb-MPH) was produced from mungbean meal protein isolate (MPI). Enzymatic bromelain, with a known protease activity of 98,652 (unit/g), was used at concentrations of 0, 2, 6, 10, 14 and 18% (w/w) and with hydrolysis times of 0.5, 3, 6, 12, and 24 h. The pH and temperature were controlled at 6.0 and 50 °C, respectively. It was found that the best treatment combination for eb-MPH production by response surface methodology (RSM) was 18% bromelain and a hydrolysis time of 3 h, resulting in the greatest degree of hydrolysis (% DH) and percent yield, with values of 61.04 and 45.63%, respectively. Results also showed that the phenylalanine, tyrosine and leucine contents of the optimally produced eb-MPH were 20.88, 14.50 and 10.93%, respectively. Twelve volatile compounds were identified using gas chromatography mass spectrometry in eb-MPH; benzaldehyde, 2-pentylfuran and furfural were the predominant odorants.

Validation of public health competencies and impact variables for low- and middle-income countries.

PubMed

Zwanikken, Prisca Ac; Alexander, Lucy; Huong, Nguyen Thanh; Qian, Xu; Valladares, Laura Magana; Mohamed, Nazar A; Ying, Xiao Hua; Gonzalez-Robledo, Maria Cecilia; Linh, Le Cu; Wadidi, Marwa Se Abuzaid; Tahir, Hanan; Neupane, Sunisha; Scherpbier, Albert

2014-01-20

The number of Master of Public Health (MPH) programmes in low- and middle-income countries (LMICs) is increasing, but questions have been raised regarding the relevance of their outcomes and impacts on context. Although processes for validating public health competencies have taken place in recent years in many high-income countries, validation in LMICs is needed. Furthermore, impact variables of MPH programmes in the workplace and in society have not been developed. A set of public health competencies and impact variables in the workplace and in society was designed using the competencies and learning objectives of six participating institutions offering MPH programmes in or for LMICs, and the set of competencies of the Council on Linkages Between Academia and Public Health Practice as a reference. The resulting competencies and impact variables differ from those of the Council on Linkages in scope and emphasis on social determinants of health, context specificity and intersectoral competencies. A modified Delphi method was used in this study to validate the public health competencies and impact variables; experts and MPH alumni from China, Vietnam, South Africa, Sudan, Mexico and the Netherlands reviewed them and made recommendations. The competencies and variables were validated across two Delphi rounds, first with public health experts (N = 31) from the six countries, then with MPH alumni (N = 30). After the first expert round, competencies and impact variables were refined based on the quantitative results and qualitative comments. Both rounds showed high consensus, more so for the competencies than the impact variables. The response rate was 100%. This is the first time that public health competencies have been validated in LMICs across continents. It is also the first time that impact variables of MPH programmes have been proposed and validated in LMICs across continents. The high degree of consensus between experts and alumni suggests that these public health competencies and impact variables can be used to design and evaluate MPH programmes, as well as for individual and team assessment and continuous professional development in LMICs.

Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients.

PubMed

Angyal, Nora; Horvath, Erzsebet Zsofia; Tarnok, Zsanett; Richman, Mara J; Bognar, Emese; Lakatos, Krisztina; Sasvari-Szekely, Maria; Nemoda, Zsofia

2018-06-08

Methylphenidate (MPH) is the most frequently prescribed drug in Attention Deficit Hyperactivity Disorder (ADHD). Hitherto mostly the dopamine transporter gene has been studied in MPH-response and only a few studies analyzed the norepinephrine transporter (NET, SLC6A2) gene, although MPH is a potent inhibitor of both dopamine and norepinephrine transporters. We aimed to analyze this monoamine transporter gene in relation to ADHD per se and MPH-response in particular to gain further knowledge in ADHD pharmacogenetics using a Caucasian sample. Six single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143, rs3785157, rs5569, rs7194256 SNP) were studied across the NET gene in 163 ADHD children (age: 9.3±2.6; 86.5% male) using ADHD-RS hyperactivity-impulsivity and inattention scales. For case-control analysis 486 control subjects were also genotyped. At the MPH-response analysis responders had minimum 25% decrease of ADHD-RS total score after 2months of treatment, and chi-square test compared 90 responders and 32 non-responders, whereas ANOVA was used to assess symptom improvement after the first month among the 122 ADHD patients. The classical case-control analysis did not yield any association with ADHD diagnosis, which was supported by meta-analysis conducted on the available genetic data (combining previously published and the present studies). On the other hand, the intronic rs3785143 showed nominal association with inattention symptoms (p=0.01). The haplotype analysis supported this association, and indicated the importance of the first haploblock encompassing the intronic and 2 promoter SNPs. With MPH-response only the promoter rs28386840 showed nominal association: Those with at least one T-allele were overrepresented in the responder group (42% vs 19%, p=0.08), and they had better improvement on the hyperactivity-impulsivity scale compared to the AA genotype (p=0.04). Although none of our single SNP findings remained significant after correcting for multiple testing, our results from the MPH-response analysis indicate the potential importance of promoter variants in the NET gene. Copyright © 2018 Elsevier Inc. All rights reserved.

Validation of public health competencies and impact variables for low- and middle-income countries

PubMed Central

2014-01-01

Background The number of Master of Public Health (MPH) programmes in low- and middle-income countries (LMICs) is increasing, but questions have been raised regarding the relevance of their outcomes and impacts on context. Although processes for validating public health competencies have taken place in recent years in many high-income countries, validation in LMICs is needed. Furthermore, impact variables of MPH programmes in the workplace and in society have not been developed. Method A set of public health competencies and impact variables in the workplace and in society was designed using the competencies and learning objectives of six participating institutions offering MPH programmes in or for LMICs, and the set of competencies of the Council on Linkages Between Academia and Public Health Practice as a reference. The resulting competencies and impact variables differ from those of the Council on Linkages in scope and emphasis on social determinants of health, context specificity and intersectoral competencies. A modified Delphi method was used in this study to validate the public health competencies and impact variables; experts and MPH alumni from China, Vietnam, South Africa, Sudan, Mexico and the Netherlands reviewed them and made recommendations. Results The competencies and variables were validated across two Delphi rounds, first with public health experts (N = 31) from the six countries, then with MPH alumni (N = 30). After the first expert round, competencies and impact variables were refined based on the quantitative results and qualitative comments. Both rounds showed high consensus, more so for the competencies than the impact variables. The response rate was 100%. Conclusion This is the first time that public health competencies have been validated in LMICs across continents. It is also the first time that impact variables of MPH programmes have been proposed and validated in LMICs across continents. The high degree of consensus between experts and alumni suggests that these public health competencies and impact variables can be used to design and evaluate MPH programmes, as well as for individual and team assessment and continuous professional development in LMICs. PMID:24438672

How do stimulant treatments for ADHD work? Evidence for mediation by improved cognition.

PubMed

Hawk, Larry W; Fosco, Whitney D; Colder, Craig R; Waxmonsky, James G; Pelham, William E; Rosch, Keri S

2018-05-07

Stimulant medications such as methylphenidate (MPH) are the frontline treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). Despite their well-documented efficacy, the mechanisms by which stimulants improve clinical outcomes are not clear. The current study evaluated whether MPH effects on classroom behavior were mediated by improved cognitive functioning. Children with ADHD (n = 82; 9-12 years old) participated in a week-long summer research camp, consisting of cognitive testing, classroom periods, and recreational activities. After a baseline day, participants completed a 3-day randomized, double-blind, placebo-controlled trial of MPH (at doses approximating 0.3 and 0.6 mg/kg of immediate-release MPH dosed TID). Cognitive domains included inhibitory control (Stop Signal Task and prepulse inhibition of startle), attention (Continuous Performance Task and reaction time variability), and working memory (forward and backward spatial span). Clinical outcomes included math seatwork productivity and teacher-rated classroom behavior. A within-subjects path-analytic approach was used to test mediation. MPH-placebo and dose-response contrasts were used to evaluate drug effects. Methylphenidate improved seatwork productivity and teacher ratings (ds = 1.4 and 1.1) and all domains of cognition (ds = 0.3-1.1). Inhibitory control (Stop Signal Task, SST) and working memory backward uniquely mediated the effect of MPH (vs. placebo) on productivity. Only working memory backward mediated the impact of MPH on teacher-rated behavior. The dose-response (0.6 vs. 0.3 mg/kg) effects were more modest for clinical outcomes (ds = 0.4 and 0.2) and cognition (ds = 0-0.3); there was no evidence of cognitive mediation of the clinical dose-response effects. These findings are novel in demonstrating that specific cognitive processes mediate clinical improvement with stimulant treatment for ADHD. They converge with work on ADHD theory, neurobiology, and treatment development in suggesting that inhibitory control and working memory may be mechanisms of stimulant treatment response in ADHD. More work is necessary to evaluate the degree to which these findings generalize to chronic treatment, a broader array of clinical outcomes, and nonstimulant treatments. © 2018 Association for Child and Adolescent Mental Health.

Human breast cancer metastases to the brain display GABAergic properties in the neural niche.

PubMed

Neman, Josh; Termini, John; Wilczynski, Sharon; Vaidehi, Nagarajan; Choy, Cecilia; Kowolik, Claudia M; Li, Hubert; Hambrecht, Amanda C; Roberts, Eugene; Jandial, Rahul

2014-01-21

Dispersion of tumors throughout the body is a neoplastic process responsible for the vast majority of deaths from cancer. Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. The physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by circulating breast cancer cells. Bidirectional interplay of breast cancer cells and native brain cells in metastasis is poorly understood and rarely studied. We had the rare opportunity to investigate uncommonly available specimens of matched fresh breast-to-brain metastases tissue and derived cells from patients undergoing neurosurgical resection. We hypothesized that, to metastasize, breast cancers may escape their normative genetic constraints by accommodating and coinhabiting the neural niche. This acquisition or expression of brain-like properties by breast cancer cells could be a malignant adaptation required for brain colonization. Indeed, we found breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metastases to the brain. Proliferative advantage was conferred by the ability of breast-to-brain metastases to take up and catabolize GABA into succinate with the resultant formation of NADH as a biosynthetic source through the GABA shunt. The results suggest that breast cancers exhibit neural characteristics when occupying the brain microenvironment and co-opt GABA as an oncometabolite.

Human breast cancer metastases to the brain display GABAergic properties in the neural niche

PubMed Central

Neman, Josh; Termini, John; Wilczynski, Sharon; Vaidehi, Nagarajan; Choy, Cecilia; Kowolik, Claudia M.; Li, Hubert; Hambrecht, Amanda C.; Roberts, Eugene; Jandial, Rahul

2014-01-01

Dispersion of tumors throughout the body is a neoplastic process responsible for the vast majority of deaths from cancer. Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. The physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by circulating breast cancer cells. Bidirectional interplay of breast cancer cells and native brain cells in metastasis is poorly understood and rarely studied. We had the rare opportunity to investigate uncommonly available specimens of matched fresh breast-to-brain metastases tissue and derived cells from patients undergoing neurosurgical resection. We hypothesized that, to metastasize, breast cancers may escape their normative genetic constraints by accommodating and coinhabiting the neural niche. This acquisition or expression of brain-like properties by breast cancer cells could be a malignant adaptation required for brain colonization. Indeed, we found breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metastases to the brain. Proliferative advantage was conferred by the ability of breast-to-brain metastases to take up and catabolize GABA into succinate with the resultant formation of NADH as a biosynthetic source through the GABA shunt. The results suggest that breast cancers exhibit neural characteristics when occupying the brain microenvironment and co-opt GABA as an oncometabolite. PMID:24395782

Annual Report to the Nation on the Status of Cancer, 1975–2007, Featuring Tumors of the Brain and Other Nervous System

PubMed Central

Ward, Elizabeth; McCarthy, Bridget J.; Schymura, Maria J.; Eheman, Christie; Jemal, Ahmedin; Anderson, Robert N.; Ajani, Umed A.; Edwards, Brenda K.

2011-01-01

Background The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information on cancer occurrence and trends in the United States. This year’s report highlights brain and other nervous system (ONS) tumors, including nonmalignant brain tumors, which became reportable on a national level in 2004. Methods Cancer incidence data were obtained from the National Cancer Institute, CDC, and NAACCR, and information on deaths was obtained from the CDC’s National Center for Health Statistics. The annual percentage changes in age-standardized incidence and death rates (2000 US population standard) for all cancers combined and for the top 15 cancers for men and for women were estimated by joinpoint analysis of long-term (1992–2007 for incidence; 1975–2007 for mortality) trends and short-term fixed interval (1998–2007) trends. Analyses of malignant neuroepithelial brain and ONS tumors were based on data from 1980–2007; data on nonmalignant tumors were available for 2004–2007. All statistical tests were two-sided. Results Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence. The death rates continued to decrease for both sexes. Childhood cancer incidence rates continued to increase, whereas death rates continued to decrease. Lung cancer death rates decreased in women for the first time during 2003–2007, more than a decade after decreasing in men. During 2004–2007, more than 213 500 primary brain and ONS tumors were diagnosed, and 35.8% were malignant. From 1987–2007, the incidence of neuroepithelial malignant brain and ONS tumors decreased by 0.4% per year in men and women combined. Conclusions The decrease in cancer incidence and mortality reflects progress in cancer prevention, early detection, and treatment. However, major challenges remain, including increasing incidence rates and continued low survival for some cancers. Malignant and nonmalignant brain tumors demonstrate differing patterns of occurrence by sex, age, and race, and exhibit considerable biologic diversity. Inclusion of nonmalignant brain tumors in cancer registries provides a fuller assessment of disease burden and medical resource needs associated with these unique tumors. PMID:21454908

Implementing speed reductions at specific interstate work zones from 65 mph to 35 mph : final report.

DOT National Transportation Integrated Search

2013-02-01

Interstate preservation projects are commonly conducted at night and often require working in close proximity to ongoing traffic. Vehicle speed and speed variability in work zones is inextricably connected to the work zone design and the selected tra...

Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies

PubMed Central

2013-01-01

Background The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed. The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. Methods A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Results Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Conclusions Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response. PMID:24074240

Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies.

PubMed

Coghill, David; Banaschewski, Tobias; Zuddas, Alessandro; Pelaz, Antonio; Gagliano, Antonella; Doepfner, Manfred

2013-09-27

The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.

Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Childress, Ann; Berry, Sally A.; Belden, Heidi; Walters, Faith; Chappell, Phillip; Sherman, Nancy; Orazem, John; Palumbo, Donna

2017-01-01

Abstract Objective: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Following a 6-week, open-label, dose-optimization period, children 6–12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20–60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). Results: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], −7.0 [−10.9, −3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. Conclusions: MPH ERCT 20–60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250. PMID:28557548

Osmotic Release Oral System Methylphenidate Versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Chinese Youth: 8-Week Comparative Efficacy and 1-Year Follow-Up.

PubMed

Su, Yi; Yang, Li; Stein, Mark A; Cao, Qingjiu; Wang, Yufeng

2016-05-01

The purpose of this study was to compare the short-term efficacy, tolerability, and 1-year adherence in Chinese children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with either osmotic release oral system methylphenidate (OROS MPH) or atomoxetine (ATX). Children and adolescents meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for ADHD were randomly assigned to receive either OROS MPH (n = 119) or ATX (n = 118). Participants underwent a 1-4 week dose titration period to determine optimal dose, and then were maintained on that dose for 4 weeks (maintenance period). Assessment for efficacy was conducted every week over the titration period and at the end of the maintenance period. The primary efficacy measure was the investigator-rated total ADHD Rating Scale-IV (ADHD-RS-IV) score. Response was further classified as remission (ADHD-RS-IV [18 or 9 items] average score ≤1), robust improvement (ADHD-RS-IV ≥40% decrease in total score), or improvement (≥ 25% decrease in total score) at the end of maintenance period. Medication adherence (taking medication at least 5 days in 1 week) and reasons for nonadherence were evaluated every week over the titration period, at the end of maintenance period, and then at 3, 6, and 12 months. At the end of maintenance period, both OROS MPH and ATX were associated with significant and similar reductions from baseline in ADHD symptoms. Percentages achieving remission, robust improvement, and improvement were comparable for OROS MPH and ATX treatment (35.3% vs. 37.1%, 45.4% vs. 44.8%, 65.5% vs. 66.4%). Medication use decreased over time for both treatments; however, at end of maintenance period, 3 month, 6 month, and 1 year follow-ups, subjects in the OROS MPH group were more likely to be compliant with treatment (74.8%, 50.4%, 38.7%, and 21.8% for OROS MPH vs. 52.5%, 33.9%, 12.7%, and 3.4% for ATX) ( p < 0.05). The most common reasons for nonadherence were adverse events and lack of efficacy. Both OROS MPH and ATX resulted in similar reductions in ADHD symptoms in Chinese children and adolescents with ADHD. Long-term adherence with medication was poor in general, although somewhat better with OROS MPH than with ATX. ClinicalTrials.gov , Identifier: NCT01065259.

Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea

PubMed Central

Duszenko, Nikolas

2017-01-01

ABSTRACT Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli. We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri. The concentration of MPh suggests the cell membrane of M. acetivorans, but not of M. barkeri, is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans. Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh. IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and supramolecular complexes to optimize electron and carbon flow to control biomass synthesis and the production of methane. Worldwide, methanogens are used to generate renewable methane for heat, electricity, and transportation. Our observations suggest Methanosarcina acetivorans, but not Methanosarcina barkeri, has electrically quantized membranes. Escherichia coli, a model facultative anaerobe, has optimal electron transport at the stationary phase but not during exponential growth. This study also suggests the metabolic efficiency of bacteria and archaea can be improved using exogenously supplied lipophilic electron carriers. The enhancement of methanogen electron transport through methanophenazine has the potential to increase renewable methane production at an industrial scale. PMID:28710268

Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea.

PubMed

Duszenko, Nikolas; Buan, Nicole R

2017-09-15

Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri The concentration of MPh suggests the cell membrane of M. acetivorans , but not of M. barkeri , is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh. IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and supramolecular complexes to optimize electron and carbon flow to control biomass synthesis and the production of methane. Worldwide, methanogens are used to generate renewable methane for heat, electricity, and transportation. Our observations suggest Methanosarcina acetivorans , but not Methanosarcina barkeri , has electrically quantized membranes. Escherichia coli , a model facultative anaerobe, has optimal electron transport at the stationary phase but not during exponential growth. This study also suggests the metabolic efficiency of bacteria and archaea can be improved using exogenously supplied lipophilic electron carriers. The enhancement of methanogen electron transport through methanophenazine has the potential to increase renewable methane production at an industrial scale. Copyright © 2017 American Society for Microbiology.

Effects of MPH-OROS on the organizational, time management, and planning behaviors of children with ADHD.

PubMed

Abikoff, Howard; Nissley-Tsiopinis, Jenelle; Gallagher, Richard; Zambenedetti, Maurizio; Seyffert, Michael; Boorady, Roy; McCarthy, John

2009-02-01

To evaluate the effects of stimulant medication on organizational, time management, and planning (OTMP) in children with attention-deficit/hyperactivity disorder (ADHD) and ascertain whether OTMP is normalized with medication. Participants included 19 stimulant-naïve children with ADHD (aged 8-13 years) and impaired OTMP functioning, defined as greater than 1 SD below norms on the Children's Organizational Skills Scale. A double-blind, placebo-controlled, crossover design, with 4 weeks of each condition, evaluated medication (methylphenidate-osmotic-release oral system [MPH-OROS]) effects on OTMP, based on the parent and teacher versions of the Children's Organizational Skills Scale. The parent and teacher Swanson, Nolan, and Pelham, Version IV, rating scales assessed ADHD symptoms. "Not impaired" in OTMP was defined as no longer meeting study entry criteria, and "not impaired" in ADHD symptoms was defined as having mean Swanson, Nolan, and Pelham, Version IV, scores of < or = 1.0. MPH-OROS significantly improved children's OTMP behaviors. These improvements were correlated with significant reductions in ADHD symptoms. However, most of the children (61%) continued to show significant OTMP impairments on MPH-OROS. The MPH-OROS reduced children's OTMP deficits, and these improvements were associated with improvements in ADHD symptoms. Some children remained impaired in OTMP even after effective stimulant treatment of ADHD symptoms. These youngsters may require other treatments that target OTMP deficits.

A pilot study: differential effects of methylphenidate-OROS on working memory and attention functions in children with attention-deficit/hyperactivity disorder with and without behavioural comorbidities.

PubMed

Rubio, Belén; Hernández, Sergio; Verche, Emilio; Martín, Raquel; González-Pérez, Pedro

2011-03-01

To examine the effects of methylphenidate-OROS (MPH-OROS) on working memory (WM) and attention functions in children with attention-deficit hyperactivity disorder (ADHD), and to investigate whether there is a differential effect in ADHD children with (ADHD+) and without (ADHD-) behavioural comorbidities. Participants included a clinic referred sample of 12 stimulant naïve school-aged children with a diagnosis of combined ADHD according to the DSM-IV criteria (6 ADHD+, 6 ADHD-), and 11 healthy children. A neuropsychological protocol was applied at three different moments: before treatment, after one those of MPH-OROS, and after one month of MPH-OROS daily treatment. The protocol was simultaneously administered to the control group. Initial differences in attention parameters between naïve children with ADHD and the control group disappeared after the first dose of MPH-OROS. For WM, one month of daily treatment was necessary to achieve this pattern of results. Both ADHD groups (ADHD+ and ADHD-) showed these differences, but there was a greater improvement in (ADHD-). MPH-OROS had an immediate effect on attention deficits, but long-term treatment was needed to improve WM to the level of healthy subjects. The presence of comorbid behavioural conditions determined a less robust response in neuropsychological performance to stimulant treatment.

Effects of concomitant methylphenidate and ethanol administration on working and reference memory in rats.

PubMed

Sloan, Anthony R; McGovern, Robin; Buffalari, Deanne M

Recent studies have suggested that college students are heavily engaged in non-medical use of stimulant drugs prescribed to treat attention deficit hyperactivity disorder. This age group is also at high risk for alcohol use. Despite their potential co-abuse, little work has examined how these drugs interact to affect cognitive abilities. In fact, these drugs have opposing effects on working memory, which brings into question how they may interact to affect this particular behavior. The purpose of this research was to examine the concomitant effects of methylphenidate (MPH) and ethanol (EtOH) on working and reference memory. Rats were first trained on the radial arm maze task to establish a baseline performance rate measured as average number of reference and working memory errors. Performance was then assessed after injections of saline, MPH alone, EtOH alone, and MPH+EtOH combined. While both doses of MPH caused nonsignificant improvements in working memory, when combined with EtOH, there was an overall impairment in working and reference memory compared to other conditions. EtOH alone also decreased memory. These data indicate increased impairment of memory function with combined MPH and EtOH use. By understanding how the combination of methylphenidate and alcohol affects memory, we can better assess the risks of taking both substances simultaneously. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Interaction Between DRD4 Methylation and Prenatal Maternal Stress on Methylphenidate-Induced Changes in Continuous Performance Test Performance in Youth with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kim, Johanna Inhyang; Kim, Jae-Won; Shin, Inkyung; Kim, Bung-Nyun

2018-06-15

Environmental factors may interact with genetic factors via the epigenetic process, and this interaction can contribute to inter-individual variability in the treatment response. The purpose of this study was to investigate the interaction effects between dopamine receptor D4 (DRD4) methylation and prenatal maternal stress on the methylphenidate (MPH) response of youth with attention-deficit/hyperactivity disorder (ADHD). This study was an 8-week open-label trial of MPH that included 74 ADHD youth. We investigated the associations between MPH treatment response, which was defined as a score ≤2 on the Clinical Global Impressions-Improvement (CGI-I) scale, and the methylation of 28 cytosine-guanine dinucleotide (CpG) sites of DRD4. Additionally, the interaction effects between DRD4 methylation and prenatal maternal stress on changes in Continuous Performance Test (CPT) scores after MPH treatment were investigated. Although there were no significant sites that showed significant association with treatment response, there was a significant interaction effect of the methylation of CpG7 and prenatal maternal stress on changes in omission errors of the CPT following treatment (p = 0.0001). The present findings indicate that the interaction between methylation of CpG7 of DRD4 and prenatal maternal stress may be predictive of the treatment response to MPH in youth with ADHD.

Effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial.

PubMed

Delbari, Ahmad; Salman-Roghani, Reza; Lokk, Johan

2011-01-01

Stimulant medications can enhance mood and cognition in stroke rehabilitation, but human clinical trial results are inconclusive. We sought to prospectively study the effects of levodopa (LD) and/or methylphenidate (MPH) in combination with physiotherapy on mood and cognition following stroke in human subjects. Ischemic stroke patients were enrolled in our study 15 to 180 days after stroke onset. The patients were randomized into four medication groups (MPH, LD, MPH + LD, or placebo) and received a 15-day course of medication therapy (1 dose daily) and 45-min standard physiotherapy treatment daily. Mood and cognitive function were assessed at the study onset and 15, 90 and 180 days after study enrollment. The strongest improvement of mood and cognition was found between baseline and the first follow-up immediately after the intervention. A significant improvement in mood was also found in the combined treatment group (MPH + LD) at 90 and 180 days, compared to the placebo group. A 15-day course of daily MPH + LD combined with physiotherapy over a 3-week period was safe and significantly improved mood status in ischemic stroke patients. Future studies are needed which determine the optimal therapeutic window for and dosage of psychostimulants as well as identify those stroke patients who might benefit the most from treatment. Copyright © 2011 S. Karger AG, Basel.

Family Medicine or Primary Care Residency Selection: Effects of Family Medicine Interest Groups, MD/MPH Dual Degrees, and Rural Medical Education.

PubMed

Wei McIntosh, Elizabeth; Morley, Christopher P

2016-05-01

If medical schools are to produce primary care physicians (family medicine, pediatrics, or general internal medicine), they must provide educational experiences that enable medical students to maintain existing or form new interests in such careers. This study examined three mechanisms for doing so, at one medical school: participation as an officer in a family medicine interest group (FMIG), completion of a dual medical/public health (MD/MPH) degree program, and participation in a rural medical education (RMED) clinical track. Specialty Match data for students who graduated from the study institution between 2006 and 2015 were included as dependent variables in bivariate analysis (c2) and logistic regression models, examining FMIG, MD/MPH, and RMED participation as independent predictors of specialty choice (family medicine yes/no, or any primary care (PC) yes/no), controlling for student demographic data. In bivariate c2 analyses, FMIG officership did not significantly predict matching with family medicine or any PC; RMED and MD/MPH education were significant predictors of both family medicine and PC. Binary logistic regression analyses replicated the bivariate findings, controlling for student demographics. Dual MD/MPH and rural medical education had stronger effects in producing primary care physicians than participation in a FMIG as an officer, at one institution. Further study at multiple institutions is warranted.

Time-resolved fluorescence spectroscopy of human brain tumors

NASA Astrophysics Data System (ADS)

Marcu, Laura; Thompson, Reid C.; Garde, Smita; Sedrak, Mark; Black, Keith L.; Yong, William H.

2002-05-01

Fluorescence spectroscopy of the endogenous emission of brain tumors has been researched as a potentially important method for the intraoperative localization of brain tumor margins. In this study, we investigate the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) for demarcation of primary brain tumors by studying the time-resolved spectra of gliomas of different histologic grades. Time-resolved fluorescence (3 ns, 337 nm excitation) from excised human brain tumor show differences between the time-resolved emission of malignant glioma and normal brain tissue (gray and white matter). Our findings suggest that brain tumors can be differentiated from normal brain tissue based upon unique time-resolved fluorescence signature.

The effectiveness of the 55 MPH national maximum speed limit as a life saving benefit

DOT National Transportation Integrated Search

1980-10-01

The report contains an analysis of the life saving benefits resulting from the 55 mph NMSL from 1974-1979. Monthly fatality data from 1970-1979 was used in a time series model to arrive at the estimated safety benefits (lives saved). The time series ...

40 CFR 610.64 - Track test procedures.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 31 2012-07-01 2012-07-01 false Track test procedures. 610.64 Section 610.64 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL... necessary to limit testing to times when the wind velocity is less than 5 mph, with gusts less than 10 mph...

40 CFR 610.64 - Track test procedures.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 31 2013-07-01 2013-07-01 false Track test procedures. 610.64 Section 610.64 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL... necessary to limit testing to times when the wind velocity is less than 5 mph, with gusts less than 10 mph...

Spray spectrum modifications through changes in airspeed to minimize drift

USDA-ARS?s Scientific Manuscript database

Management of droplet size is one of the key components to minimizing spray drift, which can be accomplished in-flight by changing airspeed. Studies were conducted measuring spray droplet spectra parameters across airspeeds ranging from 100-140 mph (in 5 mph increments). In general the volume medi...

Implementing speed reductions at specific interstate work zones from 65 mph to 35 mph : appendices to final report.

DOT National Transportation Integrated Search

2013-02-01

Interstate preservation projects are commonly conducted at night and often require working in close proximity to ongoing traffic. Vehicle speed and speed variability in work zones is inextricably connected to the work zone design and the selected tra...

Mechanism and Therapy for the Shared Susceptibility to Migraine and Epilepsy after Traumatic Brain Injury

DTIC Science & Technology

2012-10-01

malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J. Cereb. Blood Flow Metab. 31, 17–35. Leventhal, C., Rafii , S... Rafii , D., Shahar, A., Goldman, S.A., 1999. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma

mTHPC-mediated photodynamic detection for fluorescence-guided resection of brain tumors

NASA Astrophysics Data System (ADS)

Kostron, Herwig; Zimmermann, Andreas; Obwegeser, Alois

1998-06-01

A most radical resection is of great importance in the treatment of brain tumors, however they can hardly be differentiated from normal brain parenchyma by the naked eye of the neurosurgeon. Photosensitizers are highly selective taken up into malignant tissues, therefore the fluorescence properties of photosensitizers could be utilized for optical differentiation of normal and malignant tissue. Ten patients presenting with brain malignancies were sensitized for photodynamic diagnosis (PDD) and photodynamic treatment (PDT) with 0.15 mg/kg b.w. m-THPC. On day 4 intraoperative PDD and fluorescence guided tumor resection (FGR) was performed, followed by intraoperative PDT. The fluorescence was induced by a xenon lamp at an excitation wavelength ranging from 370 to 440 nm. A sensitive CCD camera was employed for imaging, equipped with a long pass filter to shut off the excitation wavelength and to improve the signal to noise ratio. The pictures are converted digitally by a standard frame grabber and processed in real time and calculated for the tissue auto fluorescence in the emission band of m-THPC at 652 nm. Out of 10 0bservations, two were false negative and 2 were false positive. Our preliminary results indicate that fluorescence guided surgery is feasible and proved to be of significant help in delineating tumor margins and in resection of residual tumor that could not be detected by the surgeon, however the sensitivity and specificity needs to be further improved.

Yoga Therapy in Treating Patients With Malignant Brain Tumors

ClinicalTrials.gov

2017-07-27

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

New study tests the safety and efficacy of combination therapy in adults with astrocytoma and glioblastoma | Center for Cancer Research

Cancer.gov

A two-part clinical trial of a multikinase inhibitor plus chemotherapy in patients with two types of brain tumors is enrolling in Bethesda, MD. The study will be open to patients with anaplastic astrocytoma, an uncommon malignant brain tumor that develops from star-shaped brain cells called astrocytes and glioblastoma, the most common and aggressive form of astrocytoma. Learn

EG-03EXPRESSION OF PRMT5 CORRELATES WITH MALIGNANT GRADE IN GLIOMAS AND PLAYS A PIVOTAL ROLE IN TUMOR GROWTH

PubMed Central

Han, Xiaosi; Li, Rong; Zhang, Wenbin; Yang, Xiuhua; Fathallah-Shaykh, Hassan; Gillespie, Yancey; Nabors, Burt

2014-01-01

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. The modification play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

Brain cancer and pesticide relationship in orchard farmers of Kashmir

PubMed Central

Bhat, Abdul Rashid; Wani, Muhammed Afzal; Kirmani, A. R.

2010-01-01

Background: The increasing trend in the incidence of primary malignant brain tumors in orchard farmers and their families in Kashmir. Aim: To determine the relationship between the patients of primary malignant brain tumors and their occupation. Materials and Methods: Retrospectively, case files along with death certificates of 432 patients of primary malignant brain tumors and 457 controls (non-tumor neurologic diseases), admitted for treatment simultaneously over a period of 4 years from January 2005 to December 2008, to the Neurosurgery, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Kashmir, were studied. Follow-up and family interaction was established. Results: Analysis revealed that 90.04% (389 out of 432) patients were orchard farm workers, orchard residents and orchard playing children exposed to the high levels of multiple types of neurotoxic and carcinogenic (chlorpyriphos, dimethoate, mancozeb and captan) chemicals for more than 10 years [relative risk (RR) = 10.6; odds ratio (OR) = >10; 95% confidence interval (CI) = >25-40]. The 9.96% (43 out of 432) patients were not exposed to pesticides. On the other hand, only 19 patients out of 457 controls had recorded history of pesticide exposure and 438 were unrelated to pesticides. Out of 389 patients, 71.7% (279 out of 389) were males and 28.3% (110 out of 389), including six members of three families, were females (one male child). Conclusion: All orchard-related 389 patients had high-grade tumors as compared to the non-pesticide tumors. Mortality in pesticide-exposed tumors was 12%. The higher or upper-normal levels of serum cholinesterase (AChE) were observed in 54.7% (213 out of 389) patients and decreased levels were found in only 45.3% (176 out of 389) orchard-related patients (RR = 19.4; OR = >5; 95% CI = >1-10). Although serum AChE levels were a routine investigation in malignant brain tumors, this was not a routine in other neurological conditions (hospitalized controls). The familial gliomas have shown an emerging trend in the orchard residents of valley of Kashmir. PMID:21461159

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes

PubMed Central

Wei, Li; Su, Yu-Kai; Lin, Chien-Min; Chao, Tsu-Yi; Huang, Shang-Pen; Huynh, Thanh-Tuan; Jan, Hsun-Jin; Whang-Peng, Jacqueline; Chiou, Jeng-Fong; Wu, Alexander T.H.; Hsiao, Michael

2016-01-01

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM. PMID:27564106

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes.

PubMed

Wei, Li; Su, Yu-Kai; Lin, Chien-Min; Chao, Tsu-Yi; Huang, Shang-Pen; Huynh, Thanh-Tuan; Jan, Hsun-Jin; Whang-Peng, Jacqueline; Chiou, Jeng-Fong; Wu, Alexander T H; Hsiao, Michael

2016-10-25

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.

Virulence of Macrophomina phaseolina isolates in common bean (Phaseolus vulgaris) genotypes

USDA-ARS?s Scientific Manuscript database

Charcoal rot caused by Macrophomina phaseolina (Tassi) Goid, is an important disease in common beans (Phaseolus vulgaris) in the dry and warmer areas of Puerto Rico and in much of the tropics and subtropics worldwide. The virulence of three isolates from Isabela (Mph-ISA-TARS), Juana Diaz (Mph-JD) a...

The effectiveness of the 55 MPH national maximum speed limit as a life saving benefit : executive summary

DOT National Transportation Integrated Search

1981-01-01

The following report contains an analysis of the life saving benefits resulting from the 55 mph NMSL from 1974-1979. Monthly fatality data from 1970-1979 was used in a time series model to arrive at the estimated safety benefits (lives saved). The ti...

Animal Model of Methylphenidate's Longterm Memory-Enhancing Effects

ERIC Educational Resources Information Center

Carmack, Stephanie A.; Howell, Kristin K.; Rasaei, Kleou; Reas, Emilie T.; Anagnostaras, Stephan G.

2014-01-01

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a…

Effects of Methylphenidate on Working Memory Components: Influence of Measurement

ERIC Educational Resources Information Center

Bedard, Anne-Claude; Jain, Umesh; Hogg-Johnson, Sheilah; Tannock, Rosemary

2007-01-01

Background: To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in attention-deficit hyperactivity disorder (ADHD) and determine the responsiveness of WM measures to MPH. Methods: Participants were a clinical sample of 50 children and adolescents with ADHD, aged 6 to 16 years old, who participated in an acute…

Epidemiology of primary brain tumors in the Middle Eastern population in California, USA 2001-2005.

PubMed

Nasseri, Kiumarss; Mills, John R

2009-01-01

The fast growing Middle Eastern (ME) population has rarely been studied in the U.S.. The purpose of this study was to compare the epidemiology of primary brain tumors in this ethnic population with the non-Hispanic, non-Middle Eastern White (NHNMW) in California. ME cases were identified by surname in the California cancer registry and ME population estimates were based on ancestry. Data for 683 cases of primary brain tumors (429 benign, 238 malignant, 16 uncertain) in the ME and 15,589 cases (8352 benign, 6812 malignant, 425 uncertain) in the NHNMW were available for this study. ME patients were significantly (p < 0.05) younger and their age-adjusted incidence rates per 100,000 for benign tumors of 10.0 in men and 17.6 in women were higher than similar rates of 7.3 and 10.6 in the NHNMW group (p < 0.05). Rates for malignant tumors were similar. Meningioma was the main histology responsible for the observed increase in patients over 40 years of age. Also increased were benign tumors of the pituitary and pineal glands. The overall mortality in patients with benign tumors was significantly lower than malignant tumors. This study presents a significantly high incidence of benign meningioma in the ME population in California. This may be due to higher susceptibility or exposure of this ethnic group to the risk factor(s) for this neoplasm. Considering the reported causal association of benign meningioma with childhood radiation exposure from Israel, exposure to this risk factor in this ethnic group needs to be evaluated in future studies.

Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

PubMed

Shelton, Laura M; Huysentruyt, Leanne C; Mukherjee, Purna; Seyfried, Thomas N

2010-07-23

GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion. CR targets glycolysis and rapid tumour cell growth in part by lowering circulating glucose levels. The VM-M3 tumour cells were implanted intracerebrally in the syngeneic VM mouse host. Approx. 12-15 days post-implantation, brains were removed and both ipsilateral and contralateral hemispheres were imaged to measure bioluminescence of invading tumour cells. CR significantly reduced the invasion of tumour cells from the implanted ipsilateral hemisphere into the contralateral hemisphere. The total percentage of Ki-67-stained cells within the primary tumour and the total number of blood vessels was also significantly lower in the CR-treated mice than in the mice fed ad libitum, suggesting that CR is anti-proliferative and anti-angiogenic. Our findings indicate that the VM-M3 GBM model is a valuable tool for studying brain tumour cell invasion and for evaluating potential therapeutic approaches for managing invasive brain cancer. In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

Magnetic resonance imaging spectroscopy in pediatric atypical teratoid rhabdoid tumors of the brain.

PubMed

Bruggers, Carol S; Moore, Kevin

2014-08-01

Pediatric central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRT) are highly malignant tumors characterized by SMARCB1 gene abnormalities. Despite chemoradiation responsiveness, most children die of disease. No imaging findings distinguish ATRT from other malignant brain tumors. This study sought to describe magnetic resonance spectroscopy (MRS) of childhood CNS ATRT and identify metabolite patterns for diagnosis and disease status monitoring. Data from 7 children diagnosed with CNS ATRT from 2007 to 2010, whose imaging included MRS, were retrospectively reviewed. Age at diagnosis ranged from 2.5 to 54 months. Tumors were large with calcium and cysts and avid gadolinium enhancement. All were isointense on T1-weighted imaging and mildly hyperintense on T2-weighted imaging. Short-TE MRS showed prominent lactate+lipid and choline, minimal N-acetyl acetate (NAA), and rarely minimal myoinositol and low creatine peaks. Long TE showed prominent choline, minimal NAA, and rarely low lactate peaks. The combination of prominent choline and lactate+lipids peaks, and generally absent NAA and myoinositol peaks by MRS in this panel of ATRT expands existing information and provides a potentially distinct metabolite profile from other malignant pediatric brain tumors, including medulloblastoma. Prospective, comparative quantitative MRS of ATRT with other pediatric CNS tumors is warranted.

Combating malignant astrocytes: Strategies mitigating tumor invasion.

PubMed

Umans, Robyn A; Sontheimer, Harald

2018-01-01

Malignant gliomas are glial-derived, primary brain tumors that carry poor prognosis. Existing therapeutics are largely ineffective and dramatically affect quality of life. The standard of care details a taxing combination of surgical resection, radiation of the resection cavity, and temozolomide (TMZ) chemotherapy, with treatment extending life by only an average of months (Maher et al., 2001; Stupp et al., 2005). Despite scientific and technological advancement, surgery remains the most important treatment modality. Therapeutic obstacles include xenobiotic protection conveyed by the blood-brain barrier (Zhang et al., 2015), invasiveness and therapeutic resistance of tumor cell populations (Bao et al., 2006), and distinctive attributes of secondary glioma occurrence (Ohgaki and Kleihues, 2013). While these brain malignancies can be classified by grade or grouped by molecular subclass, each tumor presents itself as its own complication. Based on all of these obstacles, new therapeutic approaches are urgently needed. These will likely emerge from numerous exciting studies of glioma biology that are ongoing and reviewed here. These show unexpected roles for ion channels, amino-acid transporters, and connexin gap junctions in supporting the invasive growth of gliomas. These studies have identified a number of proteins that may be targeted for therapy in the future. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Cognitive remediation of attention deficits following acquired brain injury: A systematic review and meta-analysis.

PubMed

Virk, Sohaib; Williams, Tracey; Brunsdon, Ruth; Suh, Flora; Morrow, Angie

2015-01-01

Attention deficits are common after acquired brain injury (ABI) and adversely impact academic, vocational and social outcomes. The role of cognitive interventions in post-ABI attention rehabilitation remains unclear. To evaluate effectiveness of cognitive interventions in treating attention deficits following ABI and to explore differences in treatment effect between ABI etiologies. MEDLINE, EMBASE, PsycINFO and CENTRAL databases were searched for randomized controlled trials (RCTs). Studies were selected by three reviewers. Study quality was assessed using Cochrane Collaboration tool for RCTs. Effect sizes (Hedge's g) for each attentional domain were meta-analyzed with subgroup analysis by ABI etiology. Twelve RCTs with 584 participants were included, representing individuals with stroke, traumatic brain injury (TBI) and CNS-impacting malignancy. Cognitive rehabilitation improved divided attention in stroke survivors (g 0.67; 95% confidence interval, 0.35-0.98; p <  0.0001) but not other ABI populations. Sustained, selective and alternating attention, and inhibition were not significantly improved in any ABI population. Follow-up data showed no evidence of long-term benefit. Cognitive rehabilitation resulted in short-term improvements in divided attention following stroke, but not after TBI or CNS-impacting malignancy. Cognitive interventions did not significantly improve other attentional domains in participants with stroke, TBI or CNS-impacting malignancy.

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

PubMed Central

Mastorakos, Panagiotis; Zhang, Clark; Song, Eric; Kim, Young Eun; Park, Hee Won; Berry, Sneha; Choi, Won Kyu; Hanes, Justin; Suk, Jung Soo

2018-01-01

The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain. PMID:28694032

Effects of Extended Release Methylphenidate Treatment on Ratings of Attention-Deficit/Hyperactivity Disorder (ADHD) and Associated Behavior in Children with Autism Spectrum Disorders and ADHD Symptoms

PubMed Central

Santos, Cynthia W.; Aman, Michael G.; Arnold, L. Eugene; Casat, Charles D.; Mansour, Rosleen; Lane, David M.; Loveland, Katherine A.; Bukstein, Oscar G.; Jerger, Susan W.; Factor, Perry; Vanwoerden, Salome; Perez, Evelyn; Cleveland, Lynne A.

2013-01-01

Abstract Objective The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon. Method The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design. Results MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied. Conclusions The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms. PMID:23782128

The effect of methylphenidate and rearing environment on behavioral inhibition in adult male rats.

PubMed

Hill, Jade C; Covarrubias, Pablo; Terry, Joel; Sanabria, Federico

2012-01-01

The ability to withhold reinforced responses-behavioral inhibition-is impaired in various psychiatric conditions including Attention Deficit Hyperactivity Disorder (ADHD). Methodological and analytical limitations have constrained our understanding of the effects of pharmacological and environmental factors on behavioral inhibition. To determine the effects of acute methylphenidate (MPH) administration and rearing conditions (isolated vs. pair-housed) on behavioral inhibition in adult rats. Inhibitory capacity was evaluated using two response-withholding tasks, differential reinforcement of low rates (DRL) and fixed minimum interval (FMI) schedules of reinforcement. Both tasks made sugar pellets contingent on intervals longer than 6 s between consecutive responses. Inferences on inhibitory and timing capacities were drawn from the distribution of withholding times (interresponse times, or IRTs). MPH increased the number of intervals produced in both tasks. Estimates of behavioral inhibition increased with MPH dose in FMI and with social isolation in DRL. Nonetheless, burst responding in DRL and the divergence of DRL data relative to past studies, among other limitations, undermined the reliability of DRL data as the basis for inferences on behavioral inhibition. Inhibitory capacity was more precisely estimated from FMI than from DRL performance. Based on FMI data, MPH, but not a socially enriched environment, appears to improve inhibitory capacity. The highest dose of MPH tested, 8 mg/kg, did not reduce inhibitory capacity but reduced the responsiveness to waiting contingencies. These results support the use of the FMI schedule, complemented with appropriate analytic techniques, for the assessment of behavioral inhibition in animal models.

Neurotrophin 3 genotype and emotional adverse effects of osmotic-release oral system methylphenidate (OROS-MPH) in children with attention-deficit/hyperactivity disorder.

PubMed

Park, Subin; Kim, Bung-Nyun; Kim, Jae-Won; Shin, Min-Sup; Cho, Soo-Churl; Kim, Ji-Hoon; Son, Jung-Woo; Shin, Yun-Mi; Chung, Un-Sun; Han, Doug-Hyun

2014-03-01

Neurotrophin 3 (NTF3) has been studied in relation to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and mood disorders as well as psychostimulant action. We hypothesized that the risk of an emotional side effect to methylphenidate (MPH) treatment may be associated with NTF3 genotypes. Ninety-six medication-naïve children with ADHD (mean age 8.70, standard deviation 1.41 years, 79 males) were genotyped and treated with MPH. At baseline, which was prior to MPH treatment, and after two weeks of medication, investigators asked children and their parents or caregivers about adverse events using a symptom rating scale. ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Emotionality' and 'Over-focus/euphoria' factor scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.042 and p=0.045, respectively). ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Proneness to crying' and 'Nail biting' item scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.047 and p=0.017, respectively). These data provide preliminary evidence that genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to MPH treatment in Korean children with ADHD.

Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms.

PubMed

Pearson, Deborah A; Santos, Cynthia W; Aman, Michael G; Arnold, L Eugene; Casat, Charles D; Mansour, Rosleen; Lane, David M; Loveland, Katherine A; Bukstein, Oscar G; Jerger, Susan W; Factor, Perry; Vanwoerden, Salome; Perez, Evelyn; Cleveland, Lynne A

2013-06-01

The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon. The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design. MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied. The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms.

Methylphenidate and emotional-motivational processing in attention-deficit/hyperactivity disorder.

PubMed

Conzelmann, Annette; Woidich, Eva; Mucha, Ronald F; Weyers, Peter; Müller, Mathias; Lesch, Klaus-Peter; Jacob, Christian P; Pauli, Paul

2016-08-01

In line with the assumption that emotional-motivational deficits are one core dysfunction in ADHD, in one of our previous studies we observed a reduced reactivity towards pleasant pictures in adult ADHD patients as compared to controls. This was indicated by a lack of attenuation of the startle reflex specifically during pleasant pictures in ADHD patients. The first choice medical agents in ADHD, methylphenidate (MPH), is discussed to normalize these dysfunctions. However, experimental evidence in the sense of double-blind placebo-controlled study designs is lacking. Therefore, we investigated 61 adult ADHD patients twice, one time with placebo and one time with MPH with the same experimental design as in our study previously and assessed emotion processing during the presentation of pleasant, neutral and unpleasant pictures. We obtained startle reflex data as well as valence and arousal ratings in association with the pictures. As previously shown, ADHD patients showed a diminished startle attenuation during pleasant pictures while startle potentiation during unpleasant pictures was normal. Valence and arousal ratings unsuspiciously increased with increasing pleasantness and arousal of the pictures, respectively. There were no significant influences of MPH. The study replicates that ADHD patients show a reduced reactivity towards pleasant stimuli. MPH did not normalize this dysfunction. Possibly, MPH only influences emotions during more complex behavioural tasks that involve executive functions in adults with ADHD. Our results emphasize the importance for the use of double-blind placebo-controlled designs in psychopharmacological research.

On the MAC/network/energy performance evaluation of Wireless Sensor Networks: Contrasting MPH, AODV, DSR and ZTR routing protocols.

PubMed

Del-Valle-Soto, Carolina; Mex-Perera, Carlos; Orozco-Lugo, Aldo; Lara, Mauricio; Galván-Tejada, Giselle M; Olmedo, Oscar

2014-12-02

Wireless Sensor Networks deliver valuable information for long periods, then it is desirable to have optimum performance, reduced delays, low overhead, and reliable delivery of information. In this work, proposed metrics that influence energy consumption are used for a performance comparison among our proposed routing protocol, called Multi-Parent Hierarchical (MPH), the well-known protocols for sensor networks, Ad hoc On-Demand Distance Vector (AODV), Dynamic Source Routing (DSR), and Zigbee Tree Routing (ZTR), all of them working with the IEEE 802.15.4 MAC layer. Results show how some communication metrics affect performance, throughput, reliability and energy consumption. It can be concluded that MPH is an efficient protocol since it reaches the best performance against the other three protocols under evaluation, such as 19.3% reduction of packet retransmissions, 26.9% decrease of overhead, and 41.2% improvement on the capacity of the protocol for recovering the topology from failures with respect to AODV protocol. We implemented and tested MPH in a real network of 99 nodes during ten days and analyzed parameters as number of hops, connectivity and delay, in order to validate our Sensors 2014, 14 22812 simulator and obtain reliable results. Moreover, an energy model of CC2530 chip is proposed and used for simulations of the four aforementioned protocols, showing that MPH has 15.9% reduction of energy consumption with respect to AODV, 13.7% versus DSR, and 5% against ZTR.

A novel HPLC fluorescence method for the quantification of methylphenidate in human plasma

PubMed Central

Zhu, Hao-Jie; Wang, Jun-Sheng; Patrick, Kennerly S.; Donovan, Jennifer L.; DeVane, C. Lindsay; Markowitz, John S.

2007-01-01

A number of analytical methods have been established to quantify methylphenidate (MPH). However, to date no HPLC methods are applicable to human pharmacokinetic studies without the use of mass spectrometry (MS) detection. We developed a sensitive and reliable HPLC-fluorescence method for the determination of MPH in human plasma using 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) as the derivatizing agent. An established GC-MS method was adopted in this study as a comparator assay. MPH was derivatized DIB-Cl, and separated isocratically on a C18 column using a HPLC system with fluorescence detection (λex: 330 nm, λem: 460 nm). The lower limit of determination was found to be 1 ng/mL. A linear calibration curve was obtained over the concentrations ranging from 1 to 80 ng/mL (r=0.998). The relative standard deviations of intra-day and inter-day variations were ≤ 9.10 % and ≤ 7.58 %, respectively. The accuracy ranged between 92.59 % and 103.06 %. The method was successfully applied to the pharmacokinetic study of a subject who received a single oral dose (0.3 mg/kg) of immediate-release MPH and yielded consistent results with that of the GC-MS method. This method is the first HPLC assay with non-MS detection providing sufficient reliability and sensitivity for both pre-clinical and clinical studies of MPH. PMID:17804308

Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways | Office of Cancer Genomics

Cancer.gov

Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited.

Methylphenidate, cognition, and epilepsy

PubMed Central

Alipio-Jocson, Valerie; Inoyama, Katherine; Bartlett, Victoria; Sandhu, Saira; Oso, Jemima; Barry, John J.; Loring, David W.; Meador, Kimford

2017-01-01

Objective: To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. Methods: This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. Results: Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20–62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive “fogginess” (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. Conclusions: This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. ClinicalTrials.gov identifier: NCT02178995. Classification of evidence: This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints. PMID:28031390

Methylphenidate, cognition, and epilepsy: A double-blind, placebo-controlled, single-dose study.

PubMed

Adams, Jesse; Alipio-Jocson, Valerie; Inoyama, Katherine; Bartlett, Victoria; Sandhu, Saira; Oso, Jemima; Barry, John J; Loring, David W; Meador, Kimford

2017-01-31

To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20-62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive "fogginess" (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. NCT02178995. This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints. © 2016 American Academy of Neurology.

Social reinforcement as alternative to sucrose reinforcement is increased by nicotine and methylphenidate in male Fischer-344 rats.

PubMed

Martin, Connor D; Bool, Heather M; George, Anthony M; Carr, Katelyn A; Epstein, Leonard H; Hawk, Larry W; Richards, Jerry B

2018-04-24

Stimulant drugs such as nicotine (NIC) and methylphenidate (MPH) are hypothesized to increase the reinforcing value of sensory stimuli, thus increasing the effectiveness of such reinforcers as alternatives to sucrose reinforcers. Inbred Fischer-344 rats (n = 30) were assigned to three groups: saline (SAL; n = 10), nicotine (NIC; n = 10), or methylphenidate (MPH; n = 10). Testing was done in three phases: sucrose only, (SUC), sucrose and drug (SUC/DRUG), and sucrose, drug, and social reinforcement (SUC/DRUG/SOC). During the SUC phase, rats were trained on a progressive ratio 5 (PR5) reinforcement schedule for sucrose (20% solution). In the SUC/DRUG phase, animals were treated with SAL, NIC (0.4 mg/kg, n = 10 SC), or MPH (2.0 mg/kg, n = 10 IP) 30 min prior to testing. In the SUC/DRUG/SOC phase, animals continued receiving drug treatment, and social reinforcement was introduced concurrently with the sucrose reinforcer. The progressive ratio for each reinforcer ran independently of the others. Reinforcing value was measured as break point (BP), the highest number of responses resulting in a reinforcer. SAL-treated animals showed no significant change in sucrose BP. MPH-treated animals showed decreased sucrose BP in the SUC/DRUG phase, with a further reduction in the SUC/DRUG/SOC phase. NIC-treated animals decreased sucrose BP only when a social alternative was offered. Both NIC and MPH reduce the sucrose BP in the presence of a social alternative. The decrease in sucrose responding, coupled with increased social responding, suggests that the social alternative acted as an effective alternative reinforcer to sucrose. From a translational perspective, these results suggest that stimulant drugs such as NIC and MPH may increase the effectiveness of treatments that use alternative social reinforcers to decrease eating.

Impact of attention-deficit/hyperactivity disorder (ADHD) treatment on smoking cessation intervention in ADHD smokers: a randomized, double-blind, placebo-controlled trial.

PubMed

Winhusen, Theresa M; Somoza, Eugene C; Brigham, Gregory S; Liu, David S; Green, Carla A; Covey, Lirio S; Croghan, Ivana T; Adler, Lenard A; Weiss, Roger D; Leimberger, Jeffrey D; Lewis, Daniel F; Dorer, Emily M

2010-12-01

High smoking rates in adults with attention-deficit/hyperactivity disorder (ADHD) and nicotine's amelioration of ADHD suggest that effective ADHD treatment might facilitate abstinence in smokers with ADHD. The present study evaluated if using osmotic-release oral system methylphenidate (OROS-MPH) to treat ADHD enhances response to smoking cessation treatment in smokers with ADHD. A randomized, double-blind, placebo-controlled, 11-week trial with a 1-month follow-up was conducted at 6 clinical sites between December 2005 and January 2008. Adults (aged 18-55 years) meeting DSM-IV criteria for ADHD and interested in quitting smoking were randomly assigned to OROS-MPH titrated to 72 mg/d (n = 127) or placebo (n = 128). All participants received brief weekly individual smoking cessation counseling for 11 weeks and 21 mg/d nicotine patches starting on the smoking quit day (day 27) through study week 11. Outcome measures included prolonged smoking abstinence and DSM-IV ADHD Rating Scale (ADHD-RS) score. Of 255 randomly assigned participants, 204 (80%) completed the trial. Prolonged abstinence rates, 43.3% and 42.2%, for the OROS-MPH and placebo groups, respectively, did not differ significantly (OR = 1.1; 95% CI, 0.63-1.79; P = .81). Relative to placebo, OROS-MPH evidenced a greater reduction in DSM-IV ADHD-RS score (P < .0001) and in cigarettes per day during the post-quit phase (P = .016). Relative to placebo, OROS-MPH increased blood pressure and heart rate to a statistically, but not clinically, significant degree (P < .05); medication discontinuation did not differ significantly between treatments. Treatment for ADHD did not improve smoking cessation success; OROS-MPH, relative to placebo, effectively treated ADHD and was safe and generally well tolerated in this healthy sample of adult ADHD smokers. clinical trials.gov Identifier: NCT00253747. © Copyright 2010 Physicians Postgraduate Press, Inc.

Six months methylphenidate treatment improves emotion dysregulation in adolescents with attention deficit/hyperactivity disorder: a prospective study.

PubMed

Suzer Gamli, Ipek; Tahiroglu, Aysegul Yolga

2018-01-01

Individuals with attention deficit/hyperactivity disorder (ADHD) may suffer from emotional dysregulation (ED), although this symptom is not listed among the diagnostic criteria. Methylphenidate (MPH) is useful in reducing emotional symptoms in ADHD. The aim of the present study was to determine both psychosocial risk factors and presence of ED in adolescents with ADHD before and after MPH treatment. Eighty-two patients aged 12-18 years with ADHD were included as participants. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime, the Difficulties in Emotion Regulation Scale (DERS), sociodemographic form, and the Inventory of Statements About Self-Injury were administered. Results were compared before and after 6 months MPH treatment. A significant improvement was detected on DERS for impulsivity (15.9±6.8 initial vs 14.2±6.5 final test, p <0.01) and total score (88.4±23.3 initial vs 82.4±2.7 final test, p <0.05) across all patients taking MPH regardless of subtype and sex. Despite treatment, a significant difference remained for impulsivity, strategies, and total score in patients with comorbid oppositional defiant disorder (ODD) compared with those without ODD, but no difference was detected for conduct disorder comorbidity. In patients who self-harm, scores for goals, impulsivity, strategies, clarity, and total score were higher before treatment: furthermore, impulsivity and total score remained high after treatment. In maltreated patients, goals, impulsivity, strategies, and total scores were significantly higher before treatment; however, their symptoms were ameliorated after treatment with MPH. Individuals with severe ED may "self-medicate" by smoking and/or self-harming. MPH led to significant improvements in ED possibly owing, in part, to a decrease in impulsivity, so that individuals felt more able to supervise their emotions and engage in goal-directed behaviors. ED should be considered particularly in patients with additional psychosocial factors and ODD comorbidity, and included in the treatment plan.

The effect of NACHRI children's hospital designation on outcome in pediatric malignant brain tumors.

PubMed

Donoho, Daniel A; Wen, Timothy; Liu, Jonathan; Zarabi, Hosniya; Christian, Eisha; Cen, Steven; Zada, Gabriel; McComb, J Gordon; Krieger, Mark D; Mack, William J; Attenello, Frank J

2017-08-01

OBJECTIVE Although current pediatric neurosurgery guidelines encourage the treatment of pediatric malignant brain tumors at specialized centers such as pediatric hospitals, there are limited data in support of this recommendation. Previous studies suggest that children treated by higher-volume surgeons and higher-volume hospitals may have better outcomes, but the effect of treatment at dedicated children's hospitals has not been investigated. METHODS The authors analyzed the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID) from 2000-2009 and included all patients undergoing a craniotomy for malignant pediatric brain tumors based on ICD-9-CM codes. They investigated the effects of patient demographics, tumor location, admission type, and hospital factors on rates of routine discharge and mortality. RESULTS From 2000 through 2009, 83.6% of patients had routine discharges, and the in-hospital mortality rate was 1.3%. In multivariate analysis, compared with children treated at an institution designated as a pediatric hospital by NACHRI (National Association of Children's Hospitals and Related Institutions), children receiving treatment at a pediatric unit within an adult hospital (OR 0.5, p < 0.01) or a general hospital without a designated pediatric unit (OR 0.4, p < 0.01) were less likely to have routine discharges. Treatment at a large hospital (> 400 beds; OR 1.8, p = 0.02) and treatment at a teaching hospital (OR 1.7, p = 0.02) were independently associated with greater likelihood of routine discharge. However, patients transferred between facilities had a significantly decreased likelihood of routine discharge (OR 0.5, p < 0.01) and an increased likelihood of mortality (OR 5.0, p < 0.01). Procedural volume was not associated with rate of routine discharge or mortality. CONCLUSIONS These findings may have implications for planning systems of care for pediatric patients with malignant brain tumors. The authors hope to motivate future research into the specific factors that may lead to improved outcomes at designated pediatric hospitals.

A Randomized Placebo-Controlled Double-Blind Study Evaluating the Time Course of Response to Methylphenidate Hydrochloride Extended-Release Capsules in Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Greenhill, Laurence L.; Nordbrock, Earl; Connor, Daniel F.; Kollins, Scott H.; Adjei, Akwete; Childress, Ann; Stehli, Annamarie; Kupper, Robert J.

2014-01-01

Abstract Objective: The purpose of this study was to assess the time of onset and time course of efficacy over 12.0 hours of extended-release multilayer bead formulation of methylphenidate (MPH-MLR) compared with placebo in children 6–12 years of age with attention-deficit/hyperactivity disorder (ADHD) in a laboratory school setting. Methods: This randomized double-blind placebo-controlled study included children 6–12 years of age with ADHD. Enrolled children went through four study phases: 1) Screening period (≤4 weeks) and a 2 day medication washout period; 2) open-label period with dose initiation of MPH-MLR 15 mg daily and individual dose optimization treatment period (2–4 weeks); 3) double-blind crossover period in which participants were randomized to sequences (1 week each) of placebo and the optimized MPH-MLR dose given daily; and 4) follow-up safety call. Analog classroom time course evaluations were performed at the end of each double-blind week. The primary efficacy end-point was the mean of the on-treatment/postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-Total scores over time points collected 1.0–12.0 hours after dosing. End-points were evaluated using a mixed-effects analysis of covariance. Results: The evaluable population included 20 participants. The least-squares mean postdose SKAMP-Total score was higher for placebo than for MPH-MLR (2.18 vs. 1.32, respectively; p=0.0001), indicating fewer symptoms with MPH-MLR therapy than with placebo. No difference in SKAMP-Total score between participants who received sequence 1 or sequence 2 was noted. From each of hours 1.0–12.0, least-squares mean SKAMP-Total score was significantly lower for those receiving MPH-MLR than for those receiving placebo (p≤0.0261). Neither serious adverse events nor new or unexpected safety findings were noted during the study. Conclusions: MPH-MLR showed a significant decrease in SKAMP scores compared with placebo in children with ADHD 6–12 years of age, indicating a decrease in ADHD symptoms. The estimated onset was observed within 1.0 hour, and duration was measured to 12.0 hours postdose. Trial registration: ClinicalTrials.gov Identifier: NCT01269463 PMID:25470572

The pathobiology of collagens in glioma

PubMed Central

Payne, Leo S.; Huang, Paul H.

2013-01-01

Malignant gliomas are characterised by diffuse infiltration into the surrounding brain parenchyma. Infiltrating glioma cells exist in close proximity with components of the tumour microenvironment, including the extracellular matrix (ECM). While levels of collagens in the normal adult brain are low, in glioma, collagen levels are elevated and play an important role in driving the tumor progression. In this review, we provide a comprehensive overview of the nature of collagens found in gliomas and offer insights into the mechanisms by which cancer cells interact with this ECM via receptors including the integrins, discoidin domain receptors and Endo180. We further describe the major remodelling pathways of brain tumour collagen mediated by the matrix metalloproteinases and highlight the reciprocal relationship between these enzymes and the collagen receptors. Finally, we conclude by offering a perspective on how the biophysical properties of the collagen ECM, in particular, mechanical stiffness and compliance may influence malignant outcome. Understanding the complex interactions between glioma cells and the collagen ECM may provide new avenues to combat the rampant tumor progression and chemoresistance in brain cancer patients. PMID:23861322

Second Malignant Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia

PubMed Central

Schmiegelow, Kjeld; Levinsen, Mette Frandsen; Attarbaschi, Andishe; Baruchel, Andre; Devidas, Meenakshi; Escherich, Gabriele; Gibson, Brenda; Heydrich, Christiane; Horibe, Keizo; Ishida, Yasushi; Liang, Der-Cherng; Locatelli, Franco; Michel, Gérard; Pieters, Rob; Piette, Caroline; Pui, Ching-Hon; Raimondi, Susana; Silverman, Lewis; Stanulla, Martin; Stark, Batia; Winick, Naomi; Valsecchi, Maria Grazia

2013-01-01

Purpose Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. Patients and Methods We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Results Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% ± 2.9%, 31.1% ± 6.2%, and 18.3% ± 3.8%, respectively). Five-year survival estimates for AML were 11.2% ± 2.9% for 125 patients diagnosed before 2000 and 34.1% ± 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% ± 6.4% (n = 36) and 48.2% ± 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% ± 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m2 per week and mercaptopurine of at least 75 mg/m2 per day. Myeloid malignancies with monosomy 7/5q− were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). Conclusion SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts. PMID:23690411

RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

ClinicalTrials.gov

2015-09-28

Acoustic Schwannoma; Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Primary Melanocytic Lesion of Meninges; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma

Mobile phone use and the risk for malignant brain tumors: a case-control study on deceased cases and controls.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2010-08-01

We investigated the use of mobile or cordless phones and the risk for malignant brain tumors in a group of deceased cases. Most previous studies have either left out deceased cases of brain tumors or matched them to living controls and therefore a study matching deceased cases to deceased controls is warranted. Recall error is one issue since it has been claimed that increased risks reported in some studies could be due to cases blaming mobile phones as a cause of the disease. This should be of less importance for deceased cases and if cancer controls are used. In this study brain tumor cases aged 20-80 years diagnosed during 1997-2003 that had died before inclusion in our previous studies on the same topic were included. Two control groups were used: one with controls that had died from another type of cancer than brain tumor and one with controls that had died from other diseases. Exposure was assessed by a questionnaire sent to the next-of-kin for both cases and controls. Replies were obtained for 346 (75%) cases, 343 (74%) cancer controls and 276 (60%) controls with other diseases. Use of mobile phones gave an increased risk, highest in the >10 years' latency group yielding odds ratio (OR) = 2.4, and 95% confidence interval (CI) = 1.4-4.1. The risk increased with cumulative number of lifetime hours for use, and was highest in the >2,000 h group (OR = 3.4, 95% CI = 1.6-7.1). No clear association was found for use of cordless phones, although OR = 1.7, 95% CI = 0.8-3.4 was found in the group with >2,000 h of cumulative use. This investigation confirmed our previous results of an association between mobile phone use and malignant brain tumors. Copyright 2010 S. Karger AG, Basel.

Unique Stealth Unmanned Aerial Vehicle (UAV) Houck Aircraft Design Program. Volume 2: Prototype Report

DTIC Science & Technology

2008-11-01

Configuration ................................ 23 Figure 18: Wake at 15 MPH for AOA = 6, 20 degrees...27 Figure 19: Wake at 35 MPH for AOA = 6, 20 degrees ............................................................... 28 Figure 20: Wake ...several different manners beginning with alpha (angle of attack) sweeps, then Q (velocity) sweeps, and finally randomized testing. Solid and wake

Hala Azzam, PhD, MPH | Division of Cancer Prevention

Cancer.gov

Dr. Hala Azzam is a Cancer Epidemiologist in the Cancer Prevention Fellowship Program (CPFP) in the Division of Cancer Prevention within the National Cancer Institute. She received her Bachelor's degree in molecular biology from Kings College London University, her PhD in anatomy and cell biology from Georgetown University Lombardi Cancer Center, and her MPH in epidemiology

49 CFR 325.35 - Ambient conditions; highway operations.

Code of Federal Regulations, 2012 CFR

2012-10-01

... test site at the time of testing. (b) Wind. The wind velocity at the test shall be measured at the... established that the wind velocity is essentially constant. Once this fact has been established, wind velocity... wind velocity is 12 mph (19.3 kph) or less. Gust wind measurements of up to 20 mph (33.2 kph) are...

49 CFR 325.55 - Ambient conditions; stationary test.

Code of Federal Regulations, 2012 CFR

2012-10-01

... site at the time of testing. (b) Wind. The wind velocity at the test site shall be measured at the... established that the wind velocity is essentially constant. Once this fact has been established, wind velocity... wind velocity is 12 mph (19.3 kph) or less. Gust wind measurements of up to 20 mph (33.2 kph) are...

Using COMSOL Software on the Peregrine System | High-Performance Computing

Science.gov Websites

the following command: lmstat.comsol COMSOL can be used by starting the COMSOL GUI that allows one to compute node, the following will bring up the COMSOL interface. module purge module load comsol/5.3 comsol following command comsol batch -inputfile myinputfile.mph -outputfile out.mph Running a Parallel COMSOL Job

Impact of Methylphenidate Delivery Profiles on Driving Performance of Adolescents with Attention-Deficit/hyperactivity Disorder: A Pilot Study

ERIC Educational Resources Information Center

Cox, Daniel J.; Merkel, R. Lawrence; Penberthy, Jennifer Kim; Kovatchev, Boris; Hankin, Cheryl S.

2004-01-01

Objective: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at high risk for driving accidents. One dose of methylphenidate (MPH) improves simulator driving performances of ADHD-diagnosed adolescents at 1.5 hours post-dose. However, little is known about the effects of different MPH delivery profiles on driving performance…

Earth observations taken by the Expedition Seven crew

NASA Image and Video Library

2003-09-03

ISS007-E-14419 (4 September 2003) --- This view featuring Hurricane Fabian was taken by one of the Expedition 7 crewmembers onboard the International Space Station (ISS) while it was in orbit over Hispaniola. At the time this photo was taken, Fabian had maximum sustained winds of 120 mph and was moving to the north-northwest at 12 mph.

49 CFR 325.35 - Ambient conditions; highway operations.

Code of Federal Regulations, 2011 CFR

2011-10-01

... test site at the time of testing. (b) Wind. The wind velocity at the test shall be measured at the... established that the wind velocity is essentially constant. Once this fact has been established, wind velocity... wind velocity is 12 mph (19.3 kph) or less. Gust wind measurements of up to 20 mph (33.2 kph) are...

49 CFR 325.55 - Ambient conditions; stationary test.

Code of Federal Regulations, 2011 CFR

2011-10-01

... site at the time of testing. (b) Wind. The wind velocity at the test site shall be measured at the... established that the wind velocity is essentially constant. Once this fact has been established, wind velocity... wind velocity is 12 mph (19.3 kph) or less. Gust wind measurements of up to 20 mph (33.2 kph) are...