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Sample records for vivo brain occupancy

  1. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  2. Correlation of receptor occupancy of metabotropic glutamate receptor subtype 1 (mGluR1) in mouse brain with in vivo activity of allosteric mGluR1 antagonists.

    Science.gov (United States)

    Suzuki, Gentaroh; Kawagoe-Takaki, Hiroko; Inoue, Takao; Kimura, Toshifumi; Hikichi, Hirohiko; Murai, Takashi; Satow, Akio; Hata, Mikiko; Maehara, Shunsuke; Ito, Satoru; Kawamoto, Hiroshi; Ozaki, Satoshi; Ohta, Hisashi

    2009-07-01

    The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [(3)H]FTIDC (4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide) was identified as a radioligand having high affinity for mGluR1-expressing CHO cells (K(D) = 2.1 nM) and mouse cerebellum (K(D) = 3.7 nM). [(3)H]FTIDC bound to mGluR1 was displaced by structurally unrelated allosteric antagonists, suggesting there is a mutual binding pocket shared with different allosteric antagonists. The binding specificity of [(3)H]FTIDC for mGluR1 in brain sections was demonstrated by the lack of significant binding to brain sections prepared from mGluR1-knockout mice. Ex vivo receptor occupancy with [(3)H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.

  3. Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors.

    Science.gov (United States)

    Wager, Travis T; Galatsis, Paul; Chandrasekaran, Ramalakshmi Y; Butler, Todd W; Li, Jianke; Zhang, Lei; Mente, Scot; Subramanyam, Chakrapani; Liu, Shenping; Doran, Angela C; Chang, Cheng; Fisher, Katherine; Grimwood, Sarah; Hedde, Joseph R; Marconi, Michael; Schildknegt, Klaas

    2017-09-20

    To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [3H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [3H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).

  4. Occupational Therapy and Community Reintegration of Persons with Brain Injury

    Science.gov (United States)

    Fact Sheet Occupational Therapy and Community Reintegration of Persons With Brain Injury Brain injuries can affect motor, sensory, cognitive, and behavioral functioning. A person who has sustained a brain ...

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

    Science.gov (United States)

    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.

  6. Ex-vivo MR Volumetry of Human Brain Hemispheres

    Science.gov (United States)

    Kotrotsou, Aikaterini; Bennett, David A.; Schneider, Julie A.; Dawe, Robert J.; Golak, Tom; Leurgans, Sue E.; Yu, Lei; Arfanakis, Konstantinos

    2013-01-01

    Purpose The aims of this work were to: a) develop an approach for ex-vivo MR volumetry of human brain hemispheres that does not contaminate the results of histopathological examination, b) longitudinally assess regional brain volumes postmortem, and c) investigate the relationship between MR volumetric measurements performed in-vivo and ex-vivo. Methods An approach for ex-vivo MR volumetry of human brain hemispheres was developed. Five hemispheres from elderly subjects were imaged ex-vivo longitudinally. All datasets were segmented. The longitudinal behavior of volumes measured ex-vivo was assessed. The relationship between in-vivo and ex-vivo volumetric measurements was investigated in seven elderly subjects imaged both ante-mortem and postmortem. Results The presented approach for ex-vivo MR volumetry did not contaminate the results of histopathological examination. For a period of 6 months postmortem, within-subject volume variation across time points was substantially smaller than inter-subject volume variation. A close linear correspondence was detected between in-vivo and ex-vivo volumetric measurements. Conclusion Regional brain volumes measured with the presented approach for ex-vivo MR volumetry remain relatively unchanged for a period of 6 months postmortem. Furthermore, the linear relationship between in-vivo and ex-vivo MR volumetric measurements suggests that the presented approach captures information linked to ante-mortem macrostructural brain characteristics. PMID:23440751

  7. Modulating Hippocampal Plasticity with In Vivo Brain Stimulation

    National Research Council Canada - National Science Library

    Rohan, Joyce G; Carhuatanta, Kim A; McInturf, Shawn M; Miklasevich, Molly K; Jankord, Ryan

    2015-01-01

    .... However, the mechanisms by which tDCS effects brain function remain under scrutiny. We have demonstrated that in vivo tDCS in rats produced a lasting effect on hippocampal synaptic plasticity, as measured using extracellular recordings...

  8. Reproducibility and Variation of Diffusion Measures in the Squirrel Monkey Brain, In Vivo and Ex Vivo

    Science.gov (United States)

    Schilling, Kurt; Gao, Yurui; Stepniewska, Iwona; Choe, Ann S; Landman, Bennett A; Anderson, Adam W

    2016-01-01

    Purpose Animal models are needed to better understand the relationship between diffusion MRI (dMRI) and the underlying tissue microstructure. One promising model for validation studies is the common squirrel monkey, Saimiri sciureus. This study aims to determine (1) the reproducibility of in vivo diffusion measures both within and between subjects; (2) the agreement between in vivo and ex vivo data acquired from the same specimen and (3) normal diffusion values and their variation across brain regions. Methods Data were acquired from three healthy squirrel monkeys, each imaged twice in vivo and once ex vivo. Reproducibility of fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) was assessed, and normal values were determined both in vivo and ex vivo. Results The calculated coefficients of variation (CVs) for both intra-subject and inter-subject MD were below 10% (low variability) while FA had a wider range of CVs, 2–14% intra-subject (moderate variability), and 3–31% inter-subject (high variability). MD in ex vivo tissue was lower than in vivo (30%–50% decrease), while FA values increased in all regions (30–39% increase). The mode of angular differences between in vivo and ex vivo PEVs was 12 degrees. Conclusion This study characterizes the diffusion properties of the squirrel monkey brain and serves as the groundwork for using the squirrel monkey, both in vivo and ex vivo, as a model for diffusion MRI studies. PMID:27587226

  9. A scoping review on occupational and self identity after a brain injury.

    Science.gov (United States)

    Bryson-Campbell, Mikelle; Shaw, Lynn; O'Brien, James; Holmes, Jeff; Magalhaes, Lilian

    2013-01-01

    Persons with brain injury experience a shift in their self identity that is underpinned by work loss and changes to their worker role. However, little is known on how to assist a worker with a brain injury re-establish their occupational identity. Thus, the objective of this article is to present the results of a scoping review undertaken to examine the literature on occupational identity and self identity after a brain injury. A scoping review was performed using the keywords traumatic, acquired brain injury, occupational, and self identity. Articles were narrowed through three phases which involved reviewing articles to ensure a thorough discussion of identity after a brain injury was included and to highlight the research questions. In total 16 articles and 3 theses were included. No articles were retrieved on occupational identity after a brain injury. Fourteen articles discussed the loss of self identity experienced after a brain injury while three articles highlighted rehabilitation programs. Research indicates there are extensive changes to identity after a brain injury and this impacts returning to previous occupations. This knowledge can further our understanding of returning to occupations after a brain injury and the impact on occupational identity.

  10. Metabolic flux and compartmentation analysis in the brain in vivo

    Directory of Open Access Journals (Sweden)

    Bernard eLanz

    2013-10-01

    Full Text Available Through significant developments and progresses in the last two decades, in vivo localized nuclear magnetic resonance spectroscopy (MRS became a method of choice to probe brain metabolic pathways in a non-invasive way. Beside the measurement of the total concentration of more than 20 metabolites, 1H MRS can be used to quantify the dynamics of substrate transport across the blood brain barrier (BBB by varying the plasma substrate level. On the other hand, 13C MRS with the infusion of 13C enriched substrates enables the characterization of brain oxidative metabolism and neurotransmission by incorporation of 13C in the different carbon positions of amino acid neurotransmitters. The quantitative determination of the biochemical reactions involved in these processes requires the use of appropriate metabolic models, whose level of details is strongly related to the amount of data accessible with in vivo MRS. In the present work, we present the different steps involved in the elaboration of a mathematical model of a given brain metabolic process and its application to the experimental data in order to extract quantitative brain metabolic rates. We review the recent advances in the localized measurement of brain glucose transport and compartmentalized brain energy metabolism, and how these reveal mechanistic details on glial support to glutamatergic and GABAergic neurons.

  11. Metabolic Flux and Compartmentation Analysis in the Brain In vivo

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    Lanz, Bernard; Gruetter, Rolf; Duarte, João M. N.

    2013-01-01

    Through significant developments and progresses in the last two decades, in vivo localized nuclear magnetic resonance spectroscopy (MRS) became a method of choice to probe brain metabolic pathways in a non-invasive way. Beside the measurement of the total concentration of more than 20 metabolites, 1H MRS can be used to quantify the dynamics of substrate transport across the blood-brain barrier by varying the plasma substrate level. On the other hand, 13C MRS with the infusion of 13C-enriched substrates enables the characterization of brain oxidative metabolism and neurotransmission by incorporation of 13C in the different carbon positions of amino acid neurotransmitters. The quantitative determination of the biochemical reactions involved in these processes requires the use of appropriate metabolic models, whose level of details is strongly related to the amount of data accessible with in vivo MRS. In the present work, we present the different steps involved in the elaboration of a mathematical model of a given brain metabolic process and its application to the experimental data in order to extract quantitative brain metabolic rates. We review the recent advances in the localized measurement of brain glucose transport and compartmentalized brain energy metabolism, and how these reveal mechanistic details on glial support to glutamatergic and GABAergic neurons. PMID:24194729

  12. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

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    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  13. Microsensors for in vivo Measurement of Glutamate in Brain Tissue

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    Miranda van der Zeyden

    2008-11-01

    Full Text Available Several immobilized enzyme-based electrochemical biosensors for glutamate detection have been developed over the last decade. In this review, we compare first and second generation sensors. Structures, working mechanisms, interference prevention, in vitro detection characteristics and in vivo performance are summarized here for those sensors that have successfully detected brain glutamate in vivo. In brief, first generation sensors have a simpler structure and are faster in glutamate detection. They also show a better sensitivity to glutamate during calibration in vitro. For second generation sensors, besides their less precise detection, their fabrication is difficult to reproduce, even with a semi-automatic dip-coater. Both generations of sensors can detect glutamate levels in vivo, but the reported basal levels are different. In general, second generation sensors detect higher basal levels of glutamate compared with the results obtained from first generation sensors. However, whether the detected glutamate is indeed from synaptic sources is an issue that needs further attention.

  14. Occupational exposure to radio frequency/microwave radiation and the risk of brain tumors

    DEFF Research Database (Denmark)

    Berg, Gabriele; Spallek, Jacob; Schüz, Joachim

    2006-01-01

    It is still under debate whether occupational exposure to radio frequency/microwave electromagnetic fields (RF/MW-EMF) contributes to the development of brain tumors. This analysis examined the role of occupational RF/MW-EMF exposure in the risk of glioma and meningioma. A population-based, case....... No significant association between occupational exposure to RF/MW-EMF and brain tumors was found. For glioma, the adjusted odds ratio for highly exposed persons compared with persons not highly exposed was 1.21 (95% confidence interval: 0.69, 2.13); for meningioma, it was 1.34 (95% confidence interval: 0.64, 2...

  15. Automated Segmentation of in Vivo and Ex Vivo Mouse Brain Magnetic Resonance Images

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    Alize E.H. Scheenstra

    2009-01-01

    Full Text Available Segmentation of magnetic resonance imaging (MRI data is required for many applications, such as the comparison of different structures or time points, and for annotation purposes. Currently, the gold standard for automated image segmentation is nonlinear atlas-based segmentation. However, these methods are either not sufficient or highly time consuming for mouse brains, owing to the low signal to noise ratio and low contrast between structures compared with other applications. We present a novel generic approach to reduce processing time for segmentation of various structures of mouse brains, in vivo and ex vivo. The segmentation consists of a rough affine registration to a template followed by a clustering approach to refine the rough segmentation near the edges. Compared with manual segmentations, the presented segmentation method has an average kappa index of 0.7 for 7 of 12 structures in in vivo MRI and 11 of 12 structures in ex vivo MRI. Furthermore, we found that these results were equal to the performance of a nonlinear segmentation method, but with the advantage of being 8 times faster. The presented automatic segmentation method is quick and intuitive and can be used for image registration, volume quantification of structures, and annotation.

  16. In vivo detection of brain Krebs cycle intermediate by hyperpolarized magnetic resonance

    OpenAIRE

    Mishkovsky, Mor; Comment, Arnaud; Gruetter, Rolf

    2012-01-01

    The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo. This study reports the first direct in vivo observation of a TCA cycle intermediate in intact brain, namely, 2-oxoglutarate, a key biomolecule connecting metabolism to neuronal activity. Our observation reveals important information about in vivo biochemical processes hitherto considered undet...

  17. In vivo mapping of current density distribution in brain tissues during deep brain stimulation (DBS)

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    Sajib, Saurav Z. K.; Oh, Tong In; Kim, Hyung Joong; Kwon, Oh In; Woo, Eung Je

    2017-01-01

    New methods for in vivo mapping of brain responses during deep brain stimulation (DBS) are indispensable to secure clinical applications. Assessment of current density distribution, induced by internally injected currents, may provide an alternative method for understanding the therapeutic effects of electrical stimulation. The current flow and pathway are affected by internal conductivity, and can be imaged using magnetic resonance-based conductivity imaging methods. Magnetic resonance electrical impedance tomography (MREIT) is an imaging method that can enable highly resolved mapping of electromagnetic tissue properties such as current density and conductivity of living tissues. In the current study, we experimentally imaged current density distribution of in vivo canine brains by applying MREIT to electrical stimulation. The current density maps of three canine brains were calculated from the measured magnetic flux density data. The absolute current density values of brain tissues, including gray matter, white matter, and cerebrospinal fluid were compared to assess the active regions during DBS. The resulting current density in different tissue types may provide useful information about current pathways and volume activation for adjusting surgical planning and understanding the therapeutic effects of DBS.

  18. In Vivo Detection of Brain Krebs Cycle Intermediate by Hyperpolarized Magnetic Resonance

    National Research Council Canada - National Science Library

    Mishkovsky, Mor; Comment, Arnaud; Gruetter, Rolf

    2012-01-01

    The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo...

  19. Population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space.

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    Feng, Lei; Jeon, Tina; Yu, Qiaowen; Ouyang, Minhui; Peng, Qinmu; Mishra, Virendra; Pletikos, Mihovil; Sestan, Nenad; Miller, Michael I; Mori, Susumu; Hsiao, Steven; Liu, Shuwei; Huang, Hao

    2017-12-01

    Animal models of the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate, have been irreplaceable in neurobiological studies. However, a population-averaged macaque brain diffusion tensor imaging (DTI) atlas, including comprehensive gray and white matter labeling as well as bony and facial landmarks guiding invasive experimental procedures, is not available. The macaque white matter tract pathways and microstructures have been rarely recorded. Here, we established a population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space incorporating bony and facial landmarks, and delineated microstructures and three-dimensional pathways of major white matter tracts in vivo MRI/DTI and ex vivo (postmortem) DTI of ten rhesus macaque brains were acquired. Single-subject macaque brain DTI template was obtained by transforming the postmortem high-resolution DTI data into in vivo space. Ex vivo DTI of ten macaque brains was then averaged in the in vivo single-subject template space to generate population-averaged macaque brain DTI atlas. The white matter tracts were traced with DTI-based tractography. One hundred and eighteen neural structures including all cortical gyri, white matter tracts and subcortical nuclei, were labeled manually on population-averaged DTI-derived maps. The in vivo microstructural metrics of fractional anisotropy, axial, radial and mean diffusivity of the traced white matter tracts were measured. Population-averaged digital atlas integrated into in vivo space can be used to label the experimental macaque brain automatically. Bony and facial landmarks will be available for guiding invasive procedures. The DTI metric measurements offer unique insights into heterogeneous microstructural profiles of different white matter tracts.

  20. In vivo PET imaging of brain nicotinic cholinergic receptors

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    Bottlaender, M.; Valette, H.; Saba, W.; Schollhorn-Peyronneau, M.A.; Dolle, F.; Syrota, A. [Service Hospitalier Frederic Joliot (CEA/DSV/DRM), 91 - Orsay (France)

    2006-07-01

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the {alpha}4{beta}2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [{sup 18}F]fluoro-A-85380 (Dolle et al., 1999). The [{sup 18}F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ {sup 18}F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the < 4R2 nAChRs. Competition and pre-blocking studies, using nicotinic agonists, confirm that the radiotracer binds specifically to the heteromeric nAChRs in the brain (Valette et al., 1999). The in vivo, characteristics of the [{sup 18}F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [{sup 18}F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [{sup 18}F

  1. Brain Tissue Oxygen: In Vivo Monitoring with Carbon Paste Electrodes

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    John P. Lowry

    2005-11-01

    Full Text Available In this communication we review selected experiments involving the use ofcarbon paste electrodes (CPEs to monitor and measure brain tissue O2 levels in awakefreely-moving animals. Simultaneous measurements of rCBF were performed using the H2clearance technique. Voltammetric techniques used include both differential pulse (O2 andconstant potential amperometry (rCBF. Mild hypoxia and hyperoxia produced rapidchanges (decrease and increase respectively in the in vivo O2 signal. Neuronal activation(tail pinch and stimulated grooming produced similar increases in both O2 and rCBFindicating that CPE O2 currents provide an index of increases in rCBF when such increasesexceed O2 utilization. Saline injection produced a transient increase in the O2 signal whilechloral hydrate produced slower more long-lasting changes that accompanied the behavioralchanges associated with anaesthesia. Acetazolamide increased O2 levels through an increasein rCBF.

  2. Occupational and Environmental Risk Factors of Adult Primary Brain Cancers: A Systematic Review

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    J Gomes

    2011-03-01

    Full Text Available The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and highvoltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary.

  3. Occupational and environmental risk factors of adult primary brain cancers: a systematic review.

    Science.gov (United States)

    Gomes, J; Al Zayadi, A; Guzman, A

    2011-04-01

    The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and high-voltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary.

  4. Spectroscopic optical coherence tomography for ex vivo brain tumor analysis

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    Lenz, Marcel; Krug, Robin; Dillmann, Christopher; Gerling, Alexandra; Gerhardt, Nils C.; Welp, Hubert; Schmieder, Kirsten; Hofmann, Martin R.

    2017-02-01

    For neurosurgeries precise tumor resection is essential for the subsequent recovery of the patients since nearby healthy tissue that may be harmed has a huge impact on the life quality after the surgery. However, so far no satisfying methodology has been established to assist the surgeon during surgery to distinguish between healthy and tumor tissue. Optical Coherence Tomography (OCT) potentially enables non-contact in vivo image acquisition at penetration depths of 1-2 mm with a resolution of approximately 1-15 μm. To analyze the potential of OCT for distinction between brain tumors and healthy tissue, we used a commercially available Thorlabs Callisto system to measure healthy tissue and meningioma samples ex vivo. All samples were measured with the OCT system and three dimensional datasets were generated. Afterwards they were sent to the pathology for staining with hematoxylin and eosin and then investigated with a bright field microscope to verify the tissue type. This is the actual gold standard for ex vivo analysis. The images taken by the OCT system exhibit variations in the structure for different tissue types, but these variations may not be objectively evaluated from raw OCT images. Since an automated distinction between tumor and healthy tissue would be highly desirable to guide the surgeon, we applied Spectroscopic Optical Coherence Tomography to further enhance the differences between the tissue types. Pattern recognition and machine learning algorithms were applied to classify the derived spectroscopic information. Finally, the classification results are analyzed in comparison to the histological analysis of the samples.

  5. Effectiveness of physiotherapy and occupational therapy after traumatic brain injury in the intensive care unit.

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    Hellweg, Stephanie

    2012-01-01

    Physiotherapy and occupational therapy are frequently administered in intensive care units (ICUs) after traumatic brain injury (TBI) to promote recovery. The increasing economic pressure and the growing need for evidence of therapeutic effectiveness are reasons for reviewing the currently available scientific data. The databases of OTseeker, PEDro, Medline, and Cochrane were searched for studies on frequently applied therapeutic procedures in the ICU following a TBI. It becomes evident that the currently available data on physiotherapy and occupational therapy are very limited. Consequently, it is not possible to give conclusive recommendations within an evidence-based context. Studies of other neurological disorders indicate that early mobilisation positively influences outcome parameters such as the ability to walk. It can be concluded from three studies that physiotherapy for the prevention or treatment of ventilator-associated pneumonia is not effective. The proof of effectiveness for other physiotherapeutic and occupational therapy interventions must still be demonstrated.

  6. Effectiveness of Physiotherapy and Occupational Therapy after Traumatic Brain Injury in the Intensive Care Unit

    Directory of Open Access Journals (Sweden)

    Stephanie Hellweg

    2012-01-01

    Full Text Available Physiotherapy and occupational therapy are frequently administered in intensive care units (ICUs after traumatic brain injury (TBI to promote recovery. The increasing economic pressure and the growing need for evidence of therapeutic effectiveness are reasons for reviewing the currently available scientific data. The databases of OTseeker, PEDro, Medline, and Cochrane were searched for studies on frequently applied therapeutic procedures in the ICU following a TBI. It becomes evident that the currently available data on physiotherapy and occupational therapy are very limited. Consequently, it is not possible to give conclusive recommendations within an evidence-based context. Studies of other neurological disorders indicate that early mobilisation positively influences outcome parameters such as the ability to walk. It can be concluded from three studies that physiotherapy for the prevention or treatment of ventilator-associated pneumonia is not effective. The proof of effectiveness for other physiotherapeutic and occupational therapy interventions must still be demonstrated.

  7. In vivo monitoring of occupationally exposed individuals to {sup 18}FDG in CRCN/NE; Monitoracao in vivo dos individuos ocupacionalmente expostos na producao de {sup 18}FDG no CRCN/NE

    Energy Technology Data Exchange (ETDEWEB)

    Lacerda, I.V.B. [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Programa de Pos-Graduacao em Tecnologias Energeticas e Nucleares; Xavier, A.C.S.; Oliveira, M.L.; Lima, F.F.; Lima, F.R.A., E-mail: bellelacerda@hotmail.com [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil)

    2012-07-01

    The increasing demand for PET radiopharmaceuticals in Brazil results in increasing of the number of occupationally exposed individuals (OEI) to the radiopharmaceutical {sup 18}F in the form of {sup 18}FDG, increasing thereby the risk of accidental incorporation. This work aims to implement an in vivo internal monitoring technique applied to {sup 18}FDG radiopharmaceutical at the Divisao de Producao de Radiofarmacos (DIPRA) of the Centro Regional de Ciencias Nucleares do Nordeste (CRCN/NE). The detection system used was a NaI(Tl) 3'' x 3'' detector connected to a compact electronic module operated by the Genie 2000 software. It was calibrated using a brain phantom containing a standard source of {sup 22}Na which simulates a contaminated individual. Based on the calibration factor it was possible to determine the minimum detectable activity (MDA) of the detection system and then, through use of biokinetic models provided by the ICRP in its publication 53 and edited by the AIDE version 6.0 software, it was possible to calculate the minimum detectable effective dose (MDED) which is an indication of the technique sensitivity. The MDED was estimated for the in vivo measurements performed up to 0.1 day after the occurrence of an intake by ingestion. The value obtained was compared to the Recording level of 1 mSv recommended by the IAEA. After validation of the in vivo monitoring technique, a series of measurements were performed on a group of occupationally exposed workers from DIPRA shortly after completion of production and quality control of {sup 18}FDG radiopharmaceutical procedures. It is concluded that the proposed technique is sufficiently sensitive for its application in internal occupational monitoring. (author)

  8. Effectiveness of Physiotherapy and Occupational Therapy after Traumatic Brain Injury in the Intensive Care Unit

    OpenAIRE

    Stephanie Hellweg

    2012-01-01

    Physiotherapy and occupational therapy are frequently administered in intensive care units (ICUs) after traumatic brain injury (TBI) to promote recovery. The increasing economic pressure and the growing need for evidence of therapeutic effectiveness are reasons for reviewing the currently available scientific data. The databases of OTseeker, PEDro, Medline, and Cochrane were searched for studies on frequently applied therapeutic procedures in the ICU following a TBI. It becomes evident th...

  9. The epidemiology of fatal occupational traumatic brain injury in the U.S.

    Science.gov (United States)

    Tiesman, Hope M; Konda, Srinivas; Bell, Jennifer L

    2011-07-01

    Although traumatic brain injury (TBI) is one of the leading causes of death and disability in the U.S., work-related TBI has not been well documented. The aim of this study was to describe the epidemiologic characteristics and temporal trends of fatal occupational TBI in the U.S between 2003 and 2008. A cross-sectional analysis of the Census of Fatal Occupational Injury database was performed. Both the Occupational Injury and Illness Classification System nature of injury codes and body part codes were used to define TBIs. Fatality rates were calculated using denominators derived from the Current Population Survey. Fatality rates were compared among industries, cause of death, and demographics with rate ratios (RRs) and 95% CIs. Poisson regression was used to assess trends in fatality rates. Data were analyzed in 2009-2010. Nearly 7300 occupational TBI deaths occurred between 2003 and 2008, for an average fatality rate of 0.8 per 100,000 workers per year. The leading causes of occupational TBI death were as follows: motor vehicle (31%); falls (29%); assaults and violent acts (20%); and contact with objects/equipment (18%). Fatality rates were 15 times higher in men compared with women (RR=15, 95% CI=13.7, 16.3). Workers aged ≥65 years experienced the highest TBI fatality rate of all age groups (2.5 per 100,000 per year). Construction, transportation, and agriculture/forestry/fishing industries recorded nearly half of all TBI fatalities (n=1828, n=825, n=761, respectively). Occupational TBI death rates declined 23% over the 6-year period (pfishing industry had the highest rates. Additionally, workers aged >65 years in all industries would be a good target for future prevention efforts. Published by Elsevier Inc.

  10. Factors associated with providing social security benefits for traumatic brain injury resulting from occupational accidents

    Directory of Open Access Journals (Sweden)

    Denismar Borges de Miranda

    2014-03-01

    Full Text Available INTRODUCTION: The Occupational Accident (OA is considered to be an important public health problem in Brazil. Traumatic Brain Injury (TBI is the most common among them. The TBI is associated with high morbidity and mortality rates among workers. OBJECTIVE: To identify factors associated with providing social security benefits for TBI due to occupational accidents according to the specific type of economic activity in Brazil, in 2009. METHODS: This is a cross-sectional study that was conducted with all workers who were part of the General Regime of Social Security (RGPS of Brazil. Secondary data were obtained from the National Information System Benefit, from the Synchronized National Register of the Ministry of Finance and from the General Register of Employed and Unemployed Persons. Data were analyzed using the multiple logistic regression method. RESULTS: We analyzed 2,006 cases of social security benefits for traumatic brain injury due to Occupational Accident. Factors associated with the concession of the benefit according to the economic activity of the Company of the beneficiary were identified. Associations were found with sex, income and the region of the Company. CONCLUSION: Factors associated with the concession of social security benefits by TBI resulting from OA differ depending on the type of economic activity in the study. Understanding these factors may contribute to the planning of preventive policies.

  11. Factors associated with providing social security benefits for traumatic brain injury resulting from occupational accidents.

    Science.gov (United States)

    de Miranda, Denismar Borges; Rego, Rita Franco; Viola, Denise Nunes; Lima, Verônica Maria Cadena; Teixeira, Edriene Barros

    2014-01-01

    The Occupational Accident (OA) is considered to be an important public health problem in Brazil. Traumatic Brain Injury (TBI) is the most common among them. The TBI is associated with high morbidity and mortality rates among workers. To identify factors associated with providing social security benefits for TBI due to occupational accidents according to the specific type of economic activity in Brazil, in 2009. This is a cross-sectional study that was conducted with all workers who were part of the General Regime of Social Security (RGPS) of Brazil. Secondary data were obtained from the National Information System Benefit, from the Synchronized National Register of the Ministry of Finance and from the General Register of Employed and Unemployed Persons. Data were analyzed using the multiple logistic regression method. We analyzed 2,006 cases of social security benefits for traumatic brain injury due to Occupational Accident. Factors associated with the concession of the benefit according to the economic activity of the Company of the beneficiary were identified. Associations were found with sex, income and the region of the Company. Factors associated with the concession of social security benefits by TBI resulting from OA differ depending on the type of economic activity in the study. Understanding these factors may contribute to the planning of preventive policies.

  12. Response surface optimization, Ex vivo and In vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone.

    Science.gov (United States)

    Abdelrahman, Fatma Elzahraa; Elsayed, Ibrahim; Gad, Mary Kamal; Elshafeey, Ahmed Hassen; Mohamed, Magdi Ibrahim

    2017-09-15

    Transnasal brain drug targeting could ensure better drug delivery to the brain through the olfactory pathway. Risperidone bioavailability is 66% in extensive metabolizers and 82% in slow metabolizers. The aim of this study is to investigate the ability of the nanovesicular spanlastics to effectively deliver risperidone through the nasal route to the brain and increase its bioavailability. Spanlastics formulae, composed of span and polyvinyl alcohol, were designed based on central composite statistical design. The planned formulae were prepared using ethanol injection method. The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential and encapsulation efficiency. The optimized formula having the lowest particle size, polydispersity index, the highest zeta potential and encapsulation efficiency was subjected to further investigations including characterization of its rheological properties, elasticity, transmission electron microscopy, in vitro diffusion, ex vivo permeation, histopathology and in vivo biodistribution. The optimized formula was composed of 5mg/mL span and 30mg/mL polyvinyl alcohol. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control regarding the brain targeting efficiency and the drug transport percentage (2.16 and 1.43 folds increase, respectively). The study introduced a successful and promising formula to directly and effectively carry the drug from nose to brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Exogenous anandamide protects rat brain against acute neuronal injury in vivo

    NARCIS (Netherlands)

    Vliegenthart, J.F.G.; Stelt, M. van der; Veldhuis, W.B.; Haaften, G.W. van; Fezza, F.; Bisogno, T.; Bär, P.R; Veldink, G.A.

    2001-01-01

    The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological

  14. In vivo detection of brain Krebs cycle intermediate by hyperpolarized magnetic resonance.

    Science.gov (United States)

    Mishkovsky, Mor; Comment, Arnaud; Gruetter, Rolf

    2012-12-01

    The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo. This study reports the first direct in vivo observation of a TCA cycle intermediate in intact brain, namely, 2-oxoglutarate, a key biomolecule connecting metabolism to neuronal activity. Our observation reveals important information about in vivo biochemical processes hitherto considered undetectable. In particular, it provides direct evidence that transport across the inner mitochondria membrane is rate limiting in the brain. The hyperpolarized magnetic resonance protocol designed for this study opens the way to direct and real-time studies of TCA cycle kinetics.

  15. Guidelines to PET measurements of the target occupancy in the brain for drug development

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

    2016-11-15

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

  16. Recent Methods for Measuring Dopamine D3 receptor Occupancy In Vivo: Importance for Drug Development

    Directory of Open Access Journals (Sweden)

    Bernard eLe Foll

    2014-07-01

    Full Text Available There is considerable interest in developing highly selective dopamine D3 receptor ligands for a variety of mental health disorders. Dopamine D3 receptors have been implicated in Parkinson’s Disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from preclinical studies. Recently, with the advent of [11C]-(+-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+-PHNO binding by region of interest. This novel methodology can be used in preclinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+-PHNO can provide insights into the function of D3 receptors in addiction is also presented.

  17. A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

    Science.gov (United States)

    Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

    2016-11-01

    The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

  18. Effect of Secondhand Smoke on Occupancy of Nicotinic Acetylcholine Receptors in Brain

    Science.gov (United States)

    Brody, Arthur L.; Mandelkern, Mark A.; London, Edythe D.; Khan, Aliyah; Kozman, Daniel; Costello, Matthew R.; Vellios, Evan E.; Archie, Meena M.; Bascom, Rebecca; Mukhin, Alexey G.

    2012-01-01

    Context Despite progress in tobacco control, secondhand smoke (SHS) exposure remains prevalent worldwide and is implicated in the initiation and maintenance of cigarette smoking. Objective To determine whether moderate SHS exposure results in brain α4β2* nicotinic acetylcholine receptor (nAChR) occupancy. Design, Setting, and Participants Positron emission tomography scanning and the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (also known as 2-[18F]fluoro-A-85380, or 2-FA) were used to determine α4β2* nAChR occupancy from SHS exposure in 24 young adult participants (11 moderately dependent cigarette smokers and 13 nonsmokers). Participants underwent two bolus-plus-continuous-infusion 2-FA positron emission tomography scanning sessions during which they sat in the passenger’s seat of a car for 1 hour and either were exposed to moderate SHS or had no SHS exposure. The study took place at an academic positron emission tomography center. Main Outcome Measure Changes induced by SHS in 2-FA specific binding volume of distribution as a measure of α4β2* nAChR occupancy. Results An overall multivariate analysis of variance using specific binding volume of distribution values revealed a significant main effect of condition (SHS vs control) (F1,22=42.5, P cars and other enclosed spaces. PMID:21536968

  19. Long-term occupational stress is associated with regional reductions in brain tissue volumes.

    Directory of Open Access Journals (Sweden)

    Eva Blix

    Full Text Available There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM and white matter (WM volumes, and the volumes of hippocampus, caudate, and putamen - structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment.

  20. Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model

    DEFF Research Database (Denmark)

    Andersson, O.; Badisco, L.; Hansen, A. H.

    2014-01-01

    In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain....... As in vertebrates, the locust brain–barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model...

  1. A novel ex vivo method for measuring whole brain metabolism in model systems.

    Science.gov (United States)

    Neville, Kathryn E; Bosse, Timothy L; Klekos, Mia; Mills, John F; Weicksel, Steven E; Waters, James S; Tipping, Marla

    2018-02-15

    Many neuronal and glial diseases have been associated with changes in metabolism. Therefore, metabolic reprogramming has become an important area of research to better understand disease at the cellular level, as well as to identify targets for treatment. Model systems are ideal for interrogating metabolic questions in a tissue dependent context. However, while new tools have been developed to study metabolism in cultured cells there has been less progress towards studies in vivo and ex vivo. We have developed a method using newly designed tissue restraints to adapt the Agilent XFe96 metabolic analyzer for whole brain analysis. These restraints create a chamber for Drosophila brains and other small model system tissues to reside undisrupted, while still remaining in the zone for measurements by sensor probes. This method generates reproducible oxygen consumption and extracellular acidification rate data for Drosophila larval and adult brains. Single brains are effectively treated with inhibitors and expected metabolic readings are observed. Measuring metabolic changes, such as glycolytic rate, in transgenic larval brains demonstrates the potential for studying how genotype affects metabolism. Current methodology either utilizes whole animal chambers to measure respiration, not allowing for targeted tissue analysis, or uses technically challenging MRI technology for in vivo analysis that is not suitable for smaller model systems. This new method allows for novel metabolic investigation of intact brains and other tissues ex vivo in a quick, and simplistic way with the potential for large-scale studies. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

    Science.gov (United States)

    2016-02-01

    induced TBI causes progressive tau pathology in 2 lines of transgenic mice. First, we commissioned construction , shipping and assembly of a CHIMERA...AD_________________ Award Number: W81XWH-13-2-0016 TITLE: Development of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic...of in Vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury 5b. GRANT NUMBER W81XWH-13-2-0016 5c. PROGRAM ELEMENT NUMBER 6

  3. The in vivo phosphorylation sites of rat brain dynamin I

    DEFF Research Database (Denmark)

    Graham, Mark E; Anggono, Victor; Bache, Nicolai

    2007-01-01

    -824). To resolve the discrepancy and to better understand the biological roles of dynI phosphorylation, we undertook a systematic identification of all phosphorylation sites in rat brain nerve terminal dynI. Using phosphoamino acid analysis, exclusively phospho-serine residues were found. Thr(780) phosphorylation...

  4. Adaptive optical microscope for brain imaging in vivo

    Science.gov (United States)

    Wang, Kai

    2017-04-01

    The optical heterogeneity of biological tissue imposes a major limitation to acquire detailed structural and functional information deep in the biological specimens using conventional microscopes. To restore optimal imaging performance, we developed an adaptive optical microscope based on direct wavefront sensing technique. This microscope can reliably measure and correct biological samples induced aberration. We demonstrated its performance and application in structural and functional brain imaging in various animal models, including fruit fly, zebrafish and mouse.

  5. Optical microangiography enabling visualization of change in meninges after traumatic brain injury in mice in vivo

    Science.gov (United States)

    Choi, Woo June; Qin, Wan; Qi, Xiaoli; Wang, Ruikang K.

    2016-03-01

    Traumatic brain injury (TBI) is a form of brain injury caused by sudden impact on brain by an external mechanical force. Following the damage caused at the moment of injury, TBI influences pathophysiology in the brain that takes place within the minutes or hours involving alterations in the brain tissue morphology, cerebral blood flow (CBF), and pressure within skull, which become important contributors to morbidity after TBI. While many studies for the TBI pathophysiology have been investigated with brain cortex, the effect of trauma on intracranial tissues has been poorly studied. Here, we report use of high-resolution optical microangiography (OMAG) to monitor the changes in cranial meninges beneath the skull of mouse after TBI. TBI is induced on a brain of anesthetized mouse by thinning the skull using a soft drill where a series of drilling exert mechanical stress on the brain through the skull, resulting in mild brain injury. Intracranial OMAG imaging of the injured mouse brain during post-TBI phase shows interesting pathophysiological findings in the meningeal layers such as widening of subdural space as well as vasodilation of subarachnoid vessels. These processes are acute and reversible within hours. The results indicate potential of OMAG to explore mechanism involved following TBI on small animals in vivo.

  6. The Conductivity of Brain Tissues: Comparison of Results in Vivo and In Vitro Measurements

    Science.gov (United States)

    2001-10-25

    situation in the living piglet . In [7] the estimated resistivity ratio of skull and brain is 14:1. The same ratio calculated from the results of in vivo...brain. Presumably measured from tissue samples at 390C. [19] Foster et al. 1979 2,67 (10 MHz) 3,33 (10 MHz) Tissue samples from dog’s brain at 370C. [22...Biol., vol. 41, pp. 2251-2269, 1996. [13] K. R. Foster , “Dielectric properties of tissues,” In: Bronzino J. D. (ed.). The

  7. Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

    Science.gov (United States)

    Salem, Heba F; Ahmed, Sayed M; Hassaballah, Ashraf E; Omar, Mahmoud M

    2015-01-01

    Background The blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. Methods Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. Results The size of glutathione-modulated nanoliposomes was glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824. Conclusion Overall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections. PMID:26229435

  8. Microdialysis as a tool for in vivo investigation of glutamate transport capacity in rat brain

    DEFF Research Database (Denmark)

    Bruhn, T; Christensen, Thomas; Diemer, Nils Henrik

    1995-01-01

    technique, we present a method that is suitable for the in vivo investigation of the capacity of cellular uptake of glutamate. Using 14C-mannitol as reference, we measured the cellular extraction and the cell membrane permeability of the test substance 3H-D-aspartate in the corpus striatum of the rat brain...

  9. P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood-brain barrier in vivo.

    Science.gov (United States)

    Bundgaard, Christoffer; Eneberg, Elin; Sánchez, Connie

    2016-04-01

    P-glycoprotein (P-gp)-mediated brain efflux of xenobiotics is a well-known process, which may result in suboptimal target engagement and consequently reduced efficacy of drugs exerting their therapeutic effects in the central nervous system. In the present study the role of P-gp in transport across the blood-brain barrier (BBB) was investigated with a series of newer antidepressants (levomilnacipran, vilazodone and vortioxetine) and a control substrate (escitalopram) using P-gp knock-out (KO) and P-gp competent wild-type (WT) mice. Brain and plasma exposure time-courses were measured after an acute subcutaneous dose and at steady-state obtained after subcutaneous drug infusion by osmotic minipumps. Following acute dosing, the brain-to-plasma KO/WT exposure enhancement ratios ((AUCbrain ko/AUCplasma ko)/(AUCbrain WT/AUCplasma WT)) were 5.8 (levomilnacipran), 5.4 (vilazodone), 3.1 (escitalopram) and 0.9 (vortioxetine), respectively. At steady-state, assessment of Kp,uu (unbound brain concentrations/unbound plasma concentrations) revealed a restriction in the brain distribution in WT mice for all compounds except vortioxetine. Levomilnacipran exhibited the most pronounced efflux with a Kp,uu-value of 0.038 in WT mice which was increased to 0.37 in KO mice. Based on both the acute and steady-state distribution data, the results suggest that levomilnacipran, vilazodone and escitalopram are susceptible to P-gp mediated efflux at the BBB in vivo in mice, whereas vortioxetine was practically devoid of being affected by P-gp in vivo. The functional impact of the drug transport-controlling role of P-gp at the BBB was demonstrated by in vivo cortical serotonin transporter occupancy of vilazodone, which exhibited a 20-fold higher plasma EC50 in WT mice compared to KOs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Science.gov (United States)

    Biegon, Anat; Kim, Sung-Won; Logan, Jean; Hooker, Jacob M.; Muench, Lisa; Fowler, Joanna S.

    2010-01-01

    Background Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Methods Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [11C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Results Nicotine administration produced significant, dose-dependent reductions in [11C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Conclusions Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior. PMID:20188349

  11. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  12. 7.0 tesla MRI brain atlas. In-vivo atlas with cryomacrotome correlation. 2. ed.

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Zang-Hee (ed.) [Gachon Univ., Incheon (Korea, Republic of). Neuroscience Research Institute

    2015-04-01

    Revised edition with updated in vivo images. Features a coordination matrix in each image, facilitating identification of brain structures and anatomy. User-friendly format and size. The inaugural publication of the 7.0 Tesla MRI Brain Atlas: In-vivo Atlas with Cryomacrotome Correlation in 2010 provided readers with a spectacular source of ultra-high resolution images revealing a wealth of details of the brainstem and midbrain structures. This second edition contributes additional knowledge gained as a result of technologic advances and recent research. To facilitate identification and comparison of brain structures and anatomy, a detailed coordination matrix is featured in each image. Updated axial, sagittal, and coronal images are also included. This state-of-the-art and user-friendly reference will provide researchers and clinicians with important new perspectives.

  13. Imaging plasma docosahexaenoic acid (dha incorporation into the brain in vivo, as a biomarker of brain DHA: Metabolism and neurotransmission

    Directory of Open Access Journals (Sweden)

    Rapoport Stanley I.

    2011-09-01

    Full Text Available Docosahexaenoic acid (DHA is critical for normal brain structure and function, and its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, a-linolenic acid (α-LNA. We developed an in vivo method in rats using quantitative autoradiography to image incorporation into brain of unesterified plasma DHA, and showed that the incorporation rate equals the rate of brain metabolic DHA consumption. Thus, quantitative imaging of DHA incorporation from plasma into brain can be used as a biomarker of brain DHA metabolism and neurotransmission. The method has been extended to humans with the use of positron emission tomography (PET. Furthermore, imaging in unanesthetized rats using DHA incorporation as a biomarker in response to N-methyl-D-aspartate (NMDA administration confirms that regional DHA signaling is independent of extracellular calcium, and likely mediated by a calcium-independent phospholipase A2 (iPLA2. Studies in mice in which iPLA2-VIA (β was knocked out confirmed that this enzyme is critical for baseline and muscarinic cholinergic signaling involving DHA.

  14. Occupational, Physical, and Speech Therapy Treatment Activities During Inpatient Rehabilitation for Traumatic Brain Injury.

    Science.gov (United States)

    Beaulieu, Cynthia L; Dijkers, Marcel P; Barrett, Ryan S; Horn, Susan D; Giuffrida, Clare G; Timpson, Misti L; Carroll, Deborah M; Smout, Randy J; Hammond, Flora M

    2015-08-01

    To describe the use of occupational therapy (OT), physical therapy (PT), and speech therapy (ST) treatment activities throughout the acute rehabilitation stay of patients with traumatic brain injury. Multisite prospective observational cohort study. Inpatient rehabilitation settings. Patients (N=2130) admitted for initial acute rehabilitation after traumatic brain injury. Patients were categorized on the basis of admission FIM cognitive scores, resulting in 5 fairly homogeneous cognitive groups. Not applicable. Percentage of patients engaged in specific activities and mean time patients engaged in these activities for each 10-hour block of time for OT, PT, and ST combined. Therapy activities in OT, PT, and ST across all 5 cognitive groups had a primary focus on basic activities. Although advanced activities occurred in each discipline and within each cognitive group, these advanced activities occurred with fewer patients and usually only toward the end of the rehabilitation stay. The pattern of activities engaged in was both similar to and different from patterns seen in previous practice-based evidence studies with different rehabilitation diagnostic groups. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  15. In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching.

    Science.gov (United States)

    Binder, Devin K; Papadopoulos, Marios C; Haggie, Peter M; Verkman, A S

    2004-09-15

    Molecular diffusion in the brain extracellular space (ECS) is an important determinant of neural function. We developed a brain surface photobleaching method to measure the diffusion of fluorescently labeled macromolecules in the ECS of the cerebral cortex. The ECS in mouse brain was labeled by exposure of the intact dura to fluorescein-dextrans (M(r) 4, 70, and 500 kDa). Fluorescein-dextran diffusion, detected by fluorescence recovery after laser-induced cortical photobleaching using confocal optics, was slowed approximately threefold in the brain ECS relative to solution. Cytotoxic brain edema (produced by water intoxication) or seizure activity (produced by convulsants) slowed diffusion by >10-fold and created dead-space microdomains in which free diffusion was prevented. The hindrance to diffusion was greater for the larger fluorescein-dextrans. Interestingly, slowed ECS diffusion preceded electroencephalographic seizure activity. In contrast to the slowed diffusion produced by brain edema and seizure activity, diffusion in the ECS was faster in mice lacking aquaporin-4 (AQP4), an astroglial water channel that facilitates fluid movement between cells and the ECS. Our results establish a minimally invasive method to quantify diffusion in the brain ECS in vivo, revealing stimulus-induced changes in molecular diffusion in the ECS with unprecedented spatial and temporal resolution. The in vivo mouse data provide evidence for: (1) dead-space ECS microdomains after brain swelling; (2) slowed molecular diffusion in the ECS as an early predictor of impending seizure activity; and (3) a novel role for AQP4 as a regulator of brain ECS.

  16. Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

    Science.gov (United States)

    Lu, Ming; Zhu, Xiao-Hong; Zhang, Yi; Mateescu, Gheorghe; Chen, Wei

    2017-11-01

    Quantitative assessment of cerebral glucose consumption rate (CMR glc ) and tricarboxylic acid cycle flux (V TCA ) is crucial for understanding neuroenergetics under physiopathological conditions. In this study, we report a novel in vivo Deuterium ( 2 H) MRS (DMRS) approach for simultaneously measuring and quantifying CMR glc and V TCA in rat brains at 16.4 Tesla. Following a brief infusion of deuterated glucose, dynamic changes of isotope-labeled glucose, glutamate/glutamine (Glx) and water contents in the brain can be robustly monitored from their well-resolved 2 H resonances. Dynamic DMRS glucose and Glx data were employed to determine CMR glc and V TCA concurrently. To test the sensitivity of this method in response to altered glucose metabolism, two brain conditions with different anesthetics were investigated. Increased CMR glc (0.46 vs. 0.28 µmol/g/min) and V TCA (0.96 vs. 0.6 µmol/g/min) were found in rats under morphine as compared to deeper anesthesia using 2% isoflurane. This study demonstrates the feasibility and new utility of the in vivo DMRS approach to assess cerebral glucose metabolic rates at high/ultrahigh field. It provides an alternative MRS tool for in vivo study of metabolic coupling relationship between aerobic and anaerobic glucose metabolisms in brain under physiopathological states.

  17. Transluminal gene transfer into brain capillary endothelial cells in vivo with HVJ-liposomes.

    Science.gov (United States)

    Jiang, Chen; Matsuo, Hirotami; Koyabu, Noriko; Ohtani, Hisakazu; Fujimoto, Hidenori; Yonemitsu, Yoshikazu; Kaneda, Yasufumi; Narro, Mikihiko; Tsuruo, Takashi; Sawada, Yasufumi

    2002-06-01

    Bioactive proteins or peptides cannot be effectively delivered into brain capillary endothelial cells (BCECs) or brain parenchyma. In this study, we selectively transferred Escherichia coli beta-galactosidase gene (beta-gal) as a model gene into BCECs by using the hemagglutination virus of Japan (HVJ)-liposomes. HVJ-liposomes encapsulating a beta-gal plasmid were used to transfect MBEC4 cells in vitro, and were administrated via the internal carotid artery to rat in vivo. Success of the procedure was confirmed by the detection of 116 kDa beta-gal protein in transfected MBEC4 cells and in brain capillaries isolated from transfected rats, by Western blot analysis and histological staining. The enzymatic activities of beta-galactosidase were 5- to 10-fold and 20-fold higher than when beta-gal-containing liposomes without fusogenic activity (uncoated liposomes) or plasmid alone were employed in vitro and in vivo, respectively. Thus, HVJ-liposomes were demonstrated to be a useful vector to transfer a foreign gene into the brain capillary endothelium in vivo via the transluminal route.

  18. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    Science.gov (United States)

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO 30%). For the first time a predictive model that could describe

  19. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema.

    Science.gov (United States)

    Penet, Marie-France; Viola, Angèle; Confort-Gouny, Sylviane; Le Fur, Yann; Duhamel, Guillaume; Kober, Frank; Ibarrola, Danielle; Izquierdo, Marguerite; Coltel, Nicolas; Gharib, Bouchra; Grau, Georges E; Cozzone, Patrick J

    2005-08-10

    The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

  20. In Vivo Mesoscopic Voltage-Sensitive Dye Imaging of Brain Activation

    Science.gov (United States)

    Tang, Qinggong; Tsytsarev, Vassiliy; Frank, Aaron; Wu, Yalun; Chen, Chao-Wei; Erzurumlu, Reha S.; Chen, Yu

    2016-04-01

    Functional mapping of brain activity is important in elucidating how neural networks operate in the living brain. The whisker sensory system of rodents is an excellent model to study peripherally evoked neural activity in the central nervous system. Each facial whisker is represented by discrete modules of neurons all along the pathway leading to the neocortex. These modules are called “barrels” in layer 4 of the primary somatosensory cortex. Their location (approximately 300-500 μm below cortical surface) allows for convenient imaging of whisker-evoked neural activity in vivo. Fluorescence laminar optical tomography (FLOT) provides depth-resolved fluorescence molecular information with an imaging depth of a few millimeters. Angled illumination and detection configurations can improve both resolution and penetration depth. We applied angled FLOT (aFLOT) to record 3D neural activities evoked in the whisker system of mice by deflection of a single whisker in vivo. A 100 μm capillary and a pair of microelectrodes were inserted to the mouse brain to test the capability of the imaging system. The results show that it is possible to obtain 3D functional maps of the sensory periphery in the brain. This approach can be broadly applicable to functional imaging of other brain structures.

  1. In vivo brain temperature measurements based on fiber optic Bragg grating

    Science.gov (United States)

    Zibaii, Mohammad I.; Latifi, Hamid; Karami, Fatemeh; Ronaghi, Abdolaziz; Chavoshi Nejad, Sara; Dargahi, Leila

    2017-04-01

    This work reports on the development of an optical fiber sensor based fiber Bragg Grating (FBG) probe for in vivo measurements of brain temperature. The major goal of this work is to demonstrate that the changes in brain temperature induced by drugs is an important reality, which could provide new valuable information on the mechanisms of drug action and open new therapeutic approaches. This probe can be interrogated using a portable optical measurement setup, allowing for measurements to be performed outside of standard optical laboratories.

  2. Adaptive optical versus spherical aberration corrections for in vivo brain imaging.

    Science.gov (United States)

    Turcotte, Raphaël; Liang, Yajie; Ji, Na

    2017-08-01

    Adjusting the objective correction collar is a widely used approach to correct spherical aberrations (SA) in optical microscopy. In this work, we characterized and compared its performance with adaptive optics in the context of in vivo brain imaging with two-photon fluorescence microscopy. We found that the presence of sample tilt had a deleterious effect on the performance of SA-only correction. At large tilt angles, adjusting the correction collar even worsened image quality. In contrast, adaptive optical correction always recovered optimal imaging performance regardless of sample tilt. The extent of improvement with adaptive optics was dependent on object size, with smaller objects having larger relative gains in signal intensity and image sharpness. These observations translate into a superior performance of adaptive optics for structural and functional brain imaging applications in vivo, as we confirmed experimentally.

  3. Synthesis and in vivo brain distribution of carbon-11-labeled {delta}-opioid receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Pichika, Rama, E-mail: rpichika@ucsd.ed [Department of Radiology, University of California, San Diego, CA (United States); Jewett, Douglas M.; Sherman, Philip S. [Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Traynor, John R. [Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Husbands, Stephen M. [Department of Pharmacy and Pharmacology, University of Bath, Bath (United Kingdom); Woods, James H. [Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Kilbourn, Michael R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States)

    2010-11-15

    Three new radiolabeled compounds, [{sup 11}C]SNC80 ((+)-4-[({alpha}R)-{alpha}-{l_brace}(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl{r_brace}-3-[{sup 11}C] methoxybenzyl-N,N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-1-[{sup 11}C]methylpiperidin-4-ylidenemethyl) benzamide and N,N-diethyl-4-[(1-[{sup 11}C]methylpiperidin-4-ylidene)phenylmethyl]benzamide, were prepared as potential in vivo radiotracers for the {delta}-opioid receptor. Each compound was synthesized by alkylation of the appropriate desmethyl compounds using [{sup 11}C]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds and no regional specific binding for [{sup 11}C]SNC80. A monkey positron emission tomography study of [{sup 11}C]SNC80 confirmed low brain permeability and uniform regional distribution of this class of opioid agonists in a higher species. Opioid receptor ligands of this structural class are thus unlikely to succeed as in vivo radiotracers, likely due to efficient exclusion from the brain by the P-glycoprotein efflux transporter.

  4. In vivo measurement of water self diffusion in the human brain by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Thomsen, C; Henriksen, O; Ring, P

    1987-01-01

    coefficient of water with different temperatures. This phantom study showed that the water self diffusion could be measured accurately and that the inplane deviation was less than +/- 10 per cent. Seven healthy volunteers were studied with a 10 mm thick slice through the lateral ventricles, clear differences......A new pulse sequence for in vivo diffusion measurements by magnetic resonance imaging (MRI) is introduced. The pulse sequence was tested on phantoms to evaluate the accuracy, reproducibility and inplane variations. The sensitivity of the sequence was tested by measuring the self diffusion...... intracranial hypertension. The results indicate that brain water self diffusion can be measured in vivo with reasonable accuracy. The clinical examples suggest that diffusion measurements may be clinically useful adding further information about in vivo MR tissue characterization....

  5. Segmentation of brain tumor images using in vivo spectroscopy, relaxometry and diffusometry by magnetic resonance

    Energy Technology Data Exchange (ETDEWEB)

    Martin L, M. [Universidad Central de Venezuela, A.P. 47586, Caracas 1041-A (Venezuela)

    2006-07-01

    A new methodology is developed for the segmentation of brain tumor images using information obtained by different magnetic resonance techniques such as in vivo spectroscopy, relaxometry and diffusometry. In vivo spectroscopy is used as a sort of virtual biopsy to characterize the different tissue types present in the lesion (active tumor, necrotic tissue or edema and normal or non-affected tissue). Due to the fact that in vivo spectroscopy information lacks the spatial resolution for treatment considerations, this information has to be combined or fused with images obtained by relaxometry and diffusometry with excellent spatial resolution. Some segmentation schemes are presented and discussed, using the high spatial resolution techniques individually or combined. The results show that segmentation done in this way is highly reliable for the application of future therapies such as radiosurgery or radiotherapy. (Author)

  6. Engagement in Occupations: a narrative study involving individuals who have a brain injury

    DEFF Research Database (Denmark)

    Andersen, Lone Elisabeth

    2012-01-01

    gathered from repeated narrative interview and direct observations in combination with fieldnotes. DATA PROCESSING AND ANALYSIS The analysis of data was based on an interpretative hermeneutical tradition. FINDINGS The findings show that all participants have experienced an occupational change. A complexity......'s health and sense of well-being, but there are also several barriers of patient engagement, that can result in occupational imbalance, and withdrawal from occupations. SETTING OF THE RESEARCH Occupational narratives were gathered from three participants in their own context. DATA GATHERING Data were...... engaged in occupation. Facilitating occupational engagement was connected to well-known occupations and the importance of structure, and being in familiar and supportive environments. This study shows indentified plots from experiences, and is built upon narrative theory to advance our understanding...

  7. Evidence for the in vivo polymerization of ependymin: a brain extracellular glycoprotein.

    Science.gov (United States)

    Shashoua, V E; Hesse, G W; Milinazzo, B

    1990-07-09

    Ependymin, a glycoprotein of the brain extracellular fluid, has been implicated in synaptic changes associated with the consolidation process of long-term memory formation and the activity-dependent sharpening of connections of regenerating optic nerve. In vitro experiments have demonstrated that ependymin has the capacity to form fibrous insoluble polymers (FIP) when the solvent Ca2+ concentration is reduced by the addition of EGTA. Such products, once formed, do not dissolve in 2% sodium dodecyl sulfate (SDS) in 5 M urea. This property was used to develop a method for isolating brain FIP. A reproducible quantity of FIP was found in goldfish and mouse brain. This was highly concentrated in the synaptosomal fraction and had identical immunoreactivity properties to FIP obtained by the polymerization of pure ependymin in vitro as well as a cross-reactivity to other protein components of the extracellular matrix such as fibronectin and laminin. Labeling studies with [35S]methionine showed that labeled FIP aggregates are synthesized in vivo and become associated with the synaptosomal fraction. A comparison of the amino acid sequence of ependymin with those for proteins of the extracellular matrix indicated that common sequences 5-6 amino acids long exist in the molecules. These homologies may explain why antibodies to fibronectin, laminin and tubulin can recognize the FIP prepared from pure ependymin. These results suggest that ependymin can polymerize in vivo to form FIP aggregates which have similar immunoreactivity properties to major components of the brain extracellular matrix.

  8. In vivo synthesis of phosphatidylcholine in rat brain via the phospholipid methylation pathway

    Science.gov (United States)

    Lakher, Michael; Wurtman, Richard J.

    1987-01-01

    The in vivo synthesis of brain phosphatidylcholine (PC) by the methylation of phosphatidylethanolamine (PE) was examined. (H-3)methyl)methionine was infused i.c.v., by indwelling cannula, and brain samples were taken 0.5-18 h thereafter and assayed for (H-3)PC, as well as for its biosynthetic intermediates (H-3)phosphatidyl monomethylethanolamine ((H-3)PMME) and (H-3)phosphatidyl dimethylethanolamine ((H-3)PDME), and for (H-3)lysophosphatidylcholine ((H-3)LPC) and S-(H-3)adenosylmethionine ((H-3)SAM). Most of the (H-3)PC (79-94 percent) was present ipsilateral to the infusion site; indicating that the radioactivity in the (H-3)PC was primarily of intracerebral origin, and not taken up from the blood. Moreover, only very low levels of (H-3)PC were attained in brains of animals receiving (H-3)methionine i.p. and these levels were symmetrically distributed. (H-3)PMME and (H-3)PDME turned over with apparent half-lives of 2.2 h and 2.4 h. In contrast, the accumulation of brain (H-3)PC was biphasic, suggesting the existence of two pools, the more labile of which turned over rapidly (t(sub 1/2) = 5 h) and was formed for as long as (H-3)PMME and (H-3)PDME are present in the brain, and another, which was distinguishable only at 18 h after the (H-3)methionine infusion. (The latter pool may have been synthesized from (H-3)choline that was released via the hydrolysis of some of the brain (H-3)PC previously formed by the methylation of PE.) Subcellular fractionation of brain tissue obtained after in vivo labelling with (H-3)methionine revealed that mitochondrial PC had the highest specific radioactivity (dpm per micromol total lipid phosphorus), and myelin the least. These observations affirm that rat brain does synthesize PC in vivo by methylating PE, and the technique provides an experimental system which may be useful for examining the physiological regulation of this process.

  9. In vivo modeling and molecular characterization: a path towards targeted therapy of melanoma brain metastasis

    Directory of Open Access Journals (Sweden)

    Avital eGaziel-Sovran

    2013-05-01

    Full Text Available Brain metastasis from melanoma remains mostly incurable and the main cause of death from the disease. Early stage clinical trials and case studies show some promise for targeted therapies in the treatment of melanoma brain metastasis. However, the progression-free survival for currently available therapies, although significantly improved, is still very short. The development of new potent agents to eradicate melanoma brain metastasis relies on the elucidation of the molecular mechanisms that drive melanoma cells to reach and colonize the brain. The discovery of such mechanisms depends heavily on pre-clinical models that enable the testing of candidate factors and therapeutic agents in vivo. In this review we summarize the effects of available targeted therapies on melanoma brain metastasis in the clinic. We provide an overview of existing pre-clinical models to study the disease and discuss specific molecules and mechanisms reported to modulate different aspects of melanoma brain metastasis and finally, by integrating both clinical and basic data, we summarize both opportunities and challenges currently presented to researchers in the field.

  10. Radiotracers for the in vivo PET imagine of acetylcholinesterase in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, M.R.; Snyder, S.E.; Nguyen, T.; Koeppe, R.A.; Frey, K.A.; Kuhl, D.E. [University of Michigan Medical School, An Arbor (United States). Division of Nuclear Medicine

    1997-10-01

    Regional brain pharmacokinetics of the piperidinyl esters have been determined in the primate brain, using Positron Emission Tomographic (PET) imaging. The propionate ester shows a faster and more complete rate of hydrolysis in regions of AChE, such as the striatum and the cortex. Regional hydrolysis rates (combined forward rate constants, k3) for these radiotracers can be calculated using a simplified analysis of tissue-time activity curves, without a need for determining metabolite-corrected plasma levels. In the striatum of the monkey, the propionate ester shows a reaction rate with the enzyme that is almost two-fold faster than the isobutyrate ester. These radiolabeled esters form a new approach to the measurement of in vivo function of AChE in the mammalian brain, including humans, and provide a method to assess changes in such enzyme activity as a result of disease or pharmacological intervention 10 refs., 5 figs.

  11. Nerve level traumatic brain injury in in vivo/in vitro experiments.

    Science.gov (United States)

    Matsui, Yasuhiro; Nishimoto, Tetsuya

    2010-11-01

    The number of traffic deaths in Japan was 4,914 in 2009. Since the head was the most common site of injury in traffic accidents (2,302, 47%), traumatic brain injury causes the fatalities in these accidents. The aim of the present study was to quantify micro injuries in the animal brain for gaining insight and understanding of the human brain injury tolerance. Using porcine brain matter, in vitro stress relaxation experiments and in vivo impact experiments were conducted. In both experiments, the distribution of the damage ratio of the transverse to longitudinal length of cells, hereafter, referred to as an aspect ratio, in the brain matter under loading was examined. In the in vitro stress relaxation experiments, specimens were compressed vertically with a compression velocity of 1 mm/s, and the displacement was held for 140 sec when the compression strain reached the target strain. In the experiments, there were five categories of compression strain: 10, 20, 30, 40, and 50 percent. Regarding the aspect ratio of the cell body, it was 1.5 or less in a no-load condition. On the other hand, it was observed to be greater than 1.5 in the results from the experiments if the compression strain was 30% or more. The results from the experiments show that a compression strain between 20% and 30% corresponds to the threshold for the extremely deformed cell at the micro level. In the in vivo impact experiments, pigs in an unconscious state were exposed through craniotomy, and their exposed brains were hit with a ram at a low speed of 3.3 m/s and a high speed of 7.2 m/s, respectively. It was revealed that the number of cells in which the aspect ratio was greater than 1.5 increased if the impact is provided under the high speed. At the same time, the results indicated that cell deformation was dependent on the ram velocity in the brain matter. Thus, the compression strain on the entire brain from the direction of the force applied to the brain may be one criterion for assessment

  12. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

    Science.gov (United States)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

    2017-01-04

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein synthesis

  13. Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study.

    Science.gov (United States)

    Coughlin, Jennifer M; Wang, Yuchuan; Munro, Cynthia A; Ma, Shuangchao; Yue, Chen; Chen, Shaojie; Airan, Raag; Kim, Pearl K; Adams, Ashley V; Garcia, Cinthya; Higgs, Cecilia; Sair, Haris I; Sawa, Akira; Smith, Gwenn; Lyketsos, Constantine G; Caffo, Brian; Kassiou, Michael; Guilarte, Tomas R; Pomper, Martin G

    2015-02-01

    There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to

  14. In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, John, E-mail: jmweaver@salud.unm.edu [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Yang, Yirong [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Purvis, Rebecca [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Weatherwax, Theodore [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Rosen, Gerald M. [Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201 (United States); Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201 (United States); Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Liu, Ke Jian [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)

    2014-03-01

    Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O{sub 2} may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O{sub 2} is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO{sub 2}in vivo remains largely uncharacterized. This study investigated striatal tissue pO{sub 2} changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO{sub 2}in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO{sub 2} was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO{sub 2} to 64%. More importantly, pO{sub 2} did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO{sub 2} indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO{sub 2}, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. - Highlights: • Explored striatal tissue pO{sub 2}in vivo after METH administration by EPR oximetry. • pO{sub 2} was reduced by 81% after a single dose and 64% after 3 consecutive daily doses. • pO{sub 2} did not recover fully to control levels even 24 h after a single dose. • Decrease in brain tissue pO{sub 2} may be associated with a decrease in

  15. In vivo rat deep brain imaging using photoacoustic computed tomography (Conference Presentation)

    Science.gov (United States)

    Lin, Li; Li, Lei; Zhu, Liren; Hu, Peng; Wang, Lihong V.

    2017-03-01

    The brain has been likened to a great stretch of unknown territory consisting of a number of unexplored continents. Small animal brain imaging plays an important role charting that territory. By using 1064 nm illumination from the side, we imaged the full coronal depth of rat brains in vivo. The experiment was performed using a real-time full-ring-array photoacoustic computed tomography (PACT) imaging system, which achieved an imaging depth of 11 mm and a 100 μm radial resolution. Because of the fast imaging speed of the full-ring-array PACT system, no animal motion artifact was induced. The frame rate of the system was limited by the laser repetition rate (50 Hz). In addition to anatomical imaging of the blood vessels in the brain, we continuously monitored correlations between the two brain hemispheres in one of the coronal planes. The resting states in the coronal plane were measured before and after stroke ligation surgery at a neck artery.

  16. Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging

    Directory of Open Access Journals (Sweden)

    Isabella Manni

    2016-12-01

    Full Text Available Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction.

  17. Simultaneous in vivo recording of local brain temperature and electrophysiological signals with a novel neural probe

    Science.gov (United States)

    Fekete, Z.; Csernai, M.; Kocsis, K.; Horváth, Á. C.; Pongrácz, A.; Barthó, P.

    2017-06-01

    Objective. Temperature is an important factor for neural function both in normal and pathological states, nevertheless, simultaneous monitoring of local brain temperature and neuronal activity has not yet been undertaken. Approach. In our work, we propose an implantable, calibrated multimodal biosensor that facilitates the complex investigation of thermal changes in both cortical and deep brain regions, which records multiunit activity of neuronal populations in mice. The fabricated neural probe contains four electrical recording sites and a platinum temperature sensor filament integrated on the same probe shaft within a distance of 30 µm from the closest recording site. The feasibility of the simultaneous functionality is presented in in vivo studies. The probe was tested in the thalamus of anesthetized mice while manipulating the core temperature of the animals. Main results. We obtained multiunit and local field recordings along with measurement of local brain temperature with accuracy of 0.14 °C. Brain temperature generally followed core body temperature, but also showed superimposed fluctuations corresponding to epochs of increased local neural activity. With the application of higher currents, we increased the local temperature by several degrees without observable tissue damage between 34-39 °C. Significance. The proposed multifunctional tool is envisioned to broaden our knowledge on the role of the thermal modulation of neuronal activity in both cortical and deeper brain regions.

  18. A ranking of diffusion MRI compartment models with in vivo human brain data

    Science.gov (United States)

    Ferizi, Uran; Schneider, Torben; Panagiotaki, Eleftheria; Nedjati-Gilani, Gemma; Zhang, Hui; Wheeler-Kingshott, Claudia A M; Alexander, Daniel C

    2014-01-01

    Purpose Diffusion magnetic resonance imaging (MRI) microstructure imaging provides a unique noninvasive probe into tissue microstructure. The technique relies on biophysically motivated mathematical models, relating microscopic tissue features to the magnetic resonance (MR) signal. This work aims to determine which compartment models of diffusion MRI are best at describing measurements from in vivo human brain white matter. Methods Recent work shows that three compartment models, designed to capture intra-axonal, extracellular, and isotropically restricted diffusion, best explain multi-b-value data sets from fixed rat corpus callosum. We extend this investigation to in vivo by using a live human subject on a clinical scanner. The analysis compares models of one, two, and three compartments and ranks their ability to explain the measured data. We enhance the original methodology to further evaluate the stability of the ranking. Results As with fixed tissue, three compartment models explain the data best. However, a clearer hierarchical structure and simpler models emerge. We also find that splitting the scanning into shorter sessions has little effect on the ranking of models, and that the results are broadly reproducible across sessions. Conclusion Three compartments are required to explain diffusion MR measurements from in vivo corpus callosum, which informs the choice of model for microstructure imaging applications in the brain. Magn Reson Med 72:1785–1792, 2014. © 2013 The authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance. PMID:24347370

  19. In vivo 1H spectroscopy of the human brain at 1.5 tesla. Preliminary experience at a clinical installation

    DEFF Research Database (Denmark)

    Henriksen, O; Larsson, H; Jensen, K M

    1990-01-01

    In vivo localized water suppressed proton spectroscopy of human brain was carried out on 15 healthy volunteers and 2 patients suffering from a brain tumour and an infarction, respectively. The measurements were performed on a whole body MR system, operating at 1.5 tesla using the stimulated echo...

  20. In vivo optoacoustic monitoring of calcium activity in the brain (Conference Presentation)

    Science.gov (United States)

    Deán-Ben, Xose Luís.; Gottschalk, Sven; Sela, Gali; Lauri, Antonella; Kneipp, Moritz; Ntziachristos, Vasilis; Westmeyer, Gil G.; Shoham, Shy; Razansky, Daniel

    2017-03-01

    Non-invasive observation of spatio-temporal neural activity of large neural populations distributed over the entire brain of complex organisms is a longstanding goal of neuroscience [1,2]. Recently, genetically encoded calcium indicators (GECIs) have revolutionized neuroimaging by enabling mapping the activity of entire neuronal populations in vivo [3]. Visualization of these powerful sensors with fluorescence microscopy has however been limited to superficial regions while deep brain areas have so far remained unreachable [4]. We have developed a volumetric multispectral optoacoustic tomography platform for imaging neural activation deep in scattering brains [5]. The developed methodology can render 100 volumetric frames per second across scalable fields of view ranging between 50-1000 mm3 with respective spatial resolution of 35-150µm. Experiments performed in immobilized and freely swimming larvae and in adult zebrafish brains expressing the genetically-encoded calcium indicator GCaMP5G demonstrated, for the first time, the fundamental ability to directly track neural dynamics using optoacoustics while overcoming the depth barrier of optical imaging in scattering brains [6]. It was further possible to monitor calcium transients in a scattering brain of a living adult transgenic zebrafish expressing GCaMP5G calcium indicator [7]. Fast changes in optoacoustic traces associated to GCaMP5G activity were detectable in the presence of other strongly absorbing endogenous chromophores, such as hemoglobin. The results indicate that the optoacoustic signal traces generally follow the GCaMP5G fluorescence dynamics and further enable overcoming the longstanding optical-diffusion penetration barrier associated to scattering in biological tissues [6]. The new functional optoacoustic neuroimaging method can visualize neural activity at penetration depths and spatio-temporal resolution scales not covered with the existing neuroimaging techniques. Thus, in addition to the well

  1. Brain tumor evaluation and segmentation by in vivo proton spectroscopy and relaxometry.

    Science.gov (United States)

    Martín-Landrove, Miguel; Mayobre, Finita; Bautista, Igor; Villalta, Raúl

    2005-12-01

    A new methodology has been developed for the evaluation and segmentation of brain tumors using information obtained by different magnetic resonance techniques such as in vivo proton magnetic resonance spectroscopy (1HMRS) and relaxometry. In vivo 1HMRS may be used as a preoperative technique that allows noninvasive monitoring of metabolites to identify the different tissue types present in the lesion (active tumor, necrotic tissue, edema, and normal or non-affected tissue). Spatial resolution for treatment consideration may be improved by using 1HMRS combined or fused with images obtained by relaxometry which exhibit excellent spatial resolution. Some segmentation schemes are presented and discussed. The results show that segmentation performed in this way efficiently determines the spatial localization of the tumor both qualitatively and quantitatively. It provides appropriate information for therapy planning and application of therapies such as radiosurgery or radiotherapy and future control of patient evolution.

  2. In vivo quantitation of metabolite concentrations in the brain by means of proton MRS

    DEFF Research Database (Denmark)

    Henriksen, O

    1995-01-01

    MRS offers unique possibilities for non-invasive studies of biochemistry in the human brain in vivo. A growing body of evidence suggests that proton MRS may contribute to the clinical evaluation of a number of pathologies including ischaemia, tumours, epilepsy, metabolic and neuropaediatric......, selection efficiency, outer volume depression and signal contamination is essential for validation of the measurements. Furthermore, corrections for the influence of relaxation behavior are necessary. The results published so far indicate that the concentrations of NAA, total creatine, Cho and Ins in mmoles...

  3. Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

    Science.gov (United States)

    Moriguchi, Sho; Takano, Harumasa; Kimura, Yasuyuki; Nagashima, Tomohisa; Takahata, Keisuke; Kubota, Manabu; Kitamura, Soichiro; Ishii, Tatsuya; Ichise, Masanori; Zhang, Ming-Rong; Shimada, Hitoshi; Mimura, Masaru; Meyer, Jeffrey H; Higuchi, Makoto; Suhara, Tetsuya

    2017-12-01

    The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine. We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan. Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL. Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2.

  4. In vivo transcranial measurement of light scattering in rat brains during hypoxia

    Science.gov (United States)

    Kawauchi, Satoko; Sato, Shunichi; Uozumi, Yoichi; Nawashiro, Hiroshi; Ishihara, Miya; Kikuchi, Makoto

    2009-02-01

    Measurement of intrinsic optical signals (IOSs) is attractive for noninvasive, real-time monitoring of tissue viability in brains. We previously performed measurement of IOSs for a rat global ischemic brain model that was made by rapidly removing blood by saline infusion, and observed that after an induction of ischemia, a unique triphasic change in light scattering occurred. This scattering change preceded the reduction of CuA in cytochrome c oxidase which has been shown to correlate with cerebral ATP decrease. In the present study, we examined whether such triphasic scattering change can be observed in the presence of blood in vivo. Transcranial measurement of diffuse reflectance was performed using a broadband tungsten lamp for a rat brain during hypoxia that was induced by N2 inhalation. The reflectance spectral changes in the visible (500-600 nm) and near-infrared (NIR) (650-850 nm) regions were analyzed to monitor changes in hemodynamics and light scattering, respectively. After starting N2 inhalation, reflectance signals in the visible region showed an increase in deoxy-hemoglobin concentration, and about 80 s after full deoxygenation of hemoglobins, reflectance signals in the NIR region showed a similar triphasic change, which was attributable to change in light scattering. Simultaneous measurement of cerebral EEG showed that neuronal activity ceased about 50 s before this triphasic scattering change. These results show that light scattering will become an important indicator of loss of tissue viability in brain; brain tissue can probably be saved if reoxygenation is achieved before starting this scattering change.

  5. Is brain uptake of leptin in vivo saturable and reduced by fasting?

    Energy Technology Data Exchange (ETDEWEB)

    Karonen, S.L.; Nikkinen, P. [Department of Clinical Chemistry, Helsinki University Central Hospital, FIN-00290 Helsinki (Finland); Koistinen, H.A.; Koivisto, V.A. [Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki (Finland)

    1998-06-01

    Leptin is a peptide hormone produced by adipocytes which provides a negative feedback signal to control the amount of body fat. The action of leptin on food intake and weight loss is thought to be mediated by interaction with its hypothalamic receptor. We examined the biodistribution and brain uptake of radioiodinated leptin ({sup 123}I-leptin) by dynamic gamma imaging in six anaesthetized New Zealand white rabbits. Leptin uptake was seen in the brain, lungs, liver and kidneys. In the brain, increase in radioactivity as a function of time was seen in the choroid plexus area. The choroid plexus to brain radioactivity ratio (CP/BR) was used as the target to background ratio. The CP/BR ratio increased up to approximately 40-60 min, after which a steady state in CP/BR was achieved. The steady state uptake ratio was higher in the rabbits that had fasted for only 6-8 h before the experiment (CP/BR approximately 2.5) than in those that had fasted for 25-27 h before the experiment (CP/BR approximately 1.8). Thus, leptin uptake in vivo occurs in the choroid plexus region of the brain and in the lungs, kidney and the liver. The uptake of leptin in the choroid plexus appears to be saturable, as indicated by the achieved steady state in the CP/BR radioactivity curve 40-60 min following {sup 123}I-leptin injection. The lower steady state CP/BR after prolonged fasting may be the result of the downregulation of leptin receptors in the choroid plexus. (orig.) With 4 figs., 36 refs.

  6. Acute treatment with pentobarbital alters the kinetics of in vivo receptor binding in the mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Sakiyama, Yojiro [Division of Clinical Research, National Institute of Radiological Sciences, Inage-ku, Chibashi 263-8555 (Japan)]. E-mail: yojiro.sakiyama@pfizer.com; Saito, Masao [Department of Medical Science, Institute of Medical Electronics, University of Tokyo, Bunkyo-ku, Tokyo 113-0033 (Japan); Inoue, Osamu [Department of Medical Physics, School of Allied Health Science, Faculty of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan)

    2006-05-15

    The effect of pentobarbital, a sedative-hypnotic barbiturate, on the in vivo binding of benzodiazepine receptors in the mouse brain was investigated. Dose-related changes in the apparent binding of [{sup 3}H]Ro15-1788 ([{sup 3}H]flumazenil) in the cerebral cortex, cerebellum and pons-medulla were observed by pretreatment with pentobarbital. For quantification of the kinetic properties of the in vivo binding of [{sup 3}H]Ro15-1788, time courses of radioactivity following its injection were examined, and kinetic analysis was performed using the compartment model. The time courses of radioactivity following injection of [{sup 3}H]Ro15-1788 with 3 mg/kg Ro15-1788 were used as input function. In all regions studied, rate constants between input compartment and specific binding compartment were significantly decreased by pentobarbital. However, no significant alterations in the binding potential (BP=K {sub 3}/K {sub 4}) of benzodiazepine receptors by pentobarbital were observed in any of the regions. A saturation experiment indicated that the decrease in the input rate constant (K {sub 3}), which includes both the association rate constant (k {sub on}) and the number of binding sites available (B {sub max}), was mainly due to decrease in k {sub on}. These results suggest that apparent increases in binding at 20 min after tracer injection were due to the decrease in the association and dissociation rates of binding in vivo.

  7. In vivo chlorine and sodium MRI of rat brain at 21.1 T

    Science.gov (United States)

    Elumalai, Malathy; Kitchen, Jason A.; Qian, Chunqi; Gor’kov, Peter L.; Brey, William W.

    2017-01-01

    Object MR imaging of low-gamma nuclei at the ultrahigh magnetic field of 21.1 T provides a new opportunity for understanding a variety of biological processes. Among these, chlorine and sodium are attracting attention for their involvement in brain function and cancer development. Materials and methods MRI of 35Cl and 23Na were performed and relaxation times were measured in vivo in normal rat (n = 3) and in rat with glioma (n = 3) at 21.1 T. The concentrations of both nuclei were evaluated using the center-out back-projection method. Results T1 relaxation curve of chlorine in normal rat head was fitted by bi-exponential function (T1a = 4.8 ms (0.7) T1b = 24.4 ± 7 ms (0.3) and compared with sodium (T1 = 41.4 ms). Free induction decays (FID) of chlorine and sodium in vivo were bi-exponential with similar rapidly decaying components of T2a∗=0.4 ms and T2a∗=0.53 ms, respectively. Effects of small acquisition matrix and bi-exponential FIDs were assessed for quantification of chlorine (33.2 mM) and sodium (44.4 mM) in rat brain. Conclusion The study modeled a dramatic effect of the bi-exponential decay on MRI results. The revealed increased chlorine concentration in glioma (~1.5 times) relative to a normal brain correlates with the hypothesis asserting the importance of chlorine for tumor progression. PMID:23748497

  8. Linking Binge Alcohol-Induced Neurodamage to Brain Edema and Potential Aquaporin-4 Upregulation: Evidence in Rat Organotypic Brain Slice Cultures and In Vivo

    OpenAIRE

    Sripathirathan, Kumar; Brown, James; Neafsey, Edward J.; Collins, Michael A.

    2009-01-01

    Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol–dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can...

  9. The Brain In Vivo Expresses the 2′,3′-cAMP-Adenosine Pathway

    Science.gov (United States)

    Verrier, Jonathan D.; Jackson, Travis C.; Bansal, Rashmi; Kochanek, Patrick M.; Puccio, Ava M.; Okonkwo, David O.; Jackson, Edwin K.

    2012-01-01

    Although multiple biochemical pathways produce adenosine, studies suggest that the 2′,3′-cAMP-adenosine pathway (2′,3′-cAMP → 2′-AMP/3′-AMP → adenosine) contributes to adenosine production in some cells/tissues/organs. To determine whether the 2′,3′-cAMP-adenosine pathway exists in vivo in the brain, we delivered to the brain (gray matter and white matter separately) via the inflow perfusate of a microdialysis probe either 2′,3′-cAMP, 3′,5′-cAMP, 2′-AMP, 3′-AMP, or 5′-AMP and measured the recovered metabolites in the microdialysis outflow perfusate with mass spectrometry. In both gray and white matter, 2′,3′-cAMP increased 2′-AMP, 3′-AMP and adenosine, and 3′,5′-cAMP increased 5′-AMP and adenosine. In both brain regions, 2′-AMP, 3-AMP and 5′-AMP were converted to adenosine. Microdialysis experiments in 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) wild-type mice demonstrated that traumatic brain injury (TBI; controlled cortical impact model) activated the brain 2,3′-cAMP-adenosine pathway; similar experiments in CNPase knockout mice indicated that CNPase was involved in the metabolism of endogenous 2′,3′-cAMP to 2′-AMP and to adenosine. In CSF from TBI patients, 2′,3′-cAMP was significantly increased in the initial 12 hours after injury and strongly correlated with CSF levels of 2′-AMP, 3′-AMP, adenosine and inosine. We conclude that in vivo, 2′,3′-cAMP is converted to 2′-AMP/3′-AMP, and these AMPs are metabolized to adenosine. This pathway exists endogenously in both mice and humans. PMID:22360621

  10. Effect of metal fragments in brain on electrical monitoring: In vitro and in vivo rat studies

    Science.gov (United States)

    Ahmed, A.; Bodo, M.; Armonda, R. A.

    2010-04-01

    Preliminary results showed, measurements by rheoencephalography (REG) very promising as a practical, noninvasive continuous monitoring modality of traumatic brain/blast injuries. As the impact of metal fragments on the REG signal is unknown, we report here results of our study .The in vitro study confirmed that impedance pulse amplitude waves do not change in the presence of metal (needles) placed between electrodes. In vivo studies: rats under anesthesia (10 rats, 101 trials) were measured after implantation of EEG and REG electrodes in the brain. Metal fragments were represented by 18 g needles inserted and removed between EEG and REG electrodes. Data were stored in a PC. EEG recording typically showed amplitude decrease; REG showed transitory amplitude increase after placement of a needle into either hemisphere. Removal of needles caused a decrease in REG amplitude after a transitory increase. The change in REG amplitude statistically was non-significant. Cerebral blood flow (CBF) autoregulation(AR) persisted following placement of metal fragments in rat brain.

  11. Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation.

    Science.gov (United States)

    Huang, Yu; Liu, Anli A; Lafon, Belen; Friedman, Daniel; Dayan, Michael; Wang, Xiuyuan; Bikson, Marom; Doyle, Werner K; Devinsky, Orrin; Parra, Lucas C

    2017-02-07

    Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimated electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.4 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r = 0.89) and depth (r = 0.84) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials.

  12. Viscoelastic power law parameters of in vivo human brain estimated by MR elastography.

    Science.gov (United States)

    Testu, J; McGarry, M D J; Dittmann, F; Weaver, J B; Paulsen, K D; Sack, I; Van Houten, E E W

    2017-10-01

    The noninvasive imaging technique of magnetic resonance elastography (MRE) was used to estimate the power law behavior of the viscoelastic properties of the human brain in vivo. The mechanical properties for four volunteers are investigated using shear waves induced over a frequency range of 10-50Hz to produce a displacement field measured by magnetic resonance motion-encoding gradients. The average storage modulus (μR) reconstructed with non-linear inversion (NLI) increased from approximately 0.95 to 2.58kPa over the 10-50Hz span; the average loss modulus (μI) also increased from 0.29 to 1.25kPa over the range. These increases were modeled by independent power law (PL) relations for μR and μI returning whole brain, group mean exponent values of 0.88 and 1.07 respectively. Investigation of these exponents also showed distinctly different behavior in the region of the cerebral falx compared to other brain structures. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Raman spectroscopic imaging for in vivo detection of cerebral brain metastases.

    Science.gov (United States)

    Kirsch, Matthias; Schackert, Gabriele; Salzer, Reiner; Krafft, Christoph

    2010-10-01

    We report for the first time a proof-of-concept experiment employing Raman spectroscopy to detect intracerebral tumors in vivo by brain surface mapping. Raman spectroscopy is a non-destructive biophotonic method which probes molecular vibrations. It provides a specific fingerprint of the biochemical composition and structure of tissue without using any labels. Here, the Raman system was coupled to a fiber-optic probe. Metastatic brain tumors were induced by injection of murine melanoma cells into the carotid artery of mice, which led to subcortical and cortical tumor growth within 14 days. Before data acquisition, the cortex was exposed by creating a bony window covered by a calcium fluoride window. Spectral contributions were assigned to proteins, lipids, blood, water, bone, and melanin. Based on the spectral information, Raman images enabled the localization of cortical and subcortical tumor cell aggregates with accuracy of roughly 250 μm. This study demonstrates the prospects of Raman spectroscopy as an intravital tool to detect cerebral pathologies and opens the field for biophotonic imaging of the living brain. Future investigations aim to reduce the exposure time from minutes to seconds and improve the lateral resolution.

  14. Real-Time Amperometric Recording of Extracellular H2O2 in the Brain of Immunocompromised Mice: An In Vitro, Ex Vivo and In Vivo Characterisation Study

    Science.gov (United States)

    Reid, Caroline H.; Finnerty, Niall J.

    2017-01-01

    We detail an extensive characterisation study on a previously described dual amperometric H2O2 biosensor consisting of H2O2 detection (blank) and degradation (catalase) electrodes. In vitro investigations demonstrated excellent H2O2 sensitivity and selectivity against the interferent, ascorbic acid. Ex vivo studies were performed to mimic physiological conditions prior to in vivo deployment. Exposure to brain tissue homogenate identified reliable sensitivity and selectivity recordings up to seven days for both blank and catalase electrodes. Furthermore, there was no compromise in pre- and post-implanted catalase electrode sensitivity in ex vivo mouse brain. In vivo investigations performed in anaesthetised mice confirmed the ability of the H2O2 biosensor to detect increases in amperometric current following locally perfused/infused H2O2 and antioxidant inhibitors mercaptosuccinic acid and sodium azide. Subsequent recordings in freely moving mice identified negligible effects of control saline and sodium ascorbate interference injections on amperometric H2O2 current. Furthermore, the stability of the amperometric current was confirmed over a five-day period and analysis of 24-h signal recordings identified the absence of diurnal variations in amperometric current. Collectively, these findings confirm the biosensor current responds in vivo to increasing exogenous and endogenous H2O2 and tentatively supports measurement of H2O2 dynamics in freely moving NOD SCID mice. PMID:28698470

  15. Real-Time Amperometric Recording of Extracellular H₂O₂ in the Brain of Immunocompromised Mice: An In Vitro, Ex Vivo and In Vivo Characterisation Study.

    Science.gov (United States)

    Reid, Caroline H; Finnerty, Niall J

    2017-07-08

    We detail an extensive characterisation study on a previously described dual amperometric H₂O₂ biosensor consisting of H₂O₂ detection (blank) and degradation (catalase) electrodes. In vitro investigations demonstrated excellent H₂O₂ sensitivity and selectivity against the interferent, ascorbic acid. Ex vivo studies were performed to mimic physiological conditions prior to in vivo deployment. Exposure to brain tissue homogenate identified reliable sensitivity and selectivity recordings up to seven days for both blank and catalase electrodes. Furthermore, there was no compromise in pre- and post-implanted catalase electrode sensitivity in ex vivo mouse brain. In vivo investigations performed in anaesthetised mice confirmed the ability of the H₂O₂ biosensor to detect increases in amperometric current following locally perfused/infused H₂O₂ and antioxidant inhibitors mercaptosuccinic acid and sodium azide. Subsequent recordings in freely moving mice identified negligible effects of control saline and sodium ascorbate interference injections on amperometric H₂O₂ current. Furthermore, the stability of the amperometric current was confirmed over a five-day period and analysis of 24-h signal recordings identified the absence of diurnal variations in amperometric current. Collectively, these findings confirm the biosensor current responds in vivo to increasing exogenous and endogenous H₂O₂ and tentatively supports measurement of H₂O₂ dynamics in freely moving NOD SCID mice.

  16. In vivo 1H spectroscopy of the human brain at 1.5 tesla. Preliminary experience at a clinical installation

    DEFF Research Database (Denmark)

    Henriksen, O; Larsson, H; Jensen, K M

    1990-01-01

    technique. Our preliminary results indicate that it is possible to detect a number of metabolites in the brain within a total measurement time of one hour. The dominant peaks in the spectra from healthy volunteers are N-acetyl aspartate, choline and creatine/phosphocreatine. The spectra obtained from......In vivo localized water suppressed proton spectroscopy of human brain was carried out on 15 healthy volunteers and 2 patients suffering from a brain tumour and an infarction, respectively. The measurements were performed on a whole body MR system, operating at 1.5 tesla using the stimulated echo...... the brain tumour and the infarct, respectively, differed very much from those obtained in healthy brain tissue. Our preliminary results indicate that localized proton spectroscopy may contribute to non-invasive brain tumour classification and possibly also to the differentiation between tumours and infarcts...

  17. What Goes into High Educational and Occupational Achievement? Education, Brains, Hard Work, Networks, and Other Factors

    Science.gov (United States)

    Wai, Jonathan; Rindermann, Heiner

    2017-01-01

    There are many factors that go into high educational and occupational achievement, including hard work, motivation, and luck. But how important is talent? Specifically, how likely were global innovators and leaders intellectually talented or gifted when younger? This paper reviews retrospective data on multiple US samples (Total N = 11,745),…

  18. Knowledge of Mild Traumatic Brain Injury: Effects of age, locality, occupation, media and sports participation

    Directory of Open Access Journals (Sweden)

    2015-09-01

    Results: Misconceptions about TBI were reported by participants, irrespective of gender, locality, occupation, or history of sports participation. There were no significant differences in knowledge scores across these demographic groups. In particular, healthcare and education workers did not score any higher than other occupations. At least 40% of respondents answered either incorrectly or “I don’t know” on items related to gender differences, the utility of neuroimaging, and patient insight into their impairments. For those in non-medical, professional occupations, the older they were the less they knew about TBI (r = -.299, p = 0.009. In contrast, a positive correlation (r = 0.268, p = 0.018 was found between age and TBI knowledge for workers in healthcare or education. Conclusions: Misconceptions about TBI are present in Australia and are consistent across genders, localities, occupations and sport participation groups. A concern is that risk for misconceptions is not lower in healthcare or education professions. This suggests that professional development for groups most likely to be the frontline referral resources and supports for head injured children and adults may require further training.

  19. Whole-brain ex-vivo quantitative MRI of the cuprizone mouse model

    Directory of Open Access Journals (Sweden)

    Tobias C. Wood

    2016-11-01

    Full Text Available Myelin is a critical component of the nervous system and a major contributor to contrast in Magnetic Resonance (MR images. However, the precise contribution of myelination to multiple MR modalities is still under debate. The cuprizone mouse is a well-established model of demyelination that has been used in several MR studies, but these have often imaged only a single slice and analysed a small region of interest in the corpus callosum. We imaged and analyzed the whole brain of the cuprizone mouse ex-vivo using high-resolution quantitative MR methods (multi-component relaxometry, Diffusion Tensor Imaging (DTI and morphometry and found changes in multiple regions, including the corpus callosum, cerebellum, thalamus and hippocampus. The presence of inflammation, confirmed with histology, presents difficulties in isolating the sensitivity and specificity of these MR methods to demyelination using this model.

  20. In vivo measurement of water self diffusion in the human brain by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Thomsen, C; Henriksen, O; Ring, P

    1987-01-01

    A new pulse sequence for in vivo diffusion measurements by magnetic resonance imaging (MRI) is introduced. The pulse sequence was tested on phantoms to evaluate the accuracy, reproducibility and inplane variations. The sensitivity of the sequence was tested by measuring the self diffusion...... coefficient of water with different temperatures. This phantom study showed that the water self diffusion could be measured accurately and that the inplane deviation was less than +/- 10 per cent. Seven healthy volunteers were studied with a 10 mm thick slice through the lateral ventricles, clear differences...... between grey and white matter as well as regional differences within the white matter were seen. In two patients with infarction, alternations in water self diffusion were seen in the region of the infarct. Likewise, pronounced changes in brain water self diffusion were observed in a patient with benign...

  1. Design and in vivo evaluation of more efficient and selective deep brain stimulation electrodes

    Science.gov (United States)

    Howell, Bryan; Huynh, Brian; Grill, Warren M.

    2015-08-01

    Objective. Deep brain stimulation (DBS) is an effective treatment for movement disorders and a promising therapy for treating epilepsy and psychiatric disorders. Despite its clinical success, the efficiency and selectivity of DBS can be improved. Our objective was to design electrode geometries that increased the efficiency and selectivity of DBS. Approach. We coupled computational models of electrodes in brain tissue with cable models of axons of passage (AOPs), terminating axons (TAs), and local neurons (LNs); we used engineering optimization to design electrodes for stimulating these neural elements; and the model predictions were tested in vivo. Main results. Compared with the standard electrode used in the Medtronic Model 3387 and 3389 arrays, model-optimized electrodes consumed 45-84% less power. Similar gains in selectivity were evident with the optimized electrodes: 50% of parallel AOPs could be activated while reducing activation of perpendicular AOPs from 44 to 48% with the standard electrode to 0-14% with bipolar designs; 50% of perpendicular AOPs could be activated while reducing activation of parallel AOPs from 53 to 55% with the standard electrode to 1-5% with an array of cathodes; and, 50% of TAs could be activated while reducing activation of AOPs from 43 to 100% with the standard electrode to 2-15% with a distal anode. In vivo, both the geometry and polarity of the electrode had a profound impact on the efficiency and selectivity of stimulation. Significance. Model-based design is a powerful tool that can be used to improve the efficiency and selectivity of DBS electrodes.

  2. In vivo and ex vivo regulation of breast cancer resistant protein (Bcrp) by peroxisome proliferator-activated receptor alpha (Pparα) at the blood-brain barrier.

    Science.gov (United States)

    Hoque, Md Tozammel; Shah, Arpit; More, Vijay; Miller, David S; Bendayan, Reina

    2015-12-01

    Breast cancer resistance protein (Bcrp/Abcg2) localized at the blood-brain barrier (BBB) limits permeability into the brain of many xenobiotics, including pharmacological agents. Peroxisome proliferator-activated receptor α (Pparα), a ligand-activated transcription factor, primarily involved in lipid metabolism, has been shown to regulate the functional expression of Bcrp in human cerebral microvascular endothelial cells (hCMEC/D3). The aim of this study was to investigate ex vivo and in vivo, the regulation of Bcrp by Pparα in an intact BBB. Ex vivo quantitative real-time PCR and immunoblot analyses showed significant up-regulation of Abcg2/Bcrp mRNA and protein levels in CD-1 mouse brain capillaries incubated with clofibrate, a Pparα ligand. Fluorescence-based transport assays in CD-1 and C57BL/6 brain capillaries showed that exposure to clofibrate significantly increased Bcrp transport activity. This increase was not observed in capillaries isolated from Pparα knockout mice. In vivo, we found: i) significant Bcrp protein up-regulation in clofibrate-dosed CD-1 and C57BL/6 capillary lysates, but no effect in Pparα knockout capillary lysates, and ii) significantly increased Bcrp transport activity in capillaries isolated from clofibrate-treated mice. These results demonstrate an increase in Bcrp functional expression by Pparα in brain capillaries, and suggest that Pparα is another nuclear receptor that can contribute to the regulation of membrane efflux transporters and drug permeability at the BBB. We propose the involvement of the following pathways in clofibrate-mediated induction of the drug transporter Abcg2/Bcrp mRNA, protein expression and function by the nuclear receptor Pparα, in mouse brain capillary endothelial cells. Upon activation with clofibrate (Pparα, ligand), Pparα complex translocates from the cytoplasm into the nucleus and further recruits coactivators and transcription machinery which induce the transcription of Abcg2 gene and

  3. Endogenous dopamine (DA) modulates (3H)spiperone binding in vivo in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Bischoff, S.; Krauss, J.; Grunenwald, C.; Gunst, F.; Heinrich, M.; Schaub, M.; Stoecklin, K.V.; Vassout, A.; Waldmeier, P.; Maitre, L. (Research Department, CIBA-GEIGY Ltd., Basel (Switzerland))

    1991-01-01

    (3H)spiperone (SPI) binding in vivo, biochemical parameters and behavior were measured after modulating DA levels by various drug treatments. DA releasers and uptake inhibitors increased SPI binding in rat striatum. In other brain areas, the effects were variable, but only the pituitary remained unaffected. Surprisingly, nomifensine decreased SPI binding in frontal cortex. The effects of these drugs were monitored by measuring DA, serotonin (5-HT) and their metabolites in the same rats. The increased SPI binding in striatum was parallel to the locomotor stimulation with the following rank order: amfonelic acid greater than nomifensine greater than D-amphetamine greater than or equal to methylphenidate greater than amineptine greater than bupropion. Decreasing DA levels with reserpine or alpha-methyl-para-tyrosine reduced SPI binding by 45% in striatum only when both drugs were combined. In contrast, reserpine enhanced SPI binding in pituitary. Thus, the amount of releasable DA seems to modulate SPI binding characteristics. It is suggested that in vivo, DA receptors are submitted to dynamic regulation in response to changes in intrasynaptic concentrations of DA.

  4. A novel bioelectronic tongue in vivo for highly sensitive bitterness detection with brain-machine interface.

    Science.gov (United States)

    Qin, Zhen; Zhang, Bin; Hu, Liang; Zhuang, Liujing; Hu, Ning; Wang, Ping

    2016-04-15

    Animals' gustatory system has been widely acknowledged as one of the most sensitive chemosensing systems, especially for its ability to detect bitterness. Since bitterness usually symbolizes inedibility, the potential to use rodent's gustatory system is investigated to detect bitter compounds. In this work, the extracellular potentials of a group of neurons are recorded by chronically coupling microelectrode array to rat's gustatory cortex with brain-machine interface (BMI) technology. Local field potentials (LFPs), which represent the electrophysiological activity of neural networks, are chosen as target signals due to stable response patterns across trials and are further divided into different oscillations. As a result, different taste qualities yield quality-specific LFPs in time domain which suggests the selectivity of this in vivo bioelectronic tongue. Meanwhile, more quantitative study in frequency domain indicates that the post-stimulation power of beta and low gamma oscillations shows dependence with concentrations of denatonium benzoate, a prototypical bitter compound, and the limit of detection is deduced to be 0.076 μM, which is two orders lower than previous in vitro bioelectronic tongues and conventional electronic tongues. According to the results, this in vivo bioelectronic tongue in combination with BMI presents a promising method in highly sensitive bitterness detection and is supposed to provide new platform in measuring bitterness degree. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Qualitative and quantitative evaluation of in vivo SD-OCT measurement of rat brain.

    Science.gov (United States)

    Xie, Yijing; Harsan, Laura-Adela; Bienert, Thomas; Kirch, Robert D; von Elverfeldt, Dominik; Hofmann, Ulrich G

    2017-02-01

    OCT has been demonstrated as an efficient imaging modality in various biomedical and clinical applications. However, there is a missing link with respect to the source of contrast between OCT and other modern imaging modalities, no quantitative comparison has been demonstrated between them, yet. We evaluated, to our knowledge, for the first time in vivo OCT measurement of rat brain with our previously proposed forward imaging method by both qualitatively and quantitatively correlating OCT with the corresponding T1-weighted and T2-weighted magnetic resonance images, fiber density map (FDM), and two types of histology staining (cresyl violet and acetylcholinesterase AchE), respectively. Brain anatomical structures were identified and compared across OCT, MRI and histology imaging modalities. Noticeable resemblances corresponding to certain anatomical structures were found between OCT and other image profiles. Correlation was quantitatively assessed by estimating correlation coefficient (R) and mutual information (MI). Results show that the 1-D OCT measurements in regards to the intensity profile and estimated attenuation factor, do not have profound linear correlation with the other image modalities suggested from correlation coefficient estimation. However, findings in mutual information analysis demonstrate that there are markedly high MI values in OCT-MRI signals.

  6. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in nonanesthetized rat

    NARCIS (Netherlands)

    Wong, Y.C.; Ilz, aut ikkova T.I.; Wijk, van R.C.; Hartman, R.J.; Lange, de E.C.M.

    2018-01-01

    BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to

  7. ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers.

    Science.gov (United States)

    Davis, Robert E; Vanover, Kimberly E; Zhou, Yun; Brašić, James R; Guevara, Maria; Bisuna, Blanca; Ye, Weiguo; Raymont, Vanessa; Willis, William; Kumar, Anil; Gapasin, Lorena; Goldwater, D Ronald; Mates, Sharon; Wong, Dean F

    2015-08-01

    Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

  8. Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer's disease.

    Science.gov (United States)

    Hook, Vivian; Kindy, Mark; Hook, Gregory

    2007-02-01

    Abnormal accumulation of neurotoxic beta-amyloid peptides (Abeta) in brain represents a key factor in the progression of Alzheimer's disease (AD). Identification of small molecules that effectively reduce brain levels of Abeta is important for development of Abeta-lowering agents for AD. In this study, we demonstrate that in vivo Abeta levels in brain are significantly reduced by the cysteine protease inhibitor E64d and the related CA074Me inhibitor, which inhibits cathepsin B. Direct infusion of these inhibitors into brains of guinea pigs resulted in reduced levels of Abeta by 50-70% after 30 days of treatment. Substantial decreases in Abeta also occurred after only 7 days of inhibitor infusion, with a reduction in both Abeta40 and Abeta42 peptide forms. A prominent decrease in Abeta peptides was observed in brain synaptosomal nerve terminal preparations after CA074Me treatment. Analyses of APP-derived proteolytic fragments showed that CA074Me reduced brain levels of the CTFbeta fragment, and increased amounts of the sAPPalpha fragment. These results suggest that CA074Me inhibits Abeta production by modulating APP processing. Animals appeared healthy after treatment with these inhibitors. These results, showing highly effective in vivo decreases in brain Abeta levels by these cysteine protease inhibitors, indicate the feasibility of using related compounds for lowering Abeta in AD.

  9. Effectiveness of Occupation- and Activity-Based Interventions to Improve Everyday Activities and Social Participation for People With Traumatic Brain Injury: A Systematic Review.

    Science.gov (United States)

    Powell, Janet M; Rich, Timothy J; Wise, Elizabeth K

    2016-01-01

    This systematic review presents research on the effectiveness of occupation- and activity-based interventions to improve everyday activities and areas of occupation and social participation for people with traumatic brain injury (TBI). Nineteen studies identified through a comprehensive database search were reviewed and synthesized into five themes: (1) multidisciplinary and interdisciplinary treatment approaches, (2) community-based rehabilitation programs, (3) treatment approaches using client-centered goals and relevant contexts, (4) social skills training and peer mentoring interventions, and (5) community mobility interventions. Evidence supports the use of multidisciplinary and interdisciplinary approaches across a variety of settings, with no single treatment approach or setting clearly superior to another. The specific contributions of occupational therapy practitioners and the nature of occupational therapy interventions have not been well studied, making it difficult to determine the extent to which occupation- and activity-based interventions provided by occupational therapy practitioners improve occupational performance and social participation after TBI. Copyright © 2016 by the American Occupational Therapy Association, Inc.

  10. Carboplatin loaded Surface modified PLGA nanoparticles: Optimization, characterization, and in vivo brain targeting studies.

    Science.gov (United States)

    Jose, S; Juna, B C; Cinu, T A; Jyoti, H; Aleykutty, N A

    2016-06-01

    The carboplatin (CP) loaded poly-lactide-co-glycolide (PLGA) nanoparticles (NPs) were formulated by modified solvent evaporation method. Its surface modification is done by 1% polysorbate80 (P80) to improve their entry into the brain after intraperitoneal administration (i.p) via receptor-mediated pathways. A formulation with maximum entrapment efficiency and minimal particle size was optimized by central composite design (CCD) based on mean particle size, and entrapment efficiencies as responses. The optimized formulation was characterized by mean particle size, entrapment efficiency, zeta potential, Fourier transform infrared (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) analysis. The surface modified NPs were analysed for mean particle, zeta potential, FTIR, and in vitro release studies. The spherical particles with mean particle size 161.9nm, 162.4nm and zeta potential value of -26.5, -23.9 were obtained for unmodified and surface modified NPs respectively. The in vitro release experiments of the surface modified PLGA NPs exhibited sustained release for more than 48h, which was in accordance with Higuchi's equation with Fickian diffusion-based release mechanism. The in vivo bio distribution of P80 coated CP loaded PLGA NPs was compared with CP solution, and CP loaded NPs, in adult wistar rats. In the brain, compared with CP solution, both types of NPs especially NPs coated with P80 increased the concentration of carboplatin by 3.27 fold. All these results suggest that the developed formulation may improve the targeted therapy for malignant brain tumors in future. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Comley, Robert A

    2009-01-01

    The serotonin 4 receptor (5-HT(4) receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT(4) receptor radioligand, (11)C-SB207145, for in vivo brain imaging with PET in humans. METHODS: For evaluation of reproducibility, 6...... region devoid of specific binding, and that nonspecific binding was constant across brain regions. CONCLUSION: In vivo imaging of cerebral 5-HT(4) receptors can be determined reliably using (11)C-207145 PET with arterial input in humans. SRTM showed high reproducibility and reliability but bias...... reference tissue model (SRTM). RESULTS: (11)C-SB207145 readily entered the brain and showed a distribution consistent with the known localization of the 5-HT(4) receptor. Using plasma input models, the time-activity data were well described by the 2-tissue-compartment model in all regions and allowed...

  12. Using the cognitive orientation to occupational performance (CO-OP) with adults with executive dysfunction following traumatic brain injury.

    Science.gov (United States)

    Dawson, Deirdre R; Gaya, Arvinder; Hunt, Anne; Levine, Brian; Lemsky, Carolyn; Polatajko, Helene J

    2009-04-01

    Meta-cognitive strategies have a positive effect on the rehabilitation of executive dysfunction. However, achieving generalization to daily life remains a challenge. We believe that providing rehabilitation in the person's own physical environment and using self-identified tasks will enhance the benefits of meta-cognitive training and promote generalization. This pilot study tested the applicability of the Cognitive Orientation to Occupational Performance (CO-OP) approach for use with adults with executive dysfunction arising from traumatic brain injury (TBI). A single-case design was used with 3 adults, 5 to 20 years post-TBI and their self-identified significant others. Assessments included neuropsychological tests and the Canadian Occupational Performance Measure. The intervention entailed guiding participants to use a meta-cognitive problem-solving strategy to perform self-identified daily tasks that they needed and wanted to do and with which they were having difficulties. The intervention occurred over 20 one-hour sessions in participants' environments. Performance improved to criterion (2-point positive change) on 7 of 9 trained goals and on 4 of 7 untrained goals (self-report). Improvement was maintained at a 3-month follow-up assessment. The CO-OP approach has the potential to improve performance in daily functioning for adults with executive dysfunction following TBI.

  13. Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo.

    Science.gov (United States)

    Geoghegan, James C; Keiser, Nicholas W; Okulist, Anna; Martins, Inês; Wilson, Matthew S; Davidson, Beverly L

    2014-10-14

    Recently, we described a peptide-modified AAV2 vector (AAV-GMN) containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium.

  14. Chondroitin Sulfate is the Primary Receptor for a Peptide-Modified AAV That Targets Brain Vascular Endothelium In Vivo

    Directory of Open Access Journals (Sweden)

    James C Geoghegan

    2014-01-01

    Full Text Available Recently, we described a peptide-modified AAV2 vector (AAV-GMN containing a capsid-displayed peptide that directs in vivo brain vascular targeting and transduction when delivered intravenously. In this study, we sought to identify the receptor that mediates transduction by AAV-GMN. We found that AAV-GMN, but not AAV2, readily transduces the murine brain endothelial cell line bEnd.3, a result that mirrors previously observed in vivo transduction profiles of brain vasculature. Studies in vitro revealed that the glycosaminoglycan, chondroitin sulfate C, acts as the primary receptor for AAV-GMN. Unlike AAV2, chondroitin sulfate expression is required for cell transduction by AAV-GMN, and soluble chondroitin sulfate C can robustly inhibit AAV-GMN transduction of brain endothelial cells. Interestingly, AAV-GMN retains heparin-binding properties, though in contrast to AAV2, it poorly transduces cells that express heparan sulfate but not chondroitin sulfate, indicating that the peptide insertion negatively impacts heparan-mediated transduction. Lastly, when delivered directly, this modified virus can transduce multiple brain regions, indicating that the potential of AAV-GMN as a therapeutic gene delivery vector for central nervous system disorders is not restricted to brain vascular endothelium.

  15. In vivo field dependence of proton relaxation times in human brain, liver and skeletal muscle: a multicenter study

    DEFF Research Database (Denmark)

    Henriksen, O; de Certaines, J D; Spisni, A

    1993-01-01

    and MRS, the in vivo field dispersion of T1 and T2 has been measured in order to evaluate whether ex vivo data are representative for the in vivo situation. Brain, skeletal muscle, and liver of healthy human volunteers were studied. Fifteen MR units with a field strength ranging from 0.08 T to 1.5 T took......T1 and T2 relaxation times are fundamental parameters for signal contrast behaviour in MRI. A number of ex vivo relaxometry studies have dealt with the magnetic field dispersion of T1. By means of multicenter study within the frame of the COMAC BME Concerted Action on Tissue Characterization by MRI...... part in the trial, which comprised 218 volunteers. All the MR systems were tested for measurement accuracy using the Eurospin TO5 test object. The measured relaxation data were subsequently corrected according to the obtained calibration curves. The results showed a clear field dispersion of T1...

  16. Simultaneous measurement of glucose blood–brain transport constants and metabolic rate in rat brain using in-vivo 1H MRS

    Science.gov (United States)

    Du, Fei; Zhang, Yi; Zhu, Xiao-Hong; Chen, Wei

    2012-01-01

    Cerebral glucose consumption and glucose transport across the blood–brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMRglc) and glucose transport constants (KT: half-saturation constant; Tmax: maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMRglc, KT, and Tmax via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo 1H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMRglc, Tmax, and KT were determined to be 0.44±0.17 μmol/g per minute, 1.35±0.47 μmol/g per minute, and 13.4±6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMRglc and Tmax are more reliable than that of KT. The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. PMID:22714049

  17. In vivo visualization and ex vivo quantification of murine breast cancer cells in the mouse brain using MRI cell tracking and electron paramagnetic resonance.

    Science.gov (United States)

    Danhier, Pierre; Magat, Julie; Levêque, Philippe; De Preter, Géraldine; Porporato, Paolo E; Bouzin, Caroline; Jordan, Bénédicte F; Demeur, Gladys; Haufroid, Vincent; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

    2015-03-01

    Cell tracking could be useful to elucidate fundamental processes of cancer biology such as metastasis. The aim of this study was to visualize, using MRI, and to quantify, using electron paramagnetic resonance (EPR), the entrapment of murine breast cancer cells labeled with superparamagnetic iron oxide particles (SPIOs) in the mouse brain after intracardiac injection. For this purpose, luciferase-expressing murine 4 T1-luc breast cancer cells were labeled with fluorescent Molday ION Rhodamine B SPIOs. Following intracardiac injection, SPIO-labeled 4 T1-luc cells were imaged using multiple gradient-echo sequences. Ex vivo iron oxide quantification in the mouse brain was performed using EPR (9 GHz). The long-term fate of 4 T1-luc cells after injection was characterized using bioluminescence imaging (BLI), brain MRI and immunofluorescence. We observed hypointense spots due to SPIO-labeled cells in the mouse brain 4 h after injection on T2 *-weighted images. Histology studies showed that SPIO-labeled cancer cells were localized within blood vessels shortly after delivery. Ex vivo quantification of SPIOs showed that less than 1% of the injected cells were taken up by the mouse brain after injection. MRI experiments did not reveal the development of macrometastases in the mouse brain several days after injection, but immunofluorescence studies demonstrated that these cells found in the brain established micrometastases. Concerning the metastatic patterns of 4 T1-luc cells, an EPR biodistribution study demonstrated that SPIO-labeled 4 T1-luc cells were also entrapped in the lungs of mice after intracardiac injection. BLI performed 6 days after injection of 4 T1-luc cells showed that this cell line formed macrometastases in the lungs and in the bones. Conclusively, EPR and MRI were found to be complementary for cell tracking applications. MRI cell tracking at 11.7 T allowed sensitive detection of isolated SPIO-labeled cells in the mouse brain, whereas EPR

  18. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery.

    Science.gov (United States)

    Jose, S; Anju, S S; Cinu, T A; Aleykutty, N A; Thomas, S; Souto, E B

    2014-10-20

    Resveratrol is a potent anticancer. However, because of its low half-life (particle size and zeta potential of the optimized formulation (drug-lipid ratio of 1:10) were 248.30 ± 3.80nm and -25.49 ± 0.49mV, respectively. The particle size and the encapsulation efficiency (EE) increased when varying the drug-lipid ratio from 1:5 to 1:15. Scanning electron microscopic (SEM) analysis showed that SLN were spherical in shape and had a smooth surface. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses revealed that the matrix of drug-loaded SLN was in disordered crystalline phase. The in vitro release study in phosphate buffer pH 7.4 followed a sustained release pattern. The drug release data was found to fit best into Higuchi kinetic model suggesting the diffusion controlled mechanism of drug release. The cytotoxicity assay (MAT) showed that SLN were equally effective (P<0.5) as free resveratrol, as an anti-tumor agent. The in vivo biodistribution study using Wistar rats demonstrated that SLN could significantly (P<0.001) increase the brain concentration of resveratrol (17.28 ± 0.6344 μg/g) as compared to free resveratrol (3.45 ± 0.3961 μg/g). The results showed that our resveratrol-loaded SLN serve as promising therapeutic systems to treat neoplastic diseases located in the brain tissue. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. T1-weighted in vivo human whole brain MRI dataset with an ultrahigh isotropic resolution of 250 μm

    Science.gov (United States)

    Lüsebrink, Falk; Sciarra, Alessandro; Mattern, Hendrik; Yakupov, Renat; Speck, Oliver

    2017-03-01

    We present an ultrahigh resolution in vivo human brain magnetic resonance imaging (MRI) dataset. It consists of T1-weighted whole brain anatomical data acquired at 7 Tesla with a nominal isotropic resolution of 250 μm of a single young healthy Caucasian subject and was recorded using prospective motion correction. The raw data amounts to approximately 1.2 TB and was acquired in eight hours total scan time. The resolution of this dataset is far beyond any previously published in vivo structural whole brain dataset. Its potential use is to build an in vivo MR brain atlas. Methods for image reconstruction and image restoration can be improved as the raw data is made available. Pre-processing and segmentation procedures can possibly be enhanced for high magnetic field strength and ultrahigh resolution data. Furthermore, potential resolution induced changes in quantitative data analysis can be assessed, e.g., cortical thickness or volumetric measures, as high quality images with an isotropic resolution of 1 and 0.5 mm of the same subject are included in the repository as well.

  20. Interaction of D-LSD with binding sites in brain: a study in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Ebersole, B.L.J.

    1985-01-01

    The localization of (/sup 3/H)-d-lysergic acid diethylamide ((/sup 3/H)LSD) binding sites in the mouse brain was compared in vivo and in vitro. Radioautography of brain sections incubated with (/sup 3/H)LSD in vitro revealed substantial specific (/sup 3/H)LSD binding in cortical layers III-IV and areas CA1 and dentate gyrus in hippocampus. In contrast, in brain sections from animals that received (/sup 3/H)LSD in vivo, binding in hippocampus was scant and diffuse, although the pattern of labeling in cortex was similar to that seen in vitro. The low specific binding in hippocampus relative to cortex was confirmed by homogenate filtration studies of brain areas from mice that received injections of (/sup 3/H)LSD. Time-course studies established that peak specific binding at ten minutes was the same in cortex and hippocampus. At all times, binding in hippocampus was about one-third of that in cortex; in contrast, the concentration of free (/sup 3/H)LSD did not vary between regions. This finding was unexpected, because binding studies in vitro in membrane preparations indicated that the density and affinity of (/sup 3/H)LSD binding sites were similar in both brain regions. Saturation binding studies in vivo showed that the lower amount of (/sup 3/H)LSD binding in hippocampus was attributable to a lower density of sites labeled by (/sup 3/H)LSD. The pharmacological identify of (/sub 3/H)LSD binding sites in vivo may be relevant to the hallucinogenic properties of LSD and of other related hallucinogens.

  1. Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo

    Directory of Open Access Journals (Sweden)

    Bradley S. Carter

    2013-08-01

    Full Text Available Previous studies have primarily interpreted gene expression regulation by glucocorticoids in the brain in terms of impact on neurons; however, less is known about the corresponding impact of glucocorticoids on glia and specifically astrocytes in vivo. Recent microarray experiments have identified glucocorticoid-sensitive mRNAs in primary astrocyte cell culture, including a number of mRNAs that have reported astrocyte-enriched expression patterns relative to other brain cell types. Here, we have tested whether elevations of glucocorticoids regulate a subset of these mRNAs in vivo following acute and chronic corticosterone exposure in adult mice. Acute corticosterone exposure was achieved by a single injection of 10 mg/kg corticosterone, and tissue samples were harvested two hours post-injection. Chronic corticosterone exposure was achieved by administering 10 mg/mL corticosterone via drinking water for two weeks. Gene expression was then assessed in two brain regions associated with glucocorticoid action (prefrontal cortex and hippocampus by qPCR and by in situ hybridization. The majority of measured mRNAs regulated by glucocorticoids in astrocytes in vitro were similarly regulated by acute and/or chronic glucocorticoid exposure in vivo. In addition, the expression levels for mRNAs regulated in at least one corticosterone exposure condition (acute/chronic demonstrated moderate positive correlation between the two conditions by brain region. In situ hybridization analyses suggest that select mRNAs are regulated by chronic corticosterone exposure specifically in astroctyes based on (1 similar general expression patterns between corticosterone-treated and vehicle-treated animals and (2 similar expression patterns to the pan-astrocyte marker Aldh1l1. Our findings demonstrate that glucocorticoids regulate astrocyte-enriched mRNAs in vivo and suggest that glucocorticoids regulate gene expression in the brain in a cell type-dependent fashion.

  2. Long term ex-vivo culturing of Drosophila brain as a method to live image pupal brains: insights into the cellular mechanisms of neuronal remodeling

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    Dana eRabinovich

    2015-08-01

    Full Text Available Holometabolous insects, including Drosophila melanogaster, undergo complete metamorphosis that includes a pupal stage. During metamorphosis, the Drosophila nervous system undergoes massive remodeling and growth, that include cell death and large-scale axon and synapse elimination as well as neurogenesis, developmental axon regrowth and formation of new connections. Neuronal remodeling is an essential step in the development of vertebrate and invertebrate nervous systems. Research on the stereotypic remodeling of Drosophila mushroom body (MB γ neurons has contributed to our knowledge of the molecular mechanisms of remodeling but our knowledge of the cellular mechanisms remain poorly understood. A major hurdle in understanding various dynamic processes that occur during metamorphosis is the lack of time-lapse resolution. The pupal case and opaque fat bodies that enwrap the central nervous system (CNS make live-imaging of the central brain in-vivo impossible. We have established an ex-vivo long-term brain culture system that supports the development and neuronal remodeling of pupal brains. By optimizing culture conditions and dissection protocols, we have observed development in culture at kinetics similar to what occurs in vivo. Using this new method, we have obtained the first time-lapse sequence of MB γ neurons undergoing remodeling in up to a single cell resolution. We found that axon pruning is initiated by blebbing, followed by one-two nicks that seem to initiate a more widely spread axon fragmentation. As such, we have set up some of the tools and methodologies needed for further exploration of the cellular mechanisms of neuronal remodeling, not limited to the MB. The long-term ex-vivo brain culture system that we report here could be used to study dynamic aspects of neurodevelopment of any Drosophila neuron.

  3. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR.

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    Rui V Simões

    Full Text Available Intrauterine growth restriction (IUGR is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI and spectroscopy (MRS, to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation.IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40-50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i absolute metabolite quantifications, using linear fitting; (ii local temperature estimations, based on the water chemical shift; and (iii classification, using spectral pattern analysis.Lower birth weight was associated with (i smaller brain sizes, (ii slightly lower brain temperatures, and (iii differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA in the cerebral cortex and hippocampus (suggesting neuronal impairment, and higher glycine levels in the striatum (possible marker of brain injury. Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum.IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.

  4. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR).

    Science.gov (United States)

    Simões, Rui V; Muñoz-Moreno, Emma; Carbajo, Rodrigo J; González-Tendero, Anna; Illa, Miriam; Sanz-Cortés, Magdalena; Pineda-Lucena, Antonio; Gratacós, Eduard

    2015-01-01

    Intrauterine growth restriction (IUGR) is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI) and spectroscopy (MRS), to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation. IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40-50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i) absolute metabolite quantifications, using linear fitting; (ii) local temperature estimations, based on the water chemical shift; and (iii) classification, using spectral pattern analysis. Lower birth weight was associated with (i) smaller brain sizes, (ii) slightly lower brain temperatures, and (iii) differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA) in the cerebral cortex and hippocampus (suggesting neuronal impairment), and higher glycine levels in the striatum (possible marker of brain injury). Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum. IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.

  5. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

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    Kuan Zhang

    Full Text Available Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG of the hippocampus and the sub-ventricular zone (SVZ of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCsin vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr and DG (approximately 10 Torr were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr. Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  6. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    Science.gov (United States)

    Zhang, Kuan; Zhou, Yanzhao; Zhao, Tong; Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  7. Simultaneous 3D MR elastography of the in vivo mouse brain

    Science.gov (United States)

    Kearney, Steven P.; Majumdar, Shreyan; Royston, Thomas J.; Klatt, Dieter

    2017-10-01

    The feasibility of sample interval modulation (SLIM) magnetic resonance elastography (MRE) for the in vivo mouse brain is assessed, and an alternative SLIM-MRE encoding method is introduced. In SLIM-MRE, the phase accumulation for each motion direction is encoded simultaneously by varying either the start time of the motion encoding gradient (MEG), SLIM-phase constant (SLIM-PC), or the initial phase of the MEG, SLIM-phase varying (SLIM-PV). SLIM-PC provides gradient moment nulling, but the mutual gradient shift necessitates increased echo time (TE). SLIM-PV requires no increased TE, but exhibits non-uniform flow compensation. Comparison was to conventional MRE using six C57BL/6 mice. For SLIM-PC, the Spearman’s rank correlation to conventional MRE for the shear storage and loss modulus images were 80% and 76%, respectively, and likewise for SLIM-PV, 73% and 69%, respectively. The results of the Wilcoxon rank sum test showed that there were no statistically significant differences between the spatially averaged shear moduli derived from conventional-MRE, SLIM-PC, and SLIM-PV acquisitions. Both SLIM approaches were comparable to conventional MRE scans with Spearman’s rank correlation of 69%-80% and with 3 times reduction in scan time. The SLIM-PC method had the best correlation, and SLIM-PV may be a useful tool in experimental conditions, where both measurement time and T2 relaxation is critical.

  8. Influence of Iron Supplementation on DMT1 (IRE)-induced Transport of Lead by Brain Barrier Systems in vivo.

    Science.gov (United States)

    An, Dai Zhi; Ai, Jun Tao; Fang, Hong Juan; Sun, Ru Bao; Shi, Yun; Wang, Li Li; Wang, Qiang

    2015-09-01

    To investigate the potential involvement of DMT1 (IRE) protein in the brain vascular system in vivo during Pb exposure. Three groups of male Sprague-Dawley rats were exposed to Pb in drinking water, among which two groups were concurrently administered by oral gavage once every other day as the low and high Fe treatment group, respectively, for 6 weeks. At the same time, the group only supplied with high Fe was also set as a reference. The animals were decapitated, then brain capillary-rich fraction was isolate from cerebral cortex. Western blot method was used to identify protein expression, and RT-PCR to detect the change of the mRNA. Pb exposure significantly increased Pb concentrations in cerebral cortex. Low Fe dose significantly reduced the cortex Pb levels, However, high Fe dose increased the cortex Pb levels. Interestingly, changes of DMT1 (IRE) protein in brain capillary-rich fraction were highly related to the Pb level, but those of DMT1 (IRE) mRNA were not significantly different. Moreover, the consistent changes in the levels of p-ERK1/2 or IRP1 with the changes in the levels of DMT1 (IRE). These results suggest that Pb is transported into the brain through DMT1 (IRE), and the ERK MAPK pathway is involved in DMT1 (IRE)-mediated transport regulation in brain vascular system in vivo. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  9. A 24-hour temporal profile of in vivo brain and heart pet imaging reveals a nocturnal peak in brain 18F-fluorodeoxyglucose uptake.

    Directory of Open Access Journals (Sweden)

    Daan R van der Veen

    Full Text Available Using positron emission tomography, we measured in vivo uptake of (18F-fluorodeoxyglucose (FDG in the brain and heart of C57Bl/6 mice at intervals across a 24-hour light-dark cycle. Our data describe a significant, high amplitude rhythm in FDG uptake throughout the whole brain, peaking at the mid-dark phase of the light-dark cycle, which is the active phase for nocturnal mice. Under these conditions, heart FDG uptake did not vary with time of day, but did show biological variation throughout the 24-hour period for measurements within the same mice. FDG uptake was scanned at different times of day within an individual mouse, and also compared to different times of day between individuals, showing both biological and technical reproducibility of the 24-hour pattern in FDG uptake. Regional analysis of brain FDG uptake revealed especially high amplitude rhythms in the olfactory bulb and cortex, while low amplitude rhythms were observed in the amygdala, brain stem and hypothalamus. Low amplitude 24-hour rhythms in regional FDG uptake may be due to multiple rhythms with different phases in a single brain structure, quenching some of the amplitude. Our data show that the whole brain exhibits significant, high amplitude daily variation in glucose uptake in living mice. Reports applying the 2-deoxy-D[(14C]-glucose method for the quantitative determination of the rates of local cerebral glucose utilization indicate only a small number of brain regions exhibiting a day versus night variation in glucose utilization. In contrast, our data show 24-hour patterns in glucose uptake in most of the brain regions examined, including several regions that do not show a difference in glucose utilization. Our data also emphasizes a methodological requirement of controlling for the time of day of scanning FDG uptake in the brain in both clinical and pre-clinical settings, and suggests waveform normalization of FDG measurements at different times of the day.

  10. In vivo assessment of the diaphragm in young male healthy adults: occupation-based activity-related differences

    Directory of Open Access Journals (Sweden)

    Ogugua Augustine Egwu

    2015-01-01

    Full Text Available Introduction : Very little attention has been paid to the thickness of the diaphragm (DT as an important aspect of architecture of the respiratory muscle and the possible effect of occupation-related unregulated physical activity on it. Aim of the research : This study aimed at assessing the effect of occupation-based physical activity on the thickness of the thoracic diaphragm. Material and methods : Eighty (80 males between the ages of 18 and 30 years were recruited for the study and divided into two (2 groups: a control group of forty (40 relatively inactive subjects and a quasi-experimental group of forty (40 peasant labourers. The peasant labourers were recruited from a settlement of local craftsmen and motor-mechanic artisans. B-mode ultrasound was used to measure the thickness of the diaphragm (DT. Results: The mean DT of the quasi-experimental group was higher than that of the control group (p > 0.05 – not significant, even though the control group presented significantly greater weight and body mass index (p < 0.05 than the age-matched Labourers. Conclusions: These findings indicate that occupation-based unregulated physical activity increases DT and may initiate the setting in of diaphragmatic hypertrophy induced by occupation-associated strength and anaerobic training. The findings will also serve as a guidepost in the biomechanical aspects of the muscle during respiration in our sub-Saharan African population.

  11. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Josef Jampilek

    2015-01-01

    Full Text Available The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics, which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  12. Preparation of silica nanoparticles loaded with nootropics and their in vivo permeation through blood-brain barrier.

    Science.gov (United States)

    Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  13. In-vivo imaging of the morphology and blood perfusion of brain tumours in rats with UHR-OCT (Conference Presentation)

    Science.gov (United States)

    Bizheva, Kostadinka; Tan, Bingyao; Fisher, Carl J.; Mason, Erik; Lilge, Lothar D.

    2017-02-01

    Brain tumors are characterized with morphological changes at cellular level such as enlarged, non-spherical nuclei, microcalcifications, cysts, etc., and are highly vascularized. In this study, two research-grade optical coherence tomography (OCT) systems operating at 800 nm and 1060 nm with axial resolution of 0.95 µm and 3.5 µm in biological tissue respectively, were used to image in vivo and ex vivo the structure of brain tumours in rats. Female Fischer 344 rats were used for this study, which has received ethics clearance by the Animal Research Ethics Committees of the University of Waterloo and the University Health Network, Toronto. Brain tumours were induced by injection of rat brain cancer cell line (RG2 glioma) through a small craniotomy. Presence of brain tumours was verified by MRI imaging on day 7 post tumour cells injection. The in vivo OCT imaging session was conducted on day 14 of the study with the 1060 nm OCT system and both morphological OCT, Doppler OCT and OMAG images were acquired from the brain tumour and the surrounding healthy brain tissue. After completion of the imaging procedure, the brains were harvested, fixed in formalin and reimaged after 2 weeks with the 800 nm OCT system. The in vivo and ex vivo OCT morphological images were correlated with H and E histology. Results from this study demonstrate that UHR-OCT can distinguish between healthy and cancerous brain tissue based on differences in structural and vascular pattern.

  14. High Field In Vivo 13C Magnetic Resonance Spectroscopy of Brain by Random Radiofrequency Heteronuclear Decoupling and Data Sampling

    Science.gov (United States)

    Li, Ningzhi; Li, Shizhe; Shen, Jun

    2017-06-01

    In vivo 13C magnetic resonance spectroscopy (MRS) is a unique and effective tool for studying dynamic human brain metabolism and the cycling of neurotransmitters. One of the major technical challenges for in vivo 13C-MRS is the high radio frequency (RF) power necessary for heteronuclear decoupling. In the common practice of in vivo 13C-MRS, alkanyl carbons are detected in the spectra range of 10-65ppm. The amplitude of decoupling pulses has to be significantly greater than the large one-bond 1H-13C scalar coupling (1JCH=125-145 Hz). Two main proton decoupling methods have been developed: broadband stochastic decoupling and coherent composite or adiabatic pulse decoupling (e.g., WALTZ); the latter is widely used because of its efficiency and superb performance under inhomogeneous B1 field. Because the RF power required for proton decoupling increases quadratically with field strength, in vivo 13C-MRS using coherent decoupling is often limited to low magnetic fields (Drug Administration (FDA). Alternately, carboxylic/amide carbons are coupled to protons via weak long-range 1H-13C scalar couplings, which can be decoupled using low RF power broadband stochastic decoupling. Recently, the carboxylic/amide 13C-MRS technique using low power random RF heteronuclear decoupling was safely applied to human brain studies at 7T. Here, we review the two major decoupling methods and the carboxylic/amide 13C-MRS with low power decoupling strategy. Further decreases in RF power deposition by frequency-domain windowing and time-domain random under-sampling are also discussed. Low RF power decoupling opens the possibility of performing in vivo 13C experiments of human brain at very high magnetic fields (such as 11.7T), where signal-to-noise ratio as well as spatial and temporal spectral resolution are more favorable than lower fields.

  15. Mass dose effects and in vivo affinity in brain PET receptor studies--a study of cerebral 5-HT4 receptor binding with [11C]SB207145

    DEFF Research Database (Denmark)

    Madsen, Karine; Marner, Lisbeth; Haahr, Mette

    2011-01-01

    Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity.......Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity....

  16. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

    Directory of Open Access Journals (Sweden)

    Vivek Murthy

    2008-07-01

    Full Text Available Neuromolecular Imaging (NMI with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/ voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc; dopamine (DA, serotonin (5-HT, homovanillic acid (HVA and Ltryptophan (L-TP are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a is an antihypertensive and cocaine and caffeine produce hypertension and (b acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in

  17. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

    Science.gov (United States)

    Broderick, Patricia A; Ho, Helen; Wat, Karyn; Murthy, Vivek

    2008-07-04

    Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE(®) biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/ voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE(®) laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc); dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) and Ltryptophan (L-TP) are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a) is an antihypertensive and cocaine and caffeine produce hypertension and (b) acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a) the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b) ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in NAc and open

  18. Pulsed laser diode photoacoustic tomography (PLD-PAT) system for fast in vivo imaging of small animal brain

    Science.gov (United States)

    Upputuri, Paul Kumar; Kalva, Sandeep Kumar; Moothanchery, Mohesh; Pramanik, Manojit

    2017-03-01

    In recent years, high-repetition rate pulsed laser diode (PLD) was used as an alternative to the Nd:YAG lasers for photoacoustic tomography (PAT). The use of PLD makes the overall PAT system, a low-cost, portable, and high frame rate imaging tool for preclinical applications. In this work, we will present a portable in vivo pulsed laser diode based photoacoustic tomography (PLD-PAT) system. The PLD is integrated inside a circular scanning geometry. The PLD can provide near-infrared ( 803 nm) pulses with pulse duration 136 ns, and pulse energy 1.4 mJ / pulse at 7 kHz repetition rate. The system will be demonstrated for in vivo fast imaging of small animal brain. To enhance the contrast of brain imaging, experiments will be carried out using contrast agents which have strong absorption around laser excitation wavelength. This low-cost, portable small animal brain imaging system could be very useful for brain tumor imaging and therapy.

  19. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Science.gov (United States)

    Hsu, Shu-Hui; Wen, Chih-Jen; Al-Suwayeh, S. A.; Chang, Hui-Wen; Yen, Tzu-Chen; Fang, Jia-You

    2010-10-01

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  20. Is it Possible to Extract Brain Metabolic Pathways Information from In Vivo H Nuclear Magnetic Resonance Spectroscopy Data?

    CERN Document Server

    de Lara, Alejandro Chinea Manrique

    2010-01-01

    In vivo H nuclear magnetic resonance (NMR) spectroscopy is an important tool for performing non-invasive quantitative assessments of brain tumour glucose metabolism. Brain tumours are considered as fast-growth tumours because of their high rate of proliferation. In addition, tumour cells exhibit profound genetic, biochemical and histological differences with respect to the original non-transformed cellular types. Therefore, there is a strong interest from the clinical investigator point of view in understanding the role of brain metabolites in normal and pathological conditions and especially on the development of early tumour detection techniques. Unfortunately, current diagnosis techniques ignore the dynamic aspects of these signals. It is largely believed that temporal variations of NMR Spectra are noisy or just simply do not carry enough information to be exploited by any reliable diagnosis procedure. Thus, current diagnosis procedures are mainly based on empirical observations extracted from single avera...

  1. Differential transgene expression in brain cells in vivo and in vitro from AAV-2 vectors with small transcriptional control units.

    Science.gov (United States)

    Kügler, S; Lingor, P; Schöll, U; Zolotukhin, S; Bähr, M

    2003-06-20

    Adeno-associated- (AAV) based vectors are promising tools for gene therapy applications in several organs, including the brain, but are limited by their small genome size. Two short promoters, the human synapsin 1 gene promoter (hSYN) and the murine cytomegalovirus immediate early promoter (mCMV), were evaluated in bicistronic AAV-2 vectors for their expression profiles in cultured primary brain cells and in the rat brain. Whereas transgene expression from the hSYN promoter was exclusively neuronal, the murine CMV promoter targeted expression mainly to astrocytes in vitro and showed weak transgene expression in vivo in retinal and cortical neurons, but strong expression in thalamic neurons. We propose that neuron specific transgene expression in combination with enhanced transgene capacity will further substantially improve AAV based vector technology.

  2. In vivo bioimpedance measurement of healthy and ischaemic rat brain: implications for stroke imaging using electrical impedance tomography.

    Science.gov (United States)

    Dowrick, T; Blochet, C; Holder, D

    2015-06-01

    In order to facilitate the imaging of haemorrhagic and ischaemic stroke using frequency difference electrical impedance tomography (EIT), impedance measurements of normal and ischaemic brain, and clotted blood during haemorrhage, were gathered using a four-terminal technique in an in vivo animal model, a first for ischaemic measurements. Differences of 5-10% in impedance were seen between the frequency spectrums of healthy and ischaemic brain, over the frequency range 0-3 kHz, while the spectrum of blood was predominately uniform. The implications of imaging blood/ischaemia in the brain using electrical impedance tomography are discussed, supporting the notion that it will be possible to differentiate stroke from haemorrhage.

  3. 3D high spectral and spatial resolution imaging of ex vivo mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Foxley, Sean, E-mail: sean.foxley@ndcn.ox.ac.uk; Karczmar, Gregory S. [Department of Radiology, University of Chicago, Chicago, Illinois 60637 (United States); Domowicz, Miriam [Department of Pediatrics, University of Chicago, Chicago, Illinois 60637 (United States); Schwartz, Nancy [Department of Pediatrics, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637 (United States)

    2015-03-15

    Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T{sub 2}{sup *}-weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3-dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T{sub 2}{sup *} and resonance frequency. Methods: The proton free induction decay was sampled at high resolution and Fourier transformed to produce a high-resolution water spectrum for each image voxel in a 3D volume. Data were acquired using a multigradient echo pulse sequence (i.e., echo-planar spectroscopic imaging) with a spatial resolution of 50 × 50 × 70 μm{sup 3} and spectral resolution of 3.5 Hz. Data were analyzed in the spectral domain, and images were produced from the various Fourier components of the water resonance. This allowed precise measurement of local variations in water resonance frequency and lineshape, at the expense of significantly increased run time (16–24 h). Results: High contrast T{sub 2}{sup *}-weighted images were produced from the peak of the water resonance (peak height image), revealing a high degree of anatomical detail, specifically in the hippocampus and cerebellum. In images produced from Fourier components of the water resonance at −7.0 Hz from the peak, the contrast between deep white matter tracts and the surrounding tissue is the reverse of the contrast in water peak height images. This indicates the presence of a shoulder in

  4. Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study

    NARCIS (Netherlands)

    Wiskerke, J.; Irimia, C.; Cravatt, B.F.; de Vries, T.J.; Schoffelmeer, A.N.M.; Pattij, T.; Parsons, L.H.

    2012-01-01

    The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative

  5. Linking binge alcohol-induced neurodamage to brain edema and potential aquaporin-4 upregulation: evidence in rat organotypic brain slice cultures and in vivo.

    Science.gov (United States)

    Sripathirathan, Kumar; Brown, James; Neafsey, Edward J; Collins, Michael A

    2009-02-11

    Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol-dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can cause oxidative stress through non-edemic pathways has placed edema's role in question. We therefore studied three other diuretics and a related non-diuretic that, according to our oxygen radical antioxidant capacity (ORAC) assays or the literature, possess minimal antioxidant potential. Acetazolamide (ATZ), a carbonic anhydrase inhibitor/diuretic with negligible ORAC effectiveness and, interestingly, an aquaporin-4 (AQP4) water channel inhibitor, prevented alcohol-dependent tissue edema and neurodegeneration in HEC slice cultures. Likewise, in binge alcohol-intoxicated rats, ATZ suppressed brain edema while inhibiting neurodegeneration. Torasemide, a loop diuretic lacking furosemide's ORAC capability, also prevented alcohol-induced neurodamage in HEC slice cultures. However, bumetanide (BUM), a diuretic blocker of Na(+)-K(+)-2Cl(-) channels, and L-644, 711, a nondiuretic anion channel inhibitor--both lacking antioxidant capabilities as well as reportedly ineffective against alcohol-dependent brain damage in vivo--reduced neither alcohol-induced neurotoxicity nor (with BUM) edema in HEC slices. Because an AQP4 blocker (ATZ) was neuroprotective, AQP4 expression in the HEC slices was examined and found to be elevated by binge alcohol. The results further indicate that binge ethanol-induced brain edema/swelling, potentially associated with AQP4 upregulation, may be important in consequent neurodegeneration that could derive from neuroinflammatory processes, for example, membrane

  6. The personal and workplace factors relevant to work readiness evaluation following acquired brain injury: occupational therapists' perceptions.

    Science.gov (United States)

    Stergiou-Kita, Mary; Yantzi, Amber; Wan, Jeffrey

    2010-01-01

    This study examined the personal and workplace/environmental factors perceived most relevant to work readiness evaluations following acquired brain injury. Using a qualitative secondary analysis design 'indicators of success' and 'risks of failure', identified as relevant in a primary study of occupational therapists' evaluation practices, were explored further. Data collected in the primary study, e.g. interviews, practice surveys, evaluation protocols, were re-analysed. Surveys and protocols were used to define participant and practice context characteristics. Interviews were coded, by three investigators, using a constructivist grounded theory approach. Four themes emerged describing relevant personal client attributes: (1) motivation; (2) physical and functional independence; (3) cognitive abilities; and (4) use of compensatory strategies and feedback. Four themes emerged describing relevant workplace factors: (1) workplace demands; (2) employer risks and burden; (3) risks associated with information sharing; and (4) financial implications associated with return to work. Findings suggest that work readiness needs to be viewed as both a client and a workplace issue. Findings are translated into questions for rehabilitation professionals to guide evaluations of work readiness. Recommendations for future research include investigating how professionals weigh factors in their decision-making and exploring strategies relevant from a workplace perspective.

  7. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

    Science.gov (United States)

    Kanegawa, Naoki; Collste, Karin; Forsberg, Anton; Schain, Martin; Arakawa, Ryosuke; Jucaite, Aurelija; Lekander, Mats; Olgart Höglund, Caroline; Kosek, Eva; Lampa, Jon; Halldin, Christer; Farde, Lars; Varrone, Andrea; Cervenka, Simon

    2016-05-01

    Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Recombinant Adeno-Associated Virus-Mediated microRNA Delivery into the Postnatal Mouse Brain Reveals a Role for miR-134 in Dendritogenesis in Vivo

    DEFF Research Database (Denmark)

    Christensen, Mette; Larsen, Lars A; Kauppinen, Sakari

    2010-01-01

    delivery of microRNAs in vivo by use of recombinant adeno-associated virus (rAAV). rAAV-mediated overexpression of miR-134 in neurons of the postnatal mouse brain provided evidence for a negative role of miR-134 in dendritic arborization of cortical layer V pyramidal neurons in vivo, thereby confirming...

  9. Deep-red polymer dots with bright two-photon fluorescence and high biocompatibility for in vivo mouse brain imaging

    Science.gov (United States)

    Alifu, Nuernisha; Sun, Zezhou; Zebibula, Abudureheman; Zhu, Zhenggang; Zhao, Xinyuan; Wu, Changfeng; Wang, Yalun; Qian, Jun

    2017-09-01

    With high contrast and deep penetration, two-photon fluorescence (2PF) imaging has become one of the most promising in vivo fluorescence imaging techniques. To obtain good imaging contrast, fluorescent nanoprobes with good 2PF properties are highly needed. In this work, bright 2PF polymer dots (P dots) were applied for in vivo mouse brain imaging. Deep-red emissive P dots with PFBT as the donor and PFDBT5 as the acceptor were synthesized and used as a contrast agent. P dots were further encapsulated by poly(styrene-co-maleic anhydride) (PSMA) and grafted with poly(ethylene glycol) (PEG). The P dots-PEG exhibit large two-photon absorption (2PA) cross-sections (δ≥8500 g), good water dispersibility, and high biocompatibility. P dots-PEG was further utilized first time for in vivo vascular imaging of mouse ear and brain, under 690-900 nm femtosecond (fs) laser excitation. Due to the large 2PA cross-section and deep-red emission, a large imaging depth ( 720 μm) was achieved.

  10. Cholesterol-PEG comodified poly (N-butyl) cyanoacrylate nanoparticles for brain delivery: in vitro and in vivo evaluations.

    Science.gov (United States)

    Hu, Xiao; Yang, Feifei; Liao, Yonghong; Li, Lin; Zhang, Lan

    2017-11-01

    This study investigated cholesterol-polyethylene glycol (PEG) comodified poly (ethyleneglycol)-poly (lactide) nanoparticles (CLS-PEG NPs) as a novel, biodegradable brain drug delivery system and included an evaluation of its in vitro and in vivo properties. To this end, coumarin-6 (C6), a fluorescent probe, was encapsulated into CLS-PEG NPs by an emulsion polymerization method. We reported that the use of CLS-PEG NPs led to a sustained drug release in vitro. Additionally, cell viability experiments confirmed their safety. The uptake and transport of CLS-PEG NPs, by bEnd.3 cells (an immortalized mouse brain endothelial cell line), was significantly higher than that of a control C6 solution. An investigation of the uptake mechanisms of different NP formulations demonstrated that cholesterol modifications may be the primary way to improve the efficiency of cellular uptake, wherein macropinocytosis may be the most important endocytic pathway in this process. An investigation of the transport mechanisms of CLS-PEG NPs also implicated macropinocytosis, energy and cholesterol in bEnd.3 cells lines. Following an intravenous (IV) administration to rats, pharmacokinetic experiments indicated that C6-loaded CLS-PEG NPs achieved sustained release for up to 12 h. In addition, IV delivery of CLS-PEG NPs appeared to significantly improve the ability of C6 to pass through the blood-brain barrier: the concentration of C6 found in the brain increased nearly 14.2-fold when C6 CLS-PEG NPs were used rather than a C6 solution. These in vitro and in vivo results strongly suggest that CLS-PEG NPs are a promising drug delivery system for targeting the brain, with low toxicity.

  11. In vivo quantification by SPECT of [{sup 123}I] ADAM bound to serotonin transporters in the brains of rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Ye, X.-X. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hsieh, J.-F. [Department of Nuclear Medicine, Chi-Mei Foundation Medical Center, Yungkang City 710, Taiwan (China); Chen, J.-C. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jcchen@ym.edu.tw; Chou, Y.-T. [Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan (China); Tu, K.-Y. [Department of Nuclear Medicine, Mackey Memorial Hospital, Taipei, Taiwan 104 (China); Wey, S.-P. [Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taoyuan, Taiwan 333 (China); Ting Gann [Institute of Nuclear Energy Research, Tao- Yuan 335, Taiwan (China)

    2004-11-01

    Background: A novel radioiodine ligand [{sup 123}I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [{sup 123}I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [{sup 123}I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [{sup 123}I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89{+-}0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [{sup 123}I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with

  12. Quantitative projection of human brain penetration of the H3antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy.

    Science.gov (United States)

    Sawant-Basak, Aarti; Chen, Laigao; Shaffer, Christopher L; Palumbo, Donna; Schmidt, Anne; Tseng, Elaine; Spracklin, Douglas K; Gallezot, Jean-Dominique; Labaree, David; Nabulsi, Nabeel; Huang, Yiyun; Carson, Richard E; McCarthy, Timothy

    2017-02-01

    1. Unbound brain drug concentration (C b,u ), a valid surrogate of interstitial fluid drug concentration (C ISF ), cannot be directly determined in humans, which limits accurately defining the human C b,u :C p,u of investigational molecules. 2. For the H 3 R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated C b,u :C p,u in humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood-brain barrier (BBB) equilibrium (C b,u :C p,u of 2.11). 4. In NHP and humans, the PET receptor occupancy-based C p,u IC 50 of PF-03654746 was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its in vitro human H 3 K i (2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived C b,u :C p,u of PF-03654746 was integrated with C p,u IC 50 to identify unbound (neuro) potency of PF-03654746, nIC 50 . 6. The nIC 50 of PF-03654746 was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with in vitro human H 3 K i (2.3 nM). 7. This correlation of the nIC 50 and in vitro hH 3 K i suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of C p,u as a reliable surrogate of C b,u . 8. Thus, nIC 50 quantitatively informed the human C b,u :C p,u of PF-03654746.

  13. Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

    Science.gov (United States)

    Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

    2015-11-01

    A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

  14. Reflectance-mode interferometric near-infrared spectroscopy quantifies brain absorption, scattering, and blood flow index in vivo.

    Science.gov (United States)

    Borycki, Dawid; Kholiqov, Oybek; Srinivasan, Vivek J

    2017-02-01

    Interferometric near-infrared spectroscopy (iNIRS) is a new technique that measures time-of-flight- (TOF-) resolved autocorrelations in turbid media, enabling simultaneous estimation of optical and dynamical properties. Here, we demonstrate reflectance-mode iNIRS for noninvasive monitoring of a mouse brain in vivo. A method for more precise quantification with less static interference from superficial layers, based on separating static and dynamic components of the optical field autocorrelation, is presented. Absolute values of absorption, reduced scattering, and blood flow index (BFI) are measured, and changes in BFI and absorption are monitored during a hypercapnic challenge. Absorption changes from TOF-resolved iNIRS agree with absorption changes from continuous wave NIRS analysis, based on TOF-integrated light intensity changes, an effective path length, and the modified Beer-Lambert Law. Thus, iNIRS is a promising approach for quantitative and noninvasive monitoring of perfusion and optical properties in vivo.

  15. Monitoring brain development of chick embryos in vivo using 3.0 T MRI: subdivision volume change and preliminary structural quantification using DTI.

    Science.gov (United States)

    Zhou, Zien; Chen, Zengai; Shan, Jiehui; Ma, Weiwei; Li, Lei; Zu, Jinyan; Xu, Jianrong

    2015-07-25

    Magnetic resonance imaging (MRI) has many advantages in the research of in vivo embryonic brain development, specifically its noninvasive aspects and ability to avoid skeletal interference. However, few studies have focused on brain development in chick, which is a traditional animal model in developmental biology. We aimed to serially monitor chick embryo brain development in vivo using 3.0 T MRI. Ten fertile Hy-line white eggs were incubated and seven chick embryo brains were monitored in vivo and analyzed serially from 5 to 20 days during incubation using 3.0 T MRI. A fast positioning sequence was pre-scanned to obtain sagittal and coronal brain planes corresponding to the established atlas. T2-weighted imaging (T2WI) was performed for volume estimation of the whole brain and subdivision (telencephalon, cerebellum, brainstem, and lateral ventricle [LV]); diffusion tensor imaging (DTI) was used to reflect the evolution of neural bundle structures. The chick embryos' whole brain and subdivision grew non-linearly over time; the DTI fractional anisotropy (FA) value within the telencephalon increased non-linearly as well. All seven scanned eggs hatched successfully. MRI avoids embryonic sacrifice in a way that allows serial monitoring of longitudinal developmental processes of a single embryo. Feasibility for analyzing subdivision of the brain during development, and adding structural information related to neural bundles, makes MRI a powerful tool for exploring brain development.

  16. High Field In vivo13C Magnetic Resonance Spectroscopy of Brain by Random Radiofrequency Heteronuclear Decoupling and Data Undersampling

    Directory of Open Access Journals (Sweden)

    Ningzhi Li

    2017-06-01

    Full Text Available In vivo13C magnetic resonance spectroscopy (MRS is a unique and effective tool for studying dynamic human brain metabolism and the cycling of neurotransmitters. One of the major technical challenges for in vivo13C-MRS is the high radio frequency (RF power necessary for heteronuclear decoupling. In the common practice of in vivo13C-MRS, alkanyl carbons are detected in the spectra range of 10–65 ppm. The amplitude of decoupling pulses has to be significantly greater than the large one-bond 1H-13C scalar coupling (1JCH = 125–145 Hz. Two main proton decoupling methods have been developed: broadband stochastic decoupling and coherent composite or adiabatic pulse decoupling (e.g., WALTZ; the latter is widely used because of its efficiency and superb performance under inhomogeneous B1 field. Because the RF power required for proton decoupling increases quadratically with field strength, in vivo13C-MRS using coherent decoupling is often limited to low magnetic fields [<=4 Tesla (T] to keep the local and averaged specific absorption rate (SAR under the safety guidelines established by the International Electrotechnical Commission (IEC and the US Food and Drug Administration (FDA. Alternately, carboxylic/amide carbons are coupled to protons via weak long-range 1H-13C scalar couplings, which can be decoupled using low RF power broadband stochastic decoupling. Recently, the carboxylic/amide 13C-MRS technique using low power random RF heteronuclear decoupling was safely applied to human brain studies at 7T. Here, we review the two major decoupling methods and the carboxylic/amide 13C-MRS with low power decoupling strategy. Further decreases in RF power deposition by frequency-domain windowing and time-domain random under-sampling are also discussed. Low RF power decoupling opens the possibility of performing in vivo13C experiments of human brain at very high magnetic fields (such as 11.7T, where signal-to-noise ratio as well as spatial and temporal

  17. Lab-on-a-brain: Implantable micro-optical fluidic devices for neural cell analysis in vivo

    Science.gov (United States)

    Takehara, Hiroaki; Nagaoka, Akira; Noguchi, Jun; Akagi, Takanori; Kasai, Haruo; Ichiki, Takanori

    2014-10-01

    The high-resolution imaging of neural cells in vivo has brought about great progress in neuroscience research. Here, we report a novel experimental platform, where the intact brain of a living mouse can be studied with the aid of a surgically implanted micro-optical fluidic device; acting as an interface between neurons and the outer world. The newly developed device provides the functions required for the long-term and high-resolution observation of the fine structures of neurons by two-photon laser scanning microscopy and the microfluidic delivery of chemicals or drugs directly into the brain. A proof-of-concept experiment of single-synapse stimulation by two-photon uncaging of caged glutamate and observation of dendritic spine shrinkage over subsequent days demonstrated a promising use for the present technology.

  18. An in vivo study on brain microstructure in biological and chronological ageing

    DEFF Research Database (Denmark)

    Altmann-Schneider, Irmhild; de Craen, Anton J M; van den Berg-Huysmans, Annette A

    2015-01-01

    This study aimed to investigate whether magnetization transfer imaging (MTI) parameters of cortical gray and white matter and subcortical gray matter structures differ between subjects enriched for human familial longevity and control subjects to provide a thorough description of the brain phenot...... years - not characterized by preserved macromolecular brain tissue integrity....

  19. Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema-based mechanism.

    Science.gov (United States)

    Collins, M A; Zou, J Y; Neafsey, E J

    1998-02-01

    Adult rats intubated with a single dose of ethanol (alcohol; approximately 5 g/kg) for 5 to 10 successive days incur neurodegeneration in the entorhinal cortex, dentate gyrus, and olfactory bulbs accompanied by cerebrocortical edema and electrolyte (Na+, K+) accumulation. The brain damage is not lessened by cotreatment with the NMDA receptor antagonist MK-801; also, as reported elsewhere, MK-801 as well as non-NMDA receptor and Ca2+ channel antagonists are not neuroprotective in a similar, but more compressed, intoxication protocol. However, cotreatment with the electrolyte transport inhibitor/diuretic furosemide reduces alcohol-dependent cerebrocortical damage by 75-85% while preventing brain hydration and electrolyte elevations; olfactory bulb neurodegeneration is not attenuated. In parallel in vitro studies, rat organotypic entorhinal/hippocampal slice cultures exposed to alcohol (50-200 mM) 15 h/day for 6 days, mirroring episodic intoxication in vivo, demonstrate concentration-related release of the cytotoxic indicator, lactate dehydrogenase. Analogous to the in vivo findings, furosemide blocks this alcohol-induced in vitro cytotoxicity. Our results showing neuroprotection by furosemide indicate that brain edema and swelling are essential events in the brain damage induced by episodic alcohol exposure. Furosemide and related agents might be useful as neuroprotective agents in alcohol abuse. We suggest that the neurodegeneration is elicited in part by edema-dependent oxidative stress, but the regional selectivity of the damage may be best explained by physical (mechanical) compression of the limbic cortex against the adjacent tympanic bulla and subsequent neuronal cytoskeletal collapse. A scheme for these apparently nonexcitotoxic metabolic and mechanical pathways initiated by repeated alcohol exposure is proposed.

  20. In-vivo measurements of human brain tissue conductivity using focal electrical current injection through intracerebral multicontact electrodes.

    Science.gov (United States)

    Koessler, Laurent; Colnat-Coulbois, Sophie; Cecchin, Thierry; Hofmanis, Janis; Dmochowski, Jacek P; Norcia, Anthony M; Maillard, Louis G

    2017-02-01

    In-vivo measurements of human brain tissue conductivity at body temperature were conducted using focal electrical currents injected through intracerebral multicontact electrodes. A total of 1,421 measurements in 15 epileptic patients (age: 28 ± 10) using a radiofrequency generator (50 kHz current injection) were analyzed. Each contact pair was classified as being from healthy (gray matter, n = 696; white matter, n = 530) or pathological (epileptogenic zone, n = 195) tissue using neuroimaging analysis of the local tissue environment and intracerebral EEG recordings. Brain tissue conductivities were obtained using numerical simulations based on conductivity estimates that accounted for the current flow in the local brain volume around the contact pairs (a cube with a side length of 13 mm). Conductivity values were 0.26 S/m for gray matter and 0.17 S/m for white matter. Healthy gray and white matter had statistically different median impedances (P Brain Mapp 38:974-986, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies

    DEFF Research Database (Denmark)

    Martins, S.; Tho, I.; Reimold, I.

    2012-01-01

    For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabi......For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen...... to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties...... affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed...

  2. In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain

    Directory of Open Access Journals (Sweden)

    Joo Chan-Gyu

    2009-06-01

    Full Text Available Abstract Background In vivo proton magnetic resonance spectroscopy (1H-MRS studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection. Results Changes in the N-acetylaspartate (NAA, choline (Cho, myo-inositol (MI, creatine (Cr and glutamine/glutamate (Glx resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi. At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions. Conclusion These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus.

  3. Docosahexaenoic acid and phosphatidylserine improves the antioxidant activities in vitro and in vivo and cognitive functions of the developing brain.

    Science.gov (United States)

    Chaung, Hso-Chi; Chang, Chin-Dong; Chen, Pi-Hang; Chang, Chia-Jung; Liu, Shyh-Hwa; Chen, Chih-Cheng

    2013-05-01

    Fish oil during early postnatal period may modulate the impact of oxidative stress in the developing brain and thus improve memory and cognitive behaviour. This study investigated the impacts of docosahexaenoic acid (DHA, C22:6, n-3) and/or phosphatidylserine (PS) on antioxidant activities in vitro, and the beneficial effects of feeding with DHA and/or PS on antioxidant activities in brain and liver tissues and on the cognitive functions of the developing brain. Results indicated that DHA and/or PS significantly enhanced antioxidant activities and increased cell viabilities in vitro. Feeding with DHA and/or PS supplementation not only significantly improved escape latency of animals, but it also improved the oxidative parameters in the brain, enhanced glutathione peroxidase activity as well as reduced nitric mono-oxide levels in the liver. DHA and PS may serve to protect cells from oxidative stress and further improve learning and memory ability in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with (11)C-SA4503 and microPET.

    Science.gov (United States)

    Ramakrishnan, Nisha K; Visser, Anniek K D; Schepers, Marianne; Luurtsema, Gert; Nyakas, Csaba J; Elsinga, Philip H; Ishiwata, Kiichi; Dierckx, Rudi A J O; van Waarde, Aren

    2014-10-01

    Sigma-1 receptor agonists are under investigation as potential disease-modifying agents for several CNS disorders. Donepezil, an acetylcholinesterase inhibitor used for the symptomatic treatment of Alzheimer's disease, is also a high-affinity sigma-1 agonist. The objectives of the present study were to investigate if the sigma-1 agonist tracer (11)C-SA4503 and microPET can be used to determine sigma-1 receptor occupancy (RO) of donepezil in the rat brain; to establish RO of donepezil at doses commonly used in rodent behavioural studies; and to determine the effective plasma concentration of donepezil required for 50 % of max-min occupancy (EC50). Male Wistar rats were pre-treated with donepezil (0.1 to 10 mg/kg) for about 1 h before microPET scans using (11)C-SA4503. The total distribution volume (V T) of the tracer was determined by Logan graphical analysis using time activity curves from arterial plasma and regions of interest drawn around the entire brain and individual brain regions. RO by donepezil was calculated from a modified Lassen plot, and ED50 was estimated from the sigmoidal dose-response curves obtained when the RO was plotted against log donepezil dose. A dose-dependent reduction was observed for V T in the whole brain as well as individual brain regions. RO increased dose-dependently and was 93 % at 10 mg/kg. ED50 was 1.29 mg/kg. Donepezil, in the common dose range, was found to dose-dependently occupy a significant fraction of the sigma-1 receptor population. The data indicate that it is possible to determine sigma-1 RO by an agonist drug in rat brain, using (11)C-SA4503 and microPET.

  5. Compliant intracortical implants reduce strains and strain rates in brain tissue in vivo

    Science.gov (United States)

    Sridharan, Arati; Nguyen, Jessica K.; Capadona, Jeffrey R.; Muthuswamy, Jit

    2015-06-01

    Objective. The objective of this research is to characterize the mechanical interactions of (1) soft, compliant and (2) non-compliant implants with the surrounding brain tissue in a rodent brain. Understanding such interactions will enable the engineering of novel materials that will improve stability and reliability of brain implants. Approach. Acute force measurements were made using a load cell in n = 3 live rats, each with 4 craniotomies. Using an indentation method, brain tissue was tested for changes in force using established protocols. A total of 4 non-compliant, bare silicon microshanks, 3 non-compliant polyvinyl acetate (PVAc)-coated silicon microshanks, and 6 compliant, nanocomposite microshanks were tested. Stress values were calculated by dividing the force by surface area and strain was estimated using a linear stress-strain relationship. Micromotion effects from breathing and vascular pulsatility on tissue stress were estimated from a 5 s interval of steady-state measurements. Viscoelastic properties were estimated using a second-order Prony series expansion of stress-displacement curves for each shank. Main results. The distribution of strain values imposed on brain tissue for both compliant nanocomposite microshanks and PVAc-coated, non-compliant silicon microshanks were significantly lower compared to non-compliant bare silicon shanks. Interestingly, step-indentation experiments also showed that compliant, nanocomposite materials significantly decreased stress relaxation rates in the brain tissue at the interface (p brain tissue. Understanding the material behavior at the site of tissue contact will help to improve neural implant design.

  6. In vitro and in vivo studies of Allium sativum extract against deltamethrin-induced oxidative stress in rats brain and kidney.

    Science.gov (United States)

    Ncir, Marwa; Saoudi, Mongi; Sellami, Hanen; Rahmouni, Fatma; Lahyani, Amina; Makni Ayadi, Fatma; El Feki, Abdelfattah; Allagui, Mohamed Salah

    2017-09-18

    The present study investigated the in vitro and the in vivo antioxidant capacities of Allium sativum (garlic) extract against deltamethrin-induced oxidative damage in rat's brain and kidney. The in vitro result showed that highest extraction yield was achieved with methanol (20.08%). Among the tested extracts, the methanol extract exhibited the highest total phenolic, flavonoids contents and antioxidant activity. The in vivo results showed that deltamethrin treatment caused an increase of the acetylcholinesterase level (AChE) in brain and plasma, the brain and kidney conjugated dienes and lipid peroxidation (LPO) levels as compared to control group. The antioxidant enzymes results showed that deltamethrin treatment induced a significantly decrease (p < 0.01) in brain and kidney antioxidant enzymes as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) to control group. The co-administration of garlic extract reduced the toxic effects in brain and kidney tissues induced by deltamethrin.

  7. In vivo assessment of human brain oscillations during application of transcranial electric currents

    NARCIS (Netherlands)

    Soekadar, S.R.; Witkowski, M.; Garcia Cossio, E.; Birbaumer, N.; Robinson, S.E.; Cohen, L.G.

    2013-01-01

    Brain oscillations reflect pattern formation of cell assemblies’ activity, which is often disturbed in neurological and psychiatric diseases like depression, schizophrenia and stroke. In the neurobiological analysis and treatment of these conditions, transcranial electric currents applied to the

  8. CRISPR/Cas9-induced disruption of gene expression in mouse embryonic brain and single neural stem cells in vivo.

    Science.gov (United States)

    Kalebic, Nereo; Taverna, Elena; Tavano, Stefania; Wong, Fong Kuan; Suchold, Dana; Winkler, Sylke; Huttner, Wieland B; Sarov, Mihail

    2016-03-01

    We have applied the CRISPR/Cas9 system in vivo to disrupt gene expression in neural stem cells in the developing mammalian brain. Two days after in utero electroporation of a single plasmid encoding Cas9 and an appropriate guide RNA (gRNA) into the embryonic neocortex of Tis21::GFP knock-in mice, expression of GFP, which occurs specifically in neural stem cells committed to neurogenesis, was found to be nearly completely (≈ 90%) abolished in the progeny of the targeted cells. Importantly, upon in utero electroporation directly of recombinant Cas9/gRNA complex, near-maximal efficiency of disruption of GFP expression was achieved already after 24 h. Furthermore, by using microinjection of the Cas9 protein/gRNA complex into neural stem cells in organotypic slice culture, we obtained disruption of GFP expression within a single cell cycle. Finally, we used either Cas9 plasmid in utero electroporation or Cas9 protein complex microinjection to disrupt the expression of Eomes/Tbr2, a gene fundamental for neocortical neurogenesis. This resulted in a reduction in basal progenitors and an increase in neuronal differentiation. Thus, the present in vivo application of the CRISPR/Cas9 system in neural stem cells provides a rapid, efficient and enduring disruption of expression of specific genes to dissect their role in mammalian brain development. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  9. MTR and In-vivo 1H-MRS studies on mouse brain with parkinson's disease

    Science.gov (United States)

    Yoon, Moon-Hyun; Kim, Hyeon-Jin; Chung, Jin-Yeung; Doo, Ah-Reum; Park, Hi-Joon; Kim, Seung-Nam; Choe, Bo-Young

    2012-12-01

    The aim of this study was to investigate whether the changes in the magnetization transfer ratio (MTR) histogram are related to specific characteristics of Parkinson's disease (PD) and to investigate whether the MTR histogram parameters are associated with neurochemical dysfunction by performing in vivo proton magnetic resonance spectroscopy (1H-MRS). MTR and in vivo 1H-MRS studies were performed on control mice (n = 10) and 1-methyl-1,2,3,6-tetrahydropyridine intoxicated mice (n = 10). All the MTR and in vivo 1H-MRS experiments were performed on a 9.4 T MRI/MRS system (Bruker Biospin, Germany) using a standard head coil. The protondensity fast spin echo (FSE) images and the T2-weighted spin echo (SE) images were acquired with no gap. Outer volume suppression (OVS), combined with the ultra-short echo-time stimulated echo acquisition mode (STEAM), was used for the localized in-vivo 1H-MRS. The quantitative analysis of metabolites was performed from the 1H spectra obtained in vivo on the striatum (ST) by using jMRUI (Lyon, France). The peak height of the MTR histograms in the PD model group was significantly lower than that in the control group (p early phase of neuronal dysfunction of neurotransmitters.

  10. Cre Fused with RVG Peptide Mediates Targeted Genome Editing in Mouse Brain Cells In Vivo.

    Science.gov (United States)

    Zou, Zhiyuan; Sun, Zhaolin; Li, Pan; Feng, Tao; Wu, Sen

    2016-12-14

    Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. However, whether RVG can be used for genome editing in the brain has not been reported. In this work, we combined RVG with Cre recombinase for bacterial expression. The purified RVG-Cre protein cut plasmids in vitro and traversed cell membranes in cultured Neuro2a cells. By tail vein-injecting RVG-Cre into Cre reporter mouse lines mTmG and Rosa26lacZ, we demonstrated that RVG-Cre could target brain cells and achieve targeted somatic genome editing in adult mice. This direct delivery of the gene-editing enzyme protein into mouse brains with RVG is much safer than plasmid- or viral-based methods, holding promise for further applications in the treatment of various brain diseases.

  11. Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

    Science.gov (United States)

    Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

    2016-11-01

    Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

  12. In Vivo Toxicity Assessment of Occupational Components of the Carbon Nanotube Life Cycle To Provide Context to Potential Health Effects.

    Science.gov (United States)

    Bishop, Lindsey; Cena, Lorenzo; Orandle, Marlene; Yanamala, Naveena; Dahm, Matthew M; Birch, M Eileen; Evans, Douglas E; Kodali, Vamsi K; Eye, Tracy; Battelli, Lori; Zeidler-Erdely, Patti C; Casuccio, Gary; Bunker, Kristin; Lupoi, Jason S; Lersch, Traci L; Stefaniak, Aleksandr B; Sager, Tina; Afshari, Aliakbar; Schwegler-Berry, Diane; Friend, Sherri; Kang, Jonathan; Siegrist, Katelyn J; Mitchell, Constance A; Lowry, David T; Kashon, Michael L; Mercer, Robert R; Geraci, Charles L; Schubauer-Berigan, Mary K; Sargent, Linda M; Erdely, Aaron

    2017-09-26

    Pulmonary toxicity studies on carbon nanotubes focus primarily on as-produced materials and rarely are guided by a life cycle perspective or integration with exposure assessment. Understanding toxicity beyond the as-produced, or pure native material, is critical, due to modifications needed to overcome barriers to commercialization of applications. In the first series of studies, the toxicity of as-produced carbon nanotubes and their polymer-coated counterparts was evaluated in reference to exposure assessment, material characterization, and stability of the polymer coating in biological fluids. The second series of studies examined the toxicity of aerosols generated from sanding polymer-coated carbon-nanotube-embedded or neat composites. Postproduction modification by polymer coating did not enhance pulmonary injury, inflammation, and pathology or in vitro genotoxicity of as-produced carbon nanotubes, and for a particular coating, toxicity was significantly attenuated. The aerosols generated from sanding composites embedded with polymer-coated carbon nanotubes contained no evidence of free nanotubes. The percent weight incorporation of polymer-coated carbon nanotubes, 0.15% or 3% by mass, and composite matrix utilized altered the particle size distribution and, in certain circumstances, influenced acute in vivo toxicity. Our study provides perspective that, while the number of workers and consumers increases along the life cycle, toxicity and/or potential for exposure to the as-produced material may greatly diminish.

  13. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Yokokura, Masamichi; Mori, Norio; Yoshihara, Yujiro; Wakuda, Tomoyasu; Takebayashi, Kiyokazu; Iwata, Yasuhide; Nakamura, Kazuhiko [Hamamatsu University School of Medicine, Department of Psychiatry and Neurology, Hamamatsu (Japan); Yagi, Shunsuke; Ouchi, Yasuomi [Hamamatsu University School of Medicine, Laboratory of Human Imaging Research, Molecular Imaging Frontier Research Center, Hamamatsu (Japan); Yoshikawa, Etsuji [Hamamatsu Photonics K.K., Central Research Laboratory, Hamamatsu (Japan); Kikuchi, Mitsuru [Kanazawa University, Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa (Japan); Sugihara, Genichi; Suda, Shiro; Tsuchiya, Kenji J.; Suzuki, Katsuaki [Hamamatsu University School of Medicine, Research Center for Child Mental Development, Hamamatsu (Japan); Ueki, Takatoshi [Hamamatsu University School of Medicine, Department of Anatomy, Hamamatsu (Japan)

    2011-02-15

    Amyloid {beta} protein (A{beta}) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between A{beta} accumulation and neuroinflammation in those specific brain regions in early AD. Eleven nootropic drug-naive AD patients underwent a series of positron emission tomography (PET) measurements with [{sup 11}C](R)PK11195, [{sup 11}C]PIB and [{sup 18}F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [{sup 11}C](R)PK11195 were directly compared with those of [{sup 11}C]PIB in the brain regions with reduced glucose metabolism. BPs of [{sup 11}C](R)PK11195 and [{sup 11}C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [{sup 11}C](R)PK11195 BPs, but not [{sup 11}C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [{sup 11}C](R)PK11195 and [{sup 11}C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [{sup 18}F]FDG uptake. A lack of coupling between microglial activation and amyloid deposits may indicate that A{beta} accumulation shown by [{sup 11}C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of A{beta} in early AD. (orig.)

  14. Distribution of CaMKIIα expression in the brain in vivo, studied by CaMKIIα-GFP mice

    Science.gov (United States)

    Wang, Xinjun; Zhang, Chunzhao; Szábo, Gábor; Sun, Qian-Quan

    2013-01-01

    To facilitate the study of the CaMKIIα function in vivo, a CaMKIIα-GFP transgenic mouse line was generated. Here, our goal is to provide the first neuroanatomical characterization of GFP expression in the CNS of this line of mouse. Overall, CaMKIIα -GFP expression is strong and highly heterogeneous, with the dentate gyrus of the hippocampus as the most abundantly expressed region. In the hippocampus, around 70% of granule and pyramidal neurons expressed strong GFP. In the neocortex, presumed pyramidal neurons were GFP positive: around 32% of layer II/III and 35% of layer VI neurons expressed GFP, and a lower expression rate was found in other layers. In the thalamus and hypothalamus, strong GFP signals were detected in the neuropil. GFP-positive cells were also found in many other regions such as the spinal trigeminal nucleus, cerebellum and basal ganglia. We further compared the GFP expression with specific antibody staining for CaMKIIα and GABA. We found that GFP+ neurons were mostly positive for CaMKIIα-IR throughout the brain, with some exceptions throughout the brain, especially in the deeper layers of neocortex. GFP and GABA-IR marked distinct neuronal populations in most brain regions with the exception of granule cells in the olfactory bulb, purkinje cells in the cerebellar, and some layer I cells in neocortex. In conclusion, GFP expression in the CaMKIIα-GFP mice is similar to the endogenous expression of CaMKIIα protein, thus these mice can be used in in vivo and in vitro physiological studies in which visualization of CaMKIIα- neuronal populations is required. PMID:23632380

  15. Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain.

    Science.gov (United States)

    Keevil, S F; Barbiroli, B; Brooks, J C; Cady, E B; Canese, R; Carlier, P; Collins, D J; Gilligan, P; Gobbi, G; Hennig, J; Kügel, H; Leach, M O; Metzler, D; Mlynárik, V; Moser, E; Newbold, M C; Payne, G S; Ring, P; Roberts, J N; Rowland, I J; Thiel, T; Tkác, I; Topp, S; Wittsack, H J; Podo, F

    1998-11-01

    We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

  16. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Ganz-Benjaminsen, Melanie; Feng, Ling

    2017-01-01

    ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...... autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique...

  17. In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse

    Directory of Open Access Journals (Sweden)

    Eun Seong Lee

    2015-01-01

    Full Text Available We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%, and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%. In the mice with initial lung signals (4 of 9, 44.4%, the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.

  18. Morphological maturation of the mouse brain : An in vivo MRI and histology investigation

    NARCIS (Netherlands)

    Hammelrath, Luam; Škokić, Siniša; Khmelinskii, Artem; Hess, Andreas; van der Knaap, Noortje; Staring, M.; Lelieveldt, B.P.F.; Wiedermann, Dirk; Hoehn, Mathias

    2016-01-01

    With the wide access to studies of selected gene expressions in transgenic animals,mice have become the dominant species as cerebral diseasemodels. Many of these studies are performed on animals of not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain

  19. Effects of intravenous glucose on Dopaminergic function in the human brain in vivo

    NARCIS (Netherlands)

    Haltia, Lauri T.; Rinne, Juha O.; Merisaari, Harri; Maguire, Ralph P.; Savontaus, Eriika; Helin, Semi; Nagren, Kjell; Kaasinen, Valtteri

    Dopamine is known to regulate food intake by modulating food reward via the mesolimbic circuitry of the brain. The objective of this study was to compare the effects of high energy input (i.v. glucose) on striatal and thalamic dopamine release in overweight and lean individuals. We hypothesized that

  20. Measuring antigen presentation in mouse brain endothelial cells ex vivo and in vitro.

    Science.gov (United States)

    Howland, Shanshan W; Gun, Sin Yee; Claser, Carla; Poh, Chek Meng; Rénia, Laurent

    2015-12-01

    We have recently demonstrated that brain endothelial cells cross-present parasite antigen during mouse experimental cerebral malaria (ECM). Here we describe a 2-d protocol to detect cross-presentation by isolating the brain microvessels and incubating them with a reporter cell line that expresses lacZ upon detection of the relevant peptide-major histocompatibility complex. After X-gal staining, a typical positive result consists of hundreds of blue spots, compared with fewer than 20 spots from a naive brain. The assay is generalizable to other disease contexts by using reporter cells that express appropriate specific T cell receptors. Also described is the protocol for culturing endothelial cells from brain microvessels isolated from naive mice. After 7-10 d, an in vitro cross-presentation assay can be performed by adding interferon-γ, antigen (e.g., Plasmodium berghei-infected red blood cells) and reporter cells in sequence over 3 d. This is useful for comparing different antigen forms or for probing the effects of various interventions.

  1. Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment.

    Science.gov (United States)

    Patel, Hemant K; Gajbhiye, Virendra; Kesharwani, Prashant; Jain, Narendra K

    2016-11-15

    The present investigation was aimed at developing various ligands-anchored dendrimers and comparing their brain targeting potential at one platform. Sialic acid (S), glucosamine (G) and concanavalin A (C) anchored poly(propyleneimine) (PPI) dendritic nanoconjugates were developed and evaluated for delivery of anti-cancer drug, paclitaxel (PTX) to the brain. MTT assay on U373MG human astrocytoma cells indicated IC50 values of 0.40, 0.65, 0.95, 2.00 and 3.50μM for PTX loaded SPPI, GPPI, CPPI, PPI formulations, and free PTX, respectively. The invivo pharmacokinetics and biodistribution studies in rats showed significantly higher accumulation of PTX in brain as compared to free PTX. The order of targeting potential of various ligands under investigation was found as sialic acid>glucosamine>concanavalin A. Thus, it can be concluded that sialic acid, glucosamine and Con A can be used as potential ligands to append PPI dendrimers for enhanced delivery of anticancer drugs to the brain for higher therapeutic outcome. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. In vivo magnetic resonance diffusion measurement in the brain of patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Larsson, H B; Thomsen, C; Frederiksen, J

    1992-01-01

    Measurement of water self-diffusion in the brain in 25 patients with multiple sclerosis was performed by magnetic resonance imaging. Quantitative diffusion measurements were obtained using single spin-echo pulse sequences with pulsed magnetic field gradients of different magnitude. Twenty...

  3. Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Z.; Du, C.; Yuan, Z.; Luo, Z.; Volkow, N.D.; Pan, Y.; Du, C.

    2010-09-08

    MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30 {micro}m, 10 Hz) and over a large field of view (3 x 5 mm{sup 2}). We apply it to assess cocaine's effects in rat cortical brain and show an immediate decrease 3.5 {+-} 0.9 min, phase (1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot 7.1 {+-} 0.2 min, phase (2) lasting over 20 min whereas Ca{sup 2+} increased immediately (peaked at t = 4.1 {+-} 0.4 min) and remained elevated. This enabled us to identify a delay (2.9 {+-} 0.5 min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI).

  4. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

    Science.gov (United States)

    Barrio, Jorge R; Small, Gary W; Wong, Koon-Pong; Huang, Sung-Cheng; Liu, Jie; Merrill, David A; Giza, Christopher C; Fitzsimmons, Robert P; Omalu, Bennet; Bailes, Julian; Kepe, Vladimir

    2015-04-21

    Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

  5. Brain basis of early parent-infant interactions: psychology, physiology, and in vivo functional neuroimaging studies.

    Science.gov (United States)

    Swain, James E; Lorberbaum, Jeffrey P; Kose, Samet; Strathearn, Lane

    2007-01-01

    Parenting behavior critically shapes human infants' current and future behavior. The parent-infant relationship provides infants with their first social experiences, forming templates of what they can expect from others and how to best meet others' expectations. In this review, we focus on the neurobiology of parenting behavior, including our own functional magnetic resonance imaging (fMRI) brain imaging experiments of parents. We begin with a discussion of background, perspectives and caveats for considering the neurobiology of parent-infant relationships. Then, we discuss aspects of the psychology of parenting that are significantly motivating some of the more basic neuroscience research. Following that, we discuss some of the neurohormones that are important for the regulation of social bonding, and the dysregulation of parenting with cocaine abuse. Then, we review the brain circuitry underlying parenting, proceeding from relevant rodent and nonhuman primate research to human work. Finally, we focus on a study-by-study review of functional neuroimaging studies in humans. Taken together, this research suggests that networks of highly conserved hypothalamic-midbrain-limbic-paralimbic-cortical circuits act in concert to support aspects of parent response to infants, including the emotion, attention, motivation, empathy, decision-making and other thinking that are required to navigate the complexities of parenting. Specifically, infant stimuli activate basal forebrain regions, which regulate brain circuits that handle specific nurturing and caregiving responses and activate the brain's more general circuitry for handling emotions, motivation, attention, and empathy--all of which are crucial for effective parenting. We argue that an integrated understanding of the brain basis of parenting has profound implications for mental health.

  6. Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions – extending the simplified reference tissue model.

    Science.gov (United States)

    Kågedal, Matts; Varnäs, Katarina; Hooker, Andrew C; Karlsson, Mats O

    2015-07-01

    The simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extend the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared with other brain regions, could be better explained by a difference in the extent of non-displaceable binding. The analysis was based on a PET study in six healthy volunteers using the 5-HT1B receptor radioligand [(11)C]-AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT1B receptor antagonist AZD3783. Non-linear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies. The estimate (95% CI) of Ki(PL) was 10.2 ng ml(-1) (5.4, 15) and 10.4 ng ml(-1) (8.1, 13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference, respectively. The estimate (95% CI) of Ki(PL) for caudate relative to other brain regions was 55% (48, 62%). The extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions. © 2014 The British Pharmacological Society.

  7. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

    OpenAIRE

    Vivek Murthy; Karyn Wat; Helen Ho; Broderick, Patricia A.

    2008-01-01

    Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from elec...

  8. Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier

    OpenAIRE

    Duarte, Joao M. N.; Gruetter, Rolf

    2012-01-01

    Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (Tmax) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a...

  9. Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro.

    Science.gov (United States)

    Schousboe, Arne; Waagepetersen, Helle S; Leke, Renata; Bak, Lasse K

    2014-12-01

    The literature related to the effects of elevated plasma ammonia levels on brain energy metabolism is abundant, but heterogeneous in terms of the conclusions. Thus, some studies claim that ammonia has a direct, inhibitory effect on energy metabolism whereas others find no such correlation. In this review, we discuss both recent and older literature related to this controversial topic. We find that it has been consistently reported that hepatic encephalopathy and concomitant hyperammonemia lead to reduced cerebral oxygen consumption. However, this may not be directly linked to an effect of ammonia but related to the fact that hepatic encephalopathy is always associated with reduced brain activity, a condition clearly characterized by a decreased CMRO2. Whether this may be related to changes in GABAergic function remains to be elucidated.

  10. First in vivo traumatic brain injury imaging via magnetic particle imaging

    Science.gov (United States)

    Orendorff, Ryan; Peck, Austin J.; Zheng, Bo; Shirazi, Shawn N.; Ferguson, R. Matthew; Khandhar, Amit P.; Kemp, Scott J.; Goodwill, Patrick; Krishnan, Kannan M.; Brooks, George A.; Kaufer, Daniela; Conolly, Steven

    2017-05-01

    Emergency room visits due to traumatic brain injury (TBI) is common, but classifying the severity of the injury remains an open challenge. Some subjective methods such as the Glasgow Coma Scale attempt to classify traumatic brain injuries, as well as some imaging based modalities such as computed tomography and magnetic resonance imaging. However, to date it is still difficult to detect and monitor mild to moderate injuries. In this report, we demonstrate that the magnetic particle imaging (MPI) modality can be applied to imaging TBI events with excellent contrast. MPI can monitor injected iron nanoparticles over long time scales without signal loss, allowing researchers and clinicians to monitor the change in blood pools as the wound heals.

  11. In vivo labeling of phencyclidine (PCP) receptors with sup 3 H-TCP in the mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Maurice, T.; Vignon, J. (Ecole Nationale Superieure de Chimie, Montpellier (France))

    1990-07-01

    The phencyclidine (PCP) derivative N-(1-(2-thienyl)cyclohexyl)-piperidine (3H-TCP) was used to label in vivo the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel in the mouse brain. After the injection of a tracer dose of 3H-TCP, a spread labeling throughout the brain was observed, but was the highest in the cerebellum. Preadministration of unlabeled TCP (30 mg/kg) resulted in a 90% reduction of 3H-TCP binding. PCP, TCP, MK-801, dexoxadrol, ketamine, and SKF 10,047 isomers dose-dependently prevented the in vivo 3H-TCP binding. ID50 determined in the cerebrum and the cerebellum were respectively correlated with K0.5 for 3H TCP high (rat cortex) and low affinity (rat cerebellum) sites in vitro. The pharmacological specificity of the 3H-TCP binding site in the cerebellum was significantly different from that in the cerebrum. ID50 values were generally higher than in the cerebrum and, particularly, MK-801, the most potent drug in the cerebrum, was without significant effect in the cerebellum, at any time and at doses as high as 30 mg/kg. N-(1-(2-benzo(b) thiophenyl)cyclohexyl)piperidine (BTCP), desipramine, and atropine showed a more efficient prevention of 3H-TCP binding in the cerebellum than in the cerebrum. The prevention of the binding by TCP or PCP, at doses close to their ID50 values, was rapid and then decreased slowly. The effect of MK-801 was long-lasting. This study confirm previous in vitro studies: 3H-TCP is an efficient tool for the labeling of the NMDA receptor-associated ionic channel.

  12. In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2011-01-01

    Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey\\/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood.

  13. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism

    DEFF Research Database (Denmark)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik

    2016-01-01

    , risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites......, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data...

  14. A novel approach to quantify different iron forms in ex-vivo human brain tissue

    Science.gov (United States)

    Kumar, Pravin; Bulk, Marjolein; Webb, Andrew; van der Weerd, Louise; Oosterkamp, Tjerk H.; Huber, Martina; Bossoni, Lucia

    2016-12-01

    We propose a novel combination of methods to study the physical properties of ferric ions and iron-oxide nanoparticles in post-mortem human brain, based on the combination of Electron Paramagnetic Resonance (EPR) and SQUID magnetometry. By means of EPR, we derive the concentration of the low molecular weight iron pool, as well as the product of its electron spin relaxation times. Additionally, by SQUID magnetometry we identify iron mineralization products ascribable to a magnetite/maghemite phase and a ferrihydrite (ferritin) phase. We further derive the concentration of magnetite/maghemite and of ferritin nanoparticles. To test out the new combined methodology, we studied brain tissue of an Alzheimer’s patient and a healthy control. Finally, we estimate that the size of the magnetite/maghemite nanoparticles, whose magnetic moments are blocked at room temperature, exceeds 40-50 nm, which is not compatible with the ferritin protein, the core of which is typically 6-8 nm. We believe that this methodology could be beneficial in the study of neurodegenerative diseases such as Alzheimer’s Disease which are characterized by abnormal iron accumulation in the brain.

  15. The in vivo phosphorylation sites in multiple isoforms of amphiphysin I from rat brain nerve terminals

    DEFF Research Database (Denmark)

    Craft, George E; Graham, Mark E; Bache, Nicolai

    2008-01-01

    Amphiphysin I (amphI) is dephosphorylated by calcineurin during nerve terminal depolarization and synaptic vesicle endocytosis (SVE). Some amphI phosphorylation sites (phosphosites) have been identified with in vitro studies or phosphoproteomics screens. We used a multifaceted strategy including 32......P tracking to identify all in vivo amphI phosphosites and determine their relative abundance and potential relevance to SVE. AmphI was extracted from 32P-labeled synaptosomes, phosphopeptides were isolated from proteolytic digests using TiO2 chromatography, and mass spectrometry revealed 13 sites...

  16. Evaluation of sup 3 H-paroxetine as a radioligand for in vivo study of 5-hydroxytryptamine uptake sites in mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji; Goromaru, Tsuyoshi (Fukuyama Univ., Hiroshima (Japan). Faculty of Pharmacy and Pharmaceutical Sciences)

    1990-08-01

    The distribution of radioactivity in the mouse brain after intravenous administration of {sup 3}H-paroxetine was in descending order hypothalamus > cerebral cortex > cerebellum. The radioactivity in the hypothalamus and cerebral cortex after injection of {sup 3}H-paroxetine was significantly decreased by treatment with 6-nitroquipazine or paroxetine. HPLC and TLC analyses show that no radioactive metabolites were found in the mouse brain 3 h after intravenous administration of {sup 3}H-paroxetine. The present results indicate that {sup 3}H-paroxetine would be a suitable radioligand for in vivo study of 5-HT uptake sites in mouse brain.

  17. In vivo detection of intermediate metabolic products of [1-(13) C]ethanol in the brain using (13) C MRS.

    Science.gov (United States)

    Xiang, Yun; Shen, Jun

    2011-11-01

    In this study, in vivo (13) C MRS was used to investigate the labeling of brain metabolites after intravenous administration of [1-(13) C]ethanol. After [1-(13) C]ethanol had been administered systemically to rats, (13) C labels were detected in glutamate, glutamine and aspartate in the carboxylic and amide carbon spectral region. (13) C-labeled bicarbonate HCO 3- (161.0 ppm) was also detected. Saturating acetaldehyde C1 at 207.0 ppm was found to have no effect on the ethanol C1 (57.7 ppm) signal intensity after extensive signal averaging, providing direct in vivo evidence that direct metabolism of alcohol by brain tissue is minimal. To compare the labeling of brain metabolites by ethanol with labeling by glucose, in vivo time course data were acquired during intravenous co-infusion of [1-(13) C]ethanol and [(13) C(6) ]-D-glucose. In contrast with labeling by [(13) C(6) ]-D-glucose, which produced doublets of carboxylic/amide carbons with a J coupling constant of 51 Hz, the simultaneously detected glutamate and glutamine singlets were labeled by [1-(13) C]ethanol. As (13) C labels originating from ethanol enter the brain after being converted into [1-(13) C]acetate in the liver, and the direct metabolism of ethanol by brain tissue is negligible, it is suggested that orally or intragastrically administered (13) C-labeled ethanol may be used to study brain metabolism and glutamatergic neurotransmission in investigations involving alcohol administration. In vivo (13) C MRS of rat brain following intragastric administration of (13) C-labeled ethanol is demonstrated. This article is a U.S. Government work and is in the public domain in the U.S.A. Copyright © 2011 John Wiley & Sons, Ltd.

  18. Whole-Brain In-vivo Measurements of the Axonal G-Ratio in a Group of 37 Healthy Volunteers.

    Science.gov (United States)

    Mohammadi, Siawoosh; Carey, Daniel; Dick, Fred; Diedrichsen, Joern; Sereno, Martin I; Reisert, Marco; Callaghan, Martina F; Weiskopf, Nikolaus

    2015-01-01

    The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high-fidelity magnetization transfer (MT) imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain's prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration.

  19. In vivo characterization of brain morphometric and metabolic endophenotypes in three inbred strains of mice using magnetic resonance techniques.

    Science.gov (United States)

    Penet, Marie-France; Laigle, Christophe; Fur, Yann Le; Confort-Gouny, Sylviane; Heurteaux, Catherine; Cozzone, Patrick J; Viola, Angèle

    2006-09-01

    C57BL6J, FVB/N and 129/SvJ mice are commonly used as background strains to engineer genetic models of brain pathologies and psychiatric disorders. Magnetic resonance imaging (MRI) and spectroscopy provide alternative approaches to neuroanatomy, histology and neurohistochemistry for investigating the correlation between genes and brain neuroanatomy and neurometabolism in vivo. We used these techniques to non-invasively characterize the cerebral morphologic and metabolic endophenotypes of inbred mouse strains commonly used in neurological and behavioral research. We observed a great variability in the volume of ventricles and of structures involved in cognitive function (cerebellum and hippocampus) among these strains. In addition, distinct metabolic profiles were evidenced with variable levels of N-acetylaspartate, a neuronal marker, and of choline, a compound found in membranes and myelin. Besides, significant differences in high-energy phosphates and phospholipids were detected. Our findings demonstrate the great morphologic and metabolic heterogeneity among C57BL/ 6J, FVB/N and 129/SvJ mice. They emphasize the importance of selecting the appropriate genetic background for over-expressing or silencing a gene and provide some directions for modeling symptoms that characterize psychiatric disorders such as autism, schizophrenia and depression.

  20. The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates--evidence from in vivo neuroimaging studies

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Jenkins, Bruce G; Choi, Ji-Kyung

    2009-01-01

    It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates ...

  1. In vivo binding of spiperone and N-methylspirerone to dopaminergic and serotonergic sites in the rat brain: Multiple modeling and implications for PET scanning

    NARCIS (Netherlands)

    Swart, J.A.A.; Van der Werf, J.F.; Wiegman, T.; Paans, A.M.J.; Vaalburg, W.; Korf, J.

    1990-01-01

    Equilibrium models are derived and applied to in vivo binding of spiperone in the rat brain. The models express the concentration of the ligand in the striatum and frontal cortex as a function of the accumulation in the cerebellum. The models differ with respect to the description of specific

  2. Accuracy of image registration between MRI and light microscopy in the ex vivo brain.

    Science.gov (United States)

    Choe, Ann S; Gao, Yurui; Li, Xia; Compton, Keegan B; Stepniewska, Iwona; Anderson, Adam W

    2011-06-01

    A multistep procedure was developed to register magnetic resonance imaging (MRI) and histological data from the same sample in the light microscopy image space, with the ultimate goal of allowing quantitative comparisons of the two datasets. The fixed brain of an owl monkey was used to develop and test the procedure. In addition to the MRI and histological data, photographic images of the brain tissue block acquired during sectioning were assembled into a blockface volume to provide an intermediate step for the overall registration process. The MR volume was first registered to the blockface volume using a combination of linear and nonlinear registration, and two dimensional (2D) blockface sections were registered to corresponding myelin-stained sections using a combination of linear and nonlinear registration. Before this 2D registration, two major types of tissue distortions were corrected: tissue tearing and independent movement of different parts of the brain, both introduced during histological processing of the sections. The correction procedure utilized a 2D method to close tissue tears and a multiple iterative closest point (ICP) algorithm to reposition separate pieces of tissue in the image. The accuracy of the overall MR to micrograph registration procedure was assessed by measuring the distance between registered landmarks chosen in the MR image space and the corresponding landmarks chosen in the micrograph space. The average error distance of the MR data registered to micrograph data was 0.324±0.277 mm, only 8% larger than the width of the MRI voxel (0.3 mm). Copyright © 2011 Elsevier Inc. All rights reserved.

  3. In vivo and continuous measurement of bisulfide in the hippocampus of rat's brain by an on-line integrated microdialysis/droplet-based microfluidic system.

    Science.gov (United States)

    Gu, Feidan; Zhou, Xiaoyu; Zhu, Xiaocui; Zhao, Meiping; Hao, Jie; Yu, Ping; Mao, Lanqun

    2015-06-07

    An on-line and continuous approach was demonstrated for in vivo measurement of bisulfide in rat's brain. A modified droplet-based microfluidic system was constructed, which allowed on-line qualification of the fluorescence responses of the gold nanoparticle-glutathione-fluorescein isothiocyanate probe to the variation of bisulfide in the presence of the cerebral microdialysate background. The on-line method achieved a dynamic working range from 5.0 μM to 40 μM and a detection limit of 2.5 μM. The in vivo bisulfide concentration in the hippocampus of rat's brain was measured under different physiological conditions. The on-line method may facilitate the study of H2S biology by providing a previously unattainable continuous record of H2S variation in living animals. It also provides a practical platform for in vivo and continuous monitoring of other important species in cerebral systems.

  4. In vivo studies of low level laser (light) therapy for traumatic brain injury

    Science.gov (United States)

    Xuan, Weijun; Wu, Qiuhe; Huang, Ying-Ying; Ando, Takahiro; Huang, Liyi; Hamblin, Michael R.

    2012-03-01

    Low-level laser (or light) therapy (LLLT) is attracting growing interest to treat both stroke and traumatic brain injury (TBI). The fact that near-infrared light can penetrate into the brain allows non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. It is proposed that red and NIR light is absorbed by chromophores in the mitochondria of cells leading to changes in gene transcription and upregulation of proteins involved in cell survival, antioxidant production, collagen synthesis, reduction of chronic inflammation and cell migration and proliferation. We developed a mouse model of controlled cortical impact (CCI) TBI and examined the effect of 0, 1, 3, and 14 daily 810-nm CW laser treatments in the CCI model as measured by neurological severity score and wire grip and motion test. 1 laser Tx gave a significant improvement while 3 laser Tx was even better. Surprisingly 14 laser Tx was no better than no treatment. Histological studies at necropsy suggested that the neurodegeneration was reduced at 14 days and that the cortical lesion was repaired by BrdU+ve neural progenitor (stem) cells at 28 days. Transcranial laser therapy is a promising treatment for acute (and chronic TBI) and the lack of side-effects and paucity of alternative treatments encourages early clinical trials.

  5. A Programmable High-Voltage Compliance Neural Stimulator for Deep Brain Stimulation in Vivo

    Directory of Open Access Journals (Sweden)

    Cihun-Siyong Alex Gong

    2015-05-01

    Full Text Available Deep brain stimulation (DBS is one of the most effective therapies for movement and other disorders. The DBS neurosurgical procedure involves the implantation of a DBS device and a battery-operated neurotransmitter, which delivers electrical impulses to treatment targets through implanted electrodes. The DBS modulates the neuronal activities in the brain nucleus for improving physiological responses as long as an electric discharge above the stimulation threshold can be achieved. In an effort to improve the performance of an implanted DBS device, the device size, implementation cost, and power efficiency are among the most important DBS device design aspects. This study aims to present preliminary research results of an efficient stimulator, with emphasis on conversion efficiency. The prototype stimulator features high-voltage compliance, implemented with only a standard semiconductor process, without the use of extra masks in the foundry through our proposed circuit structure. The results of animal experiments, including evaluation of evoked responses induced by thalamic electrical stimuli with our fabricated chip, were shown to demonstrate the proof of concept of our design.

  6. In vivo proton magnetic resonance spectroscopy of intraventricular tumours of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Majos, Carles; Aguilera, Carles [Hospital Universitari de Bellvitge, Institut de Diagnostic per la Imatge (IDI). Centre Bellvitge, L' Hospitalet de Llobregat, Barcelona (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Cos, Monica; Camins, Angels; Samitier, Alex; Castaner, Sara; Sanchez, Juan J. [Hospital Universitari de Bellvitge, Institut de Diagnostic per la Imatge (IDI). Centre Bellvitge, L' Hospitalet de Llobregat, Barcelona (Spain); Candiota, Ana P.; Delgado-Goni, Teresa [Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Unitat de Bioquimica de Biociencies, Department de Bioquimica i Biologia Molecular, Cerdanyola del Valles (Spain); Mato, David [Hospital Universitari de Bellvitge, Department of Neurosurgery, L' Hospitalet de Llobregat, Barcelona (Spain); Acebes, Juan J. [Hospital Universitari de Bellvitge, Department of Neurosurgery, L' Hospitalet de Llobregat, Barcelona (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain); Arus, Carles [Unitat de Bioquimica de Biociencies, Department de Bioquimica i Biologia Molecular, Cerdanyola del Valles (Spain); Biomateriales y Nanomedicina (CIBER-BBN), Centro de Investigacion Biomedica en Red en Bioingenieria, Cerdanyola del Valles (Spain)

    2009-08-15

    The aim of this study was to assess the usefulness of proton MR spectroscopy in the diagnosis of intraventricular tumours. Fifty-two intraventricular tumours pertaining to 16 different tumour types were derived from our database. All cases had single-voxel proton MR spectroscopy performed at TE at both 30 and 136 ms at 1.5 T. The Mann-Whitney U test was used to search for the most discriminative datapoints each tumour type. Characteristic trends were found for some groups: high Glx and Ala in meningiomas (p<0.001 and p<0.01, respectively), high mobile lipids in metastasis (p<0.001), high Cho in PNET (p<0.001), high mI+Gly in ependymoma (p<0.001), high NAC (p<0.01) in the absence of the normal brain parenchyma pattern in colloid cysts, and high mI/Gly and Ala in central neurocytoma. Proton MR spectroscopy provides additional metabolic information that could be useful in the diagnosis of intraventricular brain tumors. (orig.)

  7. Characterization and in vivo regulation of V sub 1 -type vasopressin receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Shewey, L.M.

    1988-01-01

    Specific, high affinity binding sites for ({sup 3}H)-arginine{sup 8}-vasopressin (AVP) have been characterized in Long-Evans rat septal membranes. Binding displacement studies with peptide analogs of AVP indicate that this binding site is similar to the V{sub 1} (pressor)-type receptor for AVP. When added to rat brain septal slices that had been pre-labeled with ({sup 3}H)-myoinositol, AVP stimulated the accumulation of ({sup 3}H)-inositol-1-phosphate (IP{sub 1}) in the presence of lithium in a dose-dependent manner. This stimulation was completely inhibited by the specific V{sub 1} antagonists, d(CH{sub 2}){sub 5}Tyr(Me)AVP, indicating that AVP stimulates hydrolysis of inositol phospholipids in rat brain septum through an interaction with V{sub 1}-type AVP receptors. Binding studies of AVP receptors in the septum of heterozygous (HE) and homozygous, Brattleboro (BB) rats revealed an increased number of receptors with a lower affinity for AVP in the HO-BB rat when compared to the HE-BB rat. AVP-stimulated accumulation of ({sup 3}H)-IP{sub 1} was significantly greater in the septum of the HO-BB rat than in the HE-BB rat. AVP receptor binding capacity correlated with release of ({sup 3}H)-IP{sub 1} for all three groups studied.

  8. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo.

    Science.gov (United States)

    Mangraviti, Antonella; Tzeng, Stephany Yi; Kozielski, Kristen Lynn; Wang, Yuan; Jin, Yike; Gullotti, David; Pedone, Mariangela; Buaron, Nitsa; Liu, Ann; Wilson, David R; Hansen, Sarah K; Rodriguez, Fausto J; Gao, Guo-Dong; DiMeco, Francesco; Brem, Henry; Olivi, Alessandro; Tyler, Betty; Green, Jordan J

    2015-02-24

    Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

  9. Different early effect of irradiation in brain and small cell lung cancer examined by in vivo 31P-magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Kristjansen, P E; Pedersen, A G; Quistorff, B

    1992-01-01

    Early effects of irradiation were evaluated by non-invasive in vivo 31P-magnetic resonance spectroscopy (31P-MRS) of two small cell lung cancer (SCLC) tumor lines CPH SCCL 54A and 54B, in nude mice. The tumors were originally derived from the same patient and have similar morphology and growth......-MRS. No effect was observed in brain at any dose level. In contrast, 40 Gy induced a statistically significant reduction in ATP/Pi ratio during the 12-h post-irradiation period. This effect was more pronounced in 54A than in 54B. Some reduction was observed following 10 Gy, whereas 2.5 Gy induced no changes...... in ATP/Pi. The differential effect on tumors and brain might be relevant for monitoring irradiation effects by in vivo 31P-MRS in patients with brain metastases....

  10. Induction of Apoptosis In Vivo in the Rabbit Brain with Focused Ultrasound

    Science.gov (United States)

    Vykhodtseva, Natalia I.; McDannold, Nathan; Hynynen, Kullervo

    2006-05-01

    Discrete lesions in the rabbit brains were created at substantially lowered acoustic power levels when FUS exposures were combined with ultrasound contrast agent. In histology, the lesions exhibited numerous red blood cell extravasations and destruction of blood vessels, presumably caused by inertial cavitation. As early as at 4 h after sonication, the lesions lost many cells, and remaining cells exhibited both necrotic and apoptotic features. Overall, it appeared that apoptosis dominated; the average number of apoptotic cells/microscopic field was high: 32.3+/-13.2 compared to the number of necrotic cells: 5.1+/-3.4. In summary, it was found that sonication combined with an ultrasound contrast agent could produce lesions that are dominated by apoptosis. Apoptosis was presumably produced mostly via ischemia after cavitation-induced damage and/or destruction of the vasculature.

  11. In vivo regulation of the serotonin-2 receptor in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Stockmeier, C.A.; Kellar, K.J.

    1986-01-13

    Serotonin-2 (5-HT-2) receptors in brain were measured using (/sup 3/H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on (/sup 3/H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC/sub 50/ nor the Hill coefficient of 5-HT in competing for (/sup 3/H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of (/sup 3/H)5-HT or (/sup 3/H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables.

  12. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    DEFF Research Database (Denmark)

    Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian

    2013-01-01

    This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3...... responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide...... a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system...

  13. Measurement of brain microglial proliferation rates in vivo in response to neuroinflammatory stimuli: application to drug discovery.

    Science.gov (United States)

    Shankaran, Mahalakshmi; Marino, Michael E; Busch, Robert; Keim, Carole; King, Chelsea; Lee, Jean; Killion, Salena; Awada, Mohamad; Hellerstein, Marc K

    2007-08-15

    Microglial activation is emerging as an important etiologic factor and therapeutic target in neurodegenerative and neuroinflammatory diseases. Techniques have been lacking, however, for measuring the different components of microglial activation independently in vivo. We describe a method for measuring microglial proliferation rates in vivo using heavy water (2H2O) labeling, and its application in screening for drugs that suppress neuro-inflammation. Brain microglia were isolated by flow cytometry as F4/80+, CD11b+, CD45(low) cells, and 2H enrichment in DNA was analyzed by gas chromatography/mass spectrometry. Basal proliferation rate was approximately 1%/week and systemic administration of bacterial lipopolysaccharide (LPS) markedly increased this rate in a dose-dependent manner. Induction of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice by MOG(35-55) peptide stimulated proliferation of CD45(low) microglia, which could be distinguished from the proliferation of CD45(high) infiltrating monocytes. Minocycline (45 mg/kg/day, i.p.) inhibited resident microglial proliferation in both the LPS and EAE models. Thirteen drugs were then screened for their ability to inhibit LPS-stimulated microglia proliferation. Female C57BL/6 mice were given LPS (1 mg/kg), and concomitant drug treatment while receiving 2H2O label for 7 days. Among the drugs screened, treatment with isotretinoin dose-dependently reduced LPS-induced microglial proliferation, representing an action of retinoids unknown previously. Follow-up studies in the EAE model confirmed that isotretinoin not only inhibited proliferation of microglia but also delayed the onset of clinical symptoms. In conclusion, 2H2O labeling represents a relatively high-throughput, quantitative, and highly reproducible technique for measuring microglial proliferation, and is useful for screening and discovering novel anti-neuroinflammatory drugs. Copyright 2007 Wiley-Liss, Inc.

  14. Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches.

    Science.gov (United States)

    Rueger, Maria Adele; Androutsellis-Theotokis, Andreas

    2013-01-01

    In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells.

  15. Exposure to household painting and floor treatments, and parental occupational paint exposure and risk of childhood brain tumors: results from an Australian case-control study.

    Science.gov (United States)

    Greenop, Kathryn R; Peters, Susan; Fritschi, Lin; Glass, Deborah C; Ashton, Lesley J; Bailey, Helen D; Scott, Rodney J; Daubenton, John; de Klerk, Nicholas H; Armstrong, Bruce K; Milne, Elizabeth

    2014-03-01

    Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. This study investigated whether household exposure to paints and floor treatments and parental occupational painting were associated with CBT risk in a population-based case-control study conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing, frequency matched to cases on age, sex, and state of residence. Data were obtained from parents in mailed questionnaires and telephone interviews. Information on domestic painting and floor treatments, and parental occupational exposure to paint, in key periods relating to the index pregnancy and childhood was obtained for 306 cases and 950 controls. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. Overall, we found little evidence that parental, fetal, or childhood exposure to home painting or floor treatments was associated with risk of CBT. There was, though, some evidence of a positive association between childhood exposure to indoor painting and risk of high-grade glioma [odds ratio (OR) 3.31, 95 % confidence interval (CI) 1.29, 8.52] based on very small numbers. The OR for the association between CBT and paternal occupational exposure to paint any time before the pregnancy was 1.32 (95 % CI 0.90, 1.92), which is consistent with the results of other studies. Overall, we found little evidence of associations between household exposure to paint and the risk of CBT in any of the time periods investigated.

  16. In vivo validation of reconstruction-based resolution recovery for human brain studies

    Science.gov (United States)

    Mourik, Jurgen EM; Lubberink, Mark; van Velden, Floris HP; Kloet, Reina W; van Berckel, Bart NM; Lammertsma, Adriaan A; Boellaard, Ronald

    2010-01-01

    The aim of this study was to validate in vivo the accuracy of a reconstruction-based partial volume correction (PVC), which takes into account the point spread function of the imaging system. The NEMA NU2 Image Quality phantom and five healthy volunteers (using [11C]flumazenil) were scanned on both HR+ and high-resolution research tomograph (HRRT) scanners. HR+ data were reconstructed using normalization and attenuation-weighted ordered subsets expectation maximization (NAW-OSEM) and a PVC algorithm (PVC-NAW-OSEM). HRRT data were reconstructed using 3D ordinary Poisson OSEM (OP-OSEM) and a PVC algorithm (PVC-OP-OSEM). For clinical studies, parametric volume of distribution (VT) images were generated. For phantom data, good recovery was found for both OP-OSEM (0.84 to 0.97) and PVC-OP-OSEM (0.91 to 0.98) HRRT reconstructions. In addition, for the HR+, good recovery was found for PVC-NAW-OSEM (0.84 to 0.94), corresponding well with OP-OSEM. Finally, for clinical data, good correspondence was found between PVC-NAW-OSEM and OP-OSEM-derived VT values (slope: 1.02±0.08). This study showed that HR+ image resolution using PVC-NAW-OSEM was comparable to that of the HRRT scanner. As the HRRT has a higher intrinsic resolution, this agreement validates reconstruction-based PVC as a means of improving the spatial resolution of the HR+ scanner and thereby improving the quantitative accuracy of positron emission tomography. PMID:19844240

  17. In vivo comparison of norepinephrine and dopamine release in rat brain by simultaneous measurements with fast-scan cyclic voltammetry.

    Science.gov (United States)

    Park, Jinwoo; Takmakov, Pavel; Wightman, R Mark

    2011-12-01

    Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. In this study, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle, the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra, the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode fast-scan cyclic voltammetry technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  18. Live cell imaging techniques to study T cell trafficking across the blood-brain barrier in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Coisne Caroline

    2013-01-01

    Full Text Available Abstract Background The central nervous system (CNS is an immunologically privileged site to which access for circulating immune cells is tightly controlled by the endothelial blood–brain barrier (BBB located in CNS microvessels. Under physiological conditions immune cell migration across the BBB is low. However, in neuroinflammatory diseases such as multiple sclerosis, many immune cells can cross the BBB and cause neurological symptoms. Extravasation of circulating immune cells is a multi-step process that is regulated by the sequential interaction of different adhesion and signaling molecules on the immune cells and on the endothelium. The specialized barrier characteristics of the BBB, therefore, imply the existence of unique mechanisms for immune cell migration across the BBB. Methods and design An in vitro mouse BBB model maintaining physiological barrier characteristics in a flow chamber and combined with high magnification live cell imaging, has been established. This model enables the molecular mechanisms involved in the multi-step extravasation of T cells across the in vitro BBB, to be defined with high-throughput analyses. Subsequently these mechanisms have been verified in vivo using a limited number of experimental animals and a spinal cord window surgical technique. The window enables live observation of the dynamic interaction between T cells and spinal cord microvessels under physiological and pathological conditions using real time epifluorescence intravital imaging. These in vitro and in vivo live cell imaging methods have shown that the BBB endothelium possesses unique and specialized mechanisms involved in the multi-step T cell migration across this endothelial barrier under physiological flow. The initial T cell interaction with the endothelium is either mediated by T cell capture or by T cell rolling. Arrest follows, and then T cells polarize and especially CD4+ T cells crawl over long distances against the direction of

  19. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    Science.gov (United States)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  20. Occupational exposure to electromagnetic fields, leukemia and brain cancer: update of two meta-analysis; Exposition professionnelle aux champs electromagnetiques, leucemie et cancer du cerveau: mise a jour de deux meta-analyses

    Energy Technology Data Exchange (ETDEWEB)

    Anon

    2008-11-15

    This new meta-analysis found a slight increase in the risk of brain cancer and of leukemia in populations occupationally exposed to electromagnetic fields. it does not, however, support the hypothesis that electromagnetic fields have an effect on these cancers. (author)

  1. Responses of the Human Brain to Mild Dehydration and Rehydration Explored In Vivo by 1H-MR Imaging and Spectroscopy.

    Science.gov (United States)

    Biller, A; Reuter, M; Patenaude, B; Homola, G A; Breuer, F; Bendszus, M; Bartsch, A J

    2015-12-01

    As yet, there are no in vivo data on tissue water changes and associated morphometric changes involved in the osmo-adaptation of normal brains. Our aim was to evaluate osmoadaptive responses of the healthy human brain to osmotic challenges of de- and rehydration by serial measurements of brain volume, tissue fluid, and metabolites. Serial T1-weighted and (1)H-MR spectroscopy data were acquired in 15 healthy individuals at normohydration, on 12 hours of dehydration, and during 1 hour of oral rehydration. Osmotic challenges were monitored by serum measures, including osmolality and hematocrit. MR imaging data were analyzed by using FreeSurfer and LCModel. On dehydration, serum osmolality increased by 0.67% and brain tissue fluid decreased by 1.63%, on average. MR imaging morphometry demonstrated corresponding decreases of cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus. These changes reversed during rehydration. Continuous fluid ingestion of 1 L of water for 1 hour within the scanner lowered serum osmolality by 0.96% and increased brain tissue fluid by 0.43%, on average. Concomitantly, cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus increased. Changes in brain tissue fluid were related to volume changes of the whole brain, the white matter, and hypothalamus/thalamus. Only volume changes of the hypothalamus/thalamus significantly correlated with serum osmolality. This is the first study simultaneously evaluating changes in brain tissue fluid, metabolites, volume, and cortical thickness. Our results reflect cellular volume regulatory mechanisms at a macroscopic level and emphasize that it is essential to control for hydration levels in studies on brain morphometry and metabolism in order to avoid confounding the findings. © 2015 by American Journal of Neuroradiology.

  2. In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1(G93A) ALS rat model.

    Science.gov (United States)

    Stamenković, Stefan; Pavićević, Aleksandra; Mojović, Miloš; Popović-Bijelić, Ana; Selaković, Vesna; Andjus, Pavle; Bačić, Goran

    2017-07-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor pathways of the central nervous system. Although a number of pathophysiological mechanisms have been described in the disease, post mortem and animal model studies indicate blood-brain barrier (BBB) disruption and elevated production of reactive oxygen species as major contributors to disease pathology. In this study, the BBB permeability and the brain tissue redox status of the SOD1(G93A) ALS rat model in the presymptomatic (preALS) and symptomatic (ALS) stages of the disease were investigated by in vivo EPR spectroscopy using three aminoxyl radicals with different cell membrane and BBB permeabilities, Tempol, 3-carbamoyl proxyl (3CP), and 3-carboxy proxyl (3CxP). Additionally, the redox status of the two brain regions previously implicated in disease pathology, brainstem and hippocampus, was investigated by spectrophotometric biochemical assays. The EPR results indicated that among the three spin probes, 3CP is the most suitable for reporting the intracellular redox status changes, as Tempol was reduced in vivo within minutes (t1/2 =2.0±0.5min), thus preventing reliable kinetic modeling, whereas 3CxP reduction kinetics gave divergent conclusions, most probably due to its membrane impermeability. It was observed that the reduction kinetics of 3CP in vivo, in the head of preALS and ALS SOD1(G93A) rats was altered compared to the controls. Pharmacokinetic modeling of 3CP reduction in vivo, revealed elevated tissue distribution and tissue reduction rate constants indicating an altered brain tissue redox status, and possibly BBB disruption in these animals. The preALS and ALS brain tissue homogenates also showed increased nitrilation, superoxide production, lipid peroxidation and manganese superoxide dismutase activity, and a decreased copper-zinc superoxide dismutase activity. The present study highlights in vivo EPR spectroscopy as a reliable tool for the investigation of

  3. Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.

    Science.gov (United States)

    Varnäs, Katarina; Finnema, Sjoerd J; Stepanov, Vladimir; Takano, Akihiro; Tóth, Miklós; Svedberg, Marie; Møller Nielsen, Søren; Khanzhin, Nikolay A; Juhl, Karsten; Bang-Andersen, Benny; Halldin, Christer; Farde, Lars

    2016-08-01

    Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein. A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey. The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding. Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  4. Two-photon microscopy imaging of thy1GFP-M transgenic mice: a novel animal model to investigate brain dendritic cell subsets in vivo.

    Directory of Open Access Journals (Sweden)

    Claudia Laperchia

    Full Text Available Transgenic mice expressing fluorescent proteins in specific cell populations are widely used for in vivo brain studies with two-photon fluorescence (TPF microscopy. Mice of the thy1GFP-M line have been engineered for selective expression of green fluorescent protein (GFP in neuronal populations. Here, we report that TPF microscopy reveals, at the brain surface of these mice, also motile non-neuronal GFP+ cells. We have analyzed the behavior of these cells in vivo and characterized in brain sections their immunophenotype.With TPF imaging, motile GFP+ cells were found in the meninges, subarachnoid space and upper cortical layers. The striking feature of these cells was their ability to move across the brain parenchyma, exhibiting evident shape changes during their scanning-like motion. In brain sections, GFP+ cells were immunonegative to antigens recognizing motile cells such as migratory neuroblasts, neuronal and glial precursors, mast cells, and fibroblasts. GFP+ non-neuronal cells exhibited instead the characteristic features and immunophenotype (CD11c and major histocompatibility complex molecule class II immunopositivity of dendritic cells (DCs, and were immunonegative to the microglial marker Iba-1. GFP+ cells were also identified in lymph nodes and blood of thy1GFP-M mice, supporting their identity as DCs. Thus, TPF microscopy has here allowed the visualization for the first time of the motile behavior of brain DCs in situ. The results indicate that the thy1GFP-M mouse line provides a novel animal model for the study of subsets of these professional antigen-presenting cells in the brain. Information on brain DCs is still very limited and imaging in thy1GFP-M mice has a great potential for analyses of DC-neuron interaction in normal and pathological conditions.

  5. In vivo evaluation of P-glycoprotein and breast cancer resistance protein modulation in the brain using [{sup 11}C]gefitinib

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Kazunori [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)], E-mail: kawamur@nirs.go.jp; Yamasaki, Tomoteru; Yui, Joji; Hatori, Akiko; Konno, Fujiko; Kumata, Katsushi; Irie, Toshiaki; Fukumura, Toshimitsu; Suzuki, Kazutoshi; Kanno, Iwao; Zhang Mingrong [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)

    2009-04-15

    Gefitinib (Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Recent studies confirmed that gefitinib interacted with the breast cancer resistance protein (BCRP) at submicromolar concentrations, whereas other multidrug transporters, including P-glycoprotein (P-gp), showed much lower reactivity toward gefitinib. Recently, many tracers for positron emission tomography (PET) have been prepared to study P-gp function in vivo; however, PET tracers had not been evaluated for both P-gp and BCRP modulation in the brain. Therefore, we evaluated in vivo brain penetration-mediated P-gp and BCRP in mice using [{sup 11}C]gefitinib. Co-injection with gefitinib (over 50 mg/kg), a nonspecific P-gp modulator cyclosporin A (50 mg/kg), and the dual P-gp and BCRP modulator GF120918 (over 5 mg/kg) induced an increase in the brain uptake of [{sup 11}C]gefitinib in mice 30 min after injection. In the PET study of mice, the radioactivity level in the brain with co-injection of GF120918 (5 mg/kg) was three- to fourfold higher than that in control after initial uptake. The radioactivity level in the brain in P-gp and Bcrp knockout mice was approximately eightfold higher than that in wild-type mice 60 min after injection. In conclusion, [{sup 11}C]gefitinib is a promising PET tracer to evaluate the penetration of gefitinib into the brain by combined therapy with P-gp or BCRP modulators, and into brain tumors. Furthermore, PET study with GF120918 is a promising approach for evaluating brain penetration-mediated P-gp and BCRP.

  6. Two-Photon Microscopy Imaging of thy1GFP-M Transgenic Mice: A Novel Animal Model to Investigate Brain Dendritic Cell Subsets In Vivo

    Science.gov (United States)

    Laperchia, Claudia; Allegra Mascaro, Anna L.; Sacconi, Leonardo; Andrioli, Anna; Mattè, Alessandro; De Franceschi, Lucia; Grassi-Zucconi, Gigliola; Bentivoglio, Marina; Buffelli, Mario; Pavone, Francesco S.

    2013-01-01

    Transgenic mice expressing fluorescent proteins in specific cell populations are widely used for in vivo brain studies with two-photon fluorescence (TPF) microscopy. Mice of the thy1GFP-M line have been engineered for selective expression of green fluorescent protein (GFP) in neuronal populations. Here, we report that TPF microscopy reveals, at the brain surface of these mice, also motile non-neuronal GFP+ cells. We have analyzed the behavior of these cells in vivo and characterized in brain sections their immunophenotype. With TPF imaging, motile GFP+ cells were found in the meninges, subarachnoid space and upper cortical layers. The striking feature of these cells was their ability to move across the brain parenchyma, exhibiting evident shape changes during their scanning-like motion. In brain sections, GFP+ cells were immunonegative to antigens recognizing motile cells such as migratory neuroblasts, neuronal and glial precursors, mast cells, and fibroblasts. GFP+ non-neuronal cells exhibited instead the characteristic features and immunophenotype (CD11c and major histocompatibility complex molecule class II immunopositivity) of dendritic cells (DCs), and were immunonegative to the microglial marker Iba-1. GFP+ cells were also identified in lymph nodes and blood of thy1GFP-M mice, supporting their identity as DCs. Thus, TPF microscopy has here allowed the visualization for the first time of the motile behavior of brain DCs in situ. The results indicate that the thy1GFP-M mouse line provides a novel animal model for the study of subsets of these professional antigen-presenting cells in the brain. Information on brain DCs is still very limited and imaging in thy1GFP-M mice has a great potential for analyses of DC-neuron interaction in normal and pathological conditions. PMID:23409142

  7. Active MR-temperature feedback control of dynamic interstitial ultrasound therapy in brain: in vivo experiments and modeling in native and coagulated tissues.

    Science.gov (United States)

    N'Djin, W A; Burtnyk, M; Lipsman, N; Bronskill, M; Kucharczyk, W; Schwartz, M L; Chopra, R

    2014-09-01

    The recent clinical emergence of minimally invasive image-guided therapy has demonstrated promise in the management of brain metastasis, although control over the spatial pattern of heating currently remains limited. Based on experience in other organs, the delivery of high-intensity contact ultrasound energy from minimally invasive applicators can enable accurate spatial control of energy deposition, large treatment volumes, and high treatment rate. In this acute study, the feasibility of active MR-Temperature feedback control of dynamic ultrasound heat deposition for interstitial thermal ablation in brain was evaluatedin vivo. A four-element linear ultrasound transducer (f=8.2 MHz) originally developed for transurethral ultrasound therapy was used in a porcine model for generating thermal ablations in brain interstitially. First, the feasibility of treating and retreating preciselyin vivo brain tissues using stationary (non-rotating device) ultrasound exposures was studied in two pigs. Experimental results were compared to numerical simulations for maximum surface acoustic intensities ranging from 5 to 20 W cm(-2). Second, active MRT feedback-controlled ultrasound treatments were performed in three pigs with a rotating device to coagulate target volumes of various shapes. The acoustic power and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary. Modeling of in vivo treatments were performed and compared to observed experimental results. Overall, the time-space evolution of the temperature profiles observedin vivo could be well estimated from numerical simulations for both stationary and dynamic interstitial ultrasound exposures. Dynamic exposures performed under closed-loop temperature control enabled accurate elevation of the brain tissues within the targeted region above the 55 °C threshold necessary for the creation of irreversible thermal damage. Treatment

  8. Hyperbaric oxygen preconditioning ameliorates hypoxia-ischemia brain damage by activating Nrf2 expression in vivo and in vitro.

    Science.gov (United States)

    Zhai, Xiao; Lin, Han; Chen, Yu; Chen, Xiao; Shi, Jiazi; Chen, Ouyang; Li, Jiasi; Sun, Xuejun

    2016-01-01

    The present study aimed to investigate whether hyperbaric oxygen preconditioning (HBO-PC) could ameliorate hypoxia-ischemia brain damage (HIBD) by an increase of Nrf2 expression. P7 Sprague-Dawley rats (aged 7 d, n = 195) were used in two in vivo experiments, including BO-PC exposure experiments in non-HIBD models and treatment experiments in HIBD models. 2,3,5-triphenyltetrazolium chloride (TTC) staining, Nissl Staining, and TUNEL staining were performed. And expressions of Nrf2, HO-1, and GSTs were measured. For in vitro studies, oxygen-glucose deprivation cells were established. Morphological and apoptotic staining and gene silencing of Nrf2 by siRNA transfection were investigated. For exposure experiments, HBO-PC for longer time increased the expression of Nrf2 significantly. And for treatment experiments, HBO-PC treatment significantly decreased infarction area, lessened neuronal injury, reduced apoptosis, and increased both the expression of Nrf2 and activities of its downstream proteins. Cytology tests confirmed effects of HBO-PC treatments. Besides, Nrf2 siRNA significantly reduced protective effects of HBO-PC. These observations demonstrated that an up-regulation of Nrf2 by HBO-PC might play an important role in the generation of tolerance against HIBD.

  9. Whole-brain in-vivo measurements of the axonal g-ratio in a group of 37 healthy volunteers

    Directory of Open Access Journals (Sweden)

    Siawoosh eMohammadi

    2015-11-01

    Full Text Available The g-ratio, quantifying the ratio between the inner and outer diameters of a fiber, is an important microstructural characteristic of fiber pathways and is functionally related to conduction velocity. We introduce a novel method for estimating the MR g-ratio non-invasively across the whole brain using high-fidelity magnetization transfer (MT imaging and single-shell diffusion MRI. These methods enabled us to map the MR g-ratio in vivo across the brain’s prominent fiber pathways in a group of 37 healthy volunteers and to estimate the inter-subject variability. Effective correction of susceptibility-related distortion artifacts was essential before combining the MT and diffusion data, in order to reduce partial volume and edge artifacts. The MR g-ratio is in good qualitative agreement with histological findings despite the different resolution and spatial coverage of MRI and histology. The MR g-ratio holds promise as an important non-invasive biomarker due to its microstructural and functional relevance in neurodegeneration.

  10. A novel bioelectronic nose based on brain-machine interface using implanted electrode recording in vivo in olfactory bulb.

    Science.gov (United States)

    Dong, Qi; Du, Liping; Zhuang, Liujing; Li, Rong; Liu, Qingjun; Wang, Ping

    2013-11-15

    The mammalian olfactory system has merits of higher sensitivity, selectivity and faster response than current electronic nose system based on chemical sensor array. It is advanced and feasible to detect and discriminate odors by mammalian olfactory system. The purpose of this study is to develop a novel bioelectronic nose based on the brain-machine interface (BMI) technology for odor detection by in vivo electrophysiological measurements of olfactory bulb. In this work, extracellular potentials of mitral/tufted (M/T) cells in olfactory bulb (OB) were recorded by implanted 16-channel microwire electrode arrays. The odor-evoked response signals were analyzed. We found that neural activities of different neurons showed visible different firing patterns both in temporal features and rate features when stimulated by different small molecular odorants. The detection low limit is below 1 ppm for some specific odors. Odors were classified by an algorithm based on population vector similarity and support vector machine (SVM). The results suggested that the novel bioelectonic nose was sensitive to odorant stimuli. The best classifying accuracy was up to 95%. With the development of the BMI and olfactory decoding methods, we believe that this system will represent emerging and promising platforms for wide applications in medical diagnosis and security fields. Copyright © 2013. Published by Elsevier B.V.

  11. 350-μm side-view optical probe for imaging the murine brain in vivo from the cortex to the hypothalamus

    Science.gov (United States)

    Kim, Jun Ki; Choi, Jin Woo; Yun, Seok Hyun

    2013-05-01

    Miniature endoscopic probes offer a solution for deep brain imaging by overcoming the limited depth of intravital microscopy. We describe a small-diameter (350 μm) graded-index optical probe with a side-view design for in vivo cellular imaging of the mammalian brain. The side-view probe provides a unique view of the vertical network of neurons and penetrating blood vessels. At a given insertion site, the translational and rotational scanning of the probe provides access to a large tissue area (>) across the cortex, hippocampus, thalamus, and hypothalamus.

  12. Stabilization of Prussian blue with polyaniline and carbon nanotubes in neutral media for in vivo determination of glucose in rat brains.

    Science.gov (United States)

    Li, Ruixin; Guo, Deyin; Ye, Jianshan; Zhang, Meining

    2015-06-07

    This study demonstrates a new electrochemical microbiosensor for selective in vivo monitoring of glucose in rat brains. The microbiosensor is prepared by using Prussian blue (PB)/polyaniline (PANI)/multi-walled carbon nanotubes (MWNTs) as the electrocatalyst for the reduction and determination of H2O2 generated from the glucose oxidase (GOx)-based enzymatic catalytic reaction. PANI and MWNTs are used to stabilize PB nanoparticles in physiological solutions. As a result, the as-formed three-dimensional (3D) PB/PANI/MWNT nanostructure exhibits a stable and large electrochemical response compared to the PB-modified electrode. The use of PB/PANI/MWNTs in this work to replace "natural peroxidase" (i.e., horseradish peroxidase) used in the existing microbiosensors enables the method developed here to be facile but selective for in vivo measurements of glucose virtually interference-free from ascorbic acid and other electroactive species coexisting in the brain. This property, along with the good linearity and stability toward glucose, makes this microbiosensor competent for continuous in vivo monitoring of the changes of glucose in rat brains during intraperitoneal injection of insulin. The method demonstrated here can be applied to develop other oxidase-based microbiosensors for other neurochemicals, which would be helpful for understanding the chemical process involved in some physiological and pathological events.

  13. In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1.

    Science.gov (United States)

    Thiesen, Louise; Kehler, Jan; Clausen, Rasmus P; Frølund, Bente; Bundgaard, Christoffer; Wellendorph, Petrine

    2015-08-01

    γ-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance that binds to both high- and low-affinity sites in the brain. For studying the molecular mechanisms and the biologic role of the GHB high-affinity binding sites, ligands with high and specific affinity are essential. The conformationally restricted GHB analog HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) is one such compound. The objective of this study was to investigate the transport of HOCPCA across the blood-brain barrier in vitro and in vivo and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, -2, and -4 were recombinantly expressed in Xenopus laevis oocytes, and the previously reported radioligand [(3)H]HOCPCA was used as substrate. HOCPCA inhibited the uptake of the endogenous MCT substrate l-[(14)C]lactate, and [(3)H]HOCPCA was shown to act as substrate for MCT1 and 2 (Km values in the low- to mid-millimolar range). Introducing single-point amino acid mutations into positions essential for MCT function supported that HOCPCA binds to the endogenous substrate pocket of MCTs. MCT1-mediated brain entry of HOCPCA (10 mg/kg s.c.) was further confirmed in vivo in mice by coadministration of increasing doses of the MCT inhibitor AR-C141990 [(R)-5-(3-hydroxypyrrolidine-1-carbonyl)-1-isobutyl-3-methyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione], which inhibited brain penetration of HOCPCA in a dose-dependent manner (ID50 = 4.6 mg/kg). Overall, our study provides evidence that MCT1 is an important brain entry site for HOCPCA and qualifies for future in vivo studies with HOCPCA. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Evaluation of the binding of the radiolabeled antidepressant drug, {sup 18}F-fluoxetine in the rodent brain: an in vitro and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar E-mail: jogeshwar_mukherjee@ketthealth.com; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-10-01

    We have developed {sup 18}F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of {sup 18}F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of {sup 18}F-fluoxetine was not obtained. Even when fluoxetine (10 {mu}M) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of {sup 18}F-fluoxetine. Ex vivo autoradiographic experiments with {sup 18}F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of {sup 18}F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of {sup 18}F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with {sup 18}F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of {sup 18}F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

  15. In vivo binding of /sup 125/I-LSD to serotonin 5-HT/sub 2/ receptors in mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Hartig, P.R.; Scheffel, U., Frost, J.J.; Wagner, H.N. Jr.

    1985-08-19

    The binding of /sup 125/I-LSD (2-(/sup 125/I)-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of /sup 125/I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of /sup 125/I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of /sup 125/I-LSD. Serotonergic compounds potently inhibited /sup 125/I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that /sup 125/I-LSD labels serotonin 5-HT/sub 2/ receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, /sup 125/I-LSD labeling occurs predominantly or entirely at serotonic 5-HT/sub 2/ sites. In the striatum, /sup 125/I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that /sup 125/I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT/sub 2/ receptors in the mammalian cortex.

  16. Post-injury administration of allicin attenuates ischemic brain injury through sphingosine kinase 2: In vivo and in vitro studies.

    Science.gov (United States)

    Lin, Jia-Ji; Chang, Ting; Cai, Wen-Ke; Zhang, Zhuo; Yang, Yong-Xiang; Sun, Chao; Li, Zhu-Yi; Li, Wei-Xin

    2015-10-01

    Allicin, one of the main biologically active compounds derived from garlic, has been shown to exert various pharmacological activities and is considered to have therapeutic potential for many pathologic conditions. In the present study, we investigated the potential post-ischemic neuroprotective effects of allicin and its underlying mechanisms. Using a rat middle cerebral artery occlusion (MCAO) model, we found that intraperitoneal treatment with 50 mg/kg allicin significantly reduced brain infarct volume, attenuated cerebral edema and decreased the neurological deficit score. Allicin treatment also diminished TUNEL positive cells and inhibited the activation of caspase-3 after MCAO. These protective effects could be observed even if the administration was delayed to 6 h after injury. In addition, we evaluated the in vitro protective effects of allicin against oxygen glucose deprivation (OGD) induced neuronal injury in primary cultured cortical neurons. Allicin (50 μM) increased neuronal viability, decreased lactate dehydrogenase (LDH) release and inhibited apoptotic neuronal death after OGD. These protective effects could be observed even if the administration was delayed to 4 h after injury. Furthermore, allicin significantly increased the expression of sphingosine kinases 2 (Sphk2) both in vivo and in vitro. Pretreatment with the Sphk2 inhibitor ABC294640 partially reversed the protective effects of allicin against MCAO and OGD injury, indicating that an Sphk2-mediated mechanism was involved in allicin-induced protection in our models. The combination of findings suggests that post-injury administration of allicin has potential as a neuroprotective strategy for ischemic stroke. Copyright © 2015. Published by Elsevier Ltd.

  17. Normothermic Ex Vivo Lung Perfusion in Brain-dead Donors Reduces Inflammatory Cytokines and Toll-like Receptor Expression.

    Science.gov (United States)

    Shafaghi, Shadi; Mortaz, Esmaeil; Abbasi Dezfuli, Azizollah; Godarzi, Hoda; Sheikhy, Kambiz; Ansari Aval, Zahra; Farzanegan, Behrooz; Emami, Habib; Hosseini-Baharanchi, Fatemeh Sadat; Najafizadeh, Katayoun

    2016-10-01

    Inflammatory responses and innate immunologic reactions play an important role in the respiratory system. Ex vivo lung perfusion (EVLP) is considered a novel method in the evaluation and reconditioning of donor lungs prior to transplantation. However, EVLP's effect on inflammatory and metabolic markers of human lung tissue is unknown.  This study investigated how the performance of EVLP on brain-dead (BD) donor lungs affects the production and release of inflammatory cytokines (IL-6, IL-8, and TNF-a), inflammatory cells and toll-like receptors (TLR) -2, 4. This study was conducted with an animal subject for qualification of EVLP team and then EVLP was performed on 4 human cases referred to Masih Daneshvari Hospital (Tehran,Iran), from May 2013 to July 2015. Two of these cases, who had acceptable lung function parameters, were enrolled in this study for immunologic investigations. Bronchoalveolar lavages (BAL) were taken before and after EVLP. Cytokines were quantitatively measured before lung retrieval, at the end of the lung removal, at the start of EVLP, and at the end of the each hour of EVLP. TLR expression was measured on the cells obtained by flow cytometry. TNF-a, IL-6 and IL-8 decreased in each stage of washing perfusate in both cases, and the level of cytokines in serum was in the normal range. Flow cytometry analysis revealed a decreasing expression of CD3, CD4/8, CD19, and CD16+56, as well as TLR-2 and TLR-4 in both cases. Intra-capillary pools of pro-inflammatory cytokines (IL-6, IL-8, and TNF-a) were determined to contribute to the lung injury during prolonged lung perfusion. This raises the possibility that EVLP donor lungs could be less immunogenic than standard lungs. However, to assess EVLP's effects on lung grafts and optimize recipient outcomes, further studies with a sufficient number of lungs are required.

  18. Mapping measures of microscopic diffusion anisotropy in human brain white matter in vivo with double-wave-vector diffusion-weighted imaging.

    Science.gov (United States)

    Lawrenz, Marco; Finsterbusch, Jürgen

    2015-02-01

    To demonstrate that rotationally invariant measures of the diffusion anisotropy on a microscopic scale can be mapped in human brain white matter in vivo. Echo-planar imaging experiments (resolution 3.0 × 3.0 × 3.0 mm(3) ) involving two diffusion-weighting periods (δ = 22 ms, Δ = 25 ms) in the same acquisition, so-called double-wave-vector or double-pulsed-field-gradient diffusion-weighting experiments, were performed on a 3 T whole-body magnetic resonance system with a long mixing time ( τm=45 ms) between the two diffusion weightings. The disturbing influences of background gradient fields, eddy currents, and the finite mixing time can be minimized using 84 direction combinations based on nine directions and their antipodes. In healthy volunteers, measures of the microscopic diffusion anisotropy ( IMA and MA indexes) could be mapped in white matter across the human brain. The measures were independent (i) of the absolute orientation of the head and of the diffusion directions and (ii) of the predominant fiber orientation. Compared to the fractional anisotropy derived from the conventional diffusion tensor, the double-wave-vector indexes exhibit a narrower distribution, which could reflect their independence of the fiber orientation distribution. Mapping measures of the microscopic diffusion anisotropy in human brain white matter is feasible in vivo and could help to characterize tissue microstructure in the healthy and pathological brain. © 2014 Wiley Periodicals, Inc.

  19. Evaluation of the binding characteristics of [{sup 18}F]fluoroproxyfan in the rat brain for in vivo visualization of histamine H{sub 3} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Funaki, Yoshihito [Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578 (Japan)], E-mail: zen@cyric.tohoku.ac.jp; Sato, Kimihiko [Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578 (Japan); Kato, Motohisa [Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Ishikawa, Yoichi; Iwata, Ren [Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578 (Japan); Yanai, Kazuhiko [Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan)

    2007-11-15

    Histamine H{sub 3} receptors play an important role in biological functions. The aim of this research was to examine whether histamine H{sub 3} receptors can be visualized in vivo and in vitro with [{sup 18}F]3-(1H-imidazol-4-yl)propyl 4-fluorobenzyl ether (fluoroproxyfan). [{sup 18}F]Fluoroproxyfan was synthesized with high specific activity using [{sup 18}F]benzyl bromide. The binding of [{sup 18}F]fluoroproxyfan to rat brain homogenates was higher in the striatum and thalamus and was lowest in the cerebellum. The in vitro autoradiographic study successfully demonstrated the specific binding of [{sup 18}F]fluoroproxyfan to the H{sub 3} receptor in the rat brain. In accordance with the in vitro bindings, the in vivo distribution of [{sup 18}F]fluoroproxyfan was heterogeneous in the rat brain. In the blocking experiments, the heterogeneous distribution disappeared in the presence of large amounts of fluoroproxyfan. These data suggest that [{sup 18}F]fluoroproxyfan can be potentially useful to image histamine H{sub 3} receptor noninvasively in the human brain by positron emission tomography.

  20. Ex-Vivo Characterization of Bioimpedance Spectroscopy of Normal, Ischemic and Hemorrhagic Rabbit Brain Tissue at Frequencies from 10 Hz to 1 MHz

    Directory of Open Access Journals (Sweden)

    Lin Yang

    2016-11-01

    Full Text Available Stroke is a severe cerebrovascular disease and is the second greatest cause of death worldwide. Because diagnostic tools (CT and MRI to detect acute stroke cannot be used until the patient reaches the hospital setting, a portable diagnostic tool is urgently needed. Because biological tissues have different impedance spectra under normal physiological conditions and different pathological states, multi-frequency electrical impedance tomography (MFEIT can potentially detect stroke. Accurate impedance spectra of normal brain tissue (gray and white matter and stroke lesions (ischemic and hemorrhagic tissue are important elements when studying stroke detection with MFEIT. To our knowledge, no study has comprehensively measured the impedance spectra of normal brain tissue and stroke lesions for the whole frequency range of 1 MHz within as short as possible an ex vivo time and using the same animal model. In this study, we established intracerebral hemorrhage and ischemic models in rabbits, then measured and analyzed the impedance spectra of normal brain tissue and stroke lesions ex vivo within 15 min after animal death at 10 Hz to 1 MHz. The results showed that the impedance spectra of stroke lesions significantly differed from those of normal brain tissue; the ratio of change in impedance of ischemic and hemorrhagic tissue with regard to frequency was distinct; and tissue type could be discriminated according to its impedance spectra. These findings further confirm the feasibility of detecting stroke with MFEIT and provide data supporting further study of MFEIT to detect stroke.

  1. CCL2-Expressing Astrocytes Mediate the Extravasation of T Lymphocytes in the Brain. Evidence from Patients with Glioma and Experimental Models In Vivo

    Science.gov (United States)

    Ros, Carmen María; Ros-Bernal, Francisco; Martín, Eduardo D.; Perez-Vallés, Ana; Gallego-Sanchez, José M.; Fernández-Villalba, Emiliano; Barcia, Carlos; Barcia, Carlos; Herrero, Maria-Trinidad

    2012-01-01

    CCL2 is a chemokine involved in brain inflammation, but the way in which it contributes to the entrance of lymphocytes in the parenchyma is unclear. Imaging of the cell type responsible for this task and details on how the process takes place in vivo remain elusive. Herein, we analyze the cell type that overexpresses CCL2 in multiple scenarios of T-cell infiltration in the brain and in three different species. We observe that CCL2+ astrocytes play a part in the infiltration of T-cells in the brain and our analysis shows that the contact of T-cells with perivascular astrocytes occurs, suggesting that may be an important event for lymphocyte extravasation. PMID:22319587

  2. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes

    National Research Council Canada - National Science Library

    Hong, Soyon; Ostaszewski, Beth L; Yang, Ting; O'Malley, Tiernan T; Jin, Ming; Yanagisawa, Katsuhiko; Li, Shaomin; Bartels, Tim; Selkoe, Dennis J

    2014-01-01

    .... Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ...

  3. Occupational Therapy's Role with Autism

    Science.gov (United States)

    Fact Sheet Occupational Therapy’s Role with Autism Autism is a developmental disorder—typically diagnosed around age 3 years— that affects brain functions, specifically those areas that control social behaviors ...

  4. A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype

    Energy Technology Data Exchange (ETDEWEB)

    Gitler, M.S.; Cohen, V.I.; De La Cruz, R.; Boulay, S.F.; Jin, B.; Zeeberg, B.R. (George Washington Univ. Medical Center, Washington, DC (United States)); Reba, R.C. (George Washington Univ. Medical Center, Washington, DC (United States) Univ. of Chicago Hospital, IL (United States))

    1993-01-01

    Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, the authors have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [[sup 3]H](R)-3-quinuclidinylbenzilate ([[sup 3]H]QNB) and [[sup 3]H]N-methylscopolamine ([[sup 3]H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[[sup 125]I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[[sup 125]I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. The authors conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system.

  5. FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

    Science.gov (United States)

    2012-01-01

    Phosphocreatine is a major cellular source of high energy phosphates, which is crucial to maintain cell viability under conditions of impaired metabolic states, such as decreased oxygen and energy availability (i.e., ischemia). Many methods exist for the bulk analysis of phosphocreatine and its dephosphorylated product creatine; however, no method exists to image the distribution of creatine or phosphocreatine at the cellular level. In this study, Fourier transform infrared (FTIR) spectroscopic imaging has revealed the ex vivo development of creatine microdeposits in situ in the brain region most affected by the disease, the cerebellum of cerebral malaria (CM) diseased mice; however, such deposits were also observed at significantly lower levels in the brains of control mice and mice with severe malaria. In addition, the number of deposits was observed to increase in a time-dependent manner during dehydration post tissue cutting. This challenges the hypotheses in recent reports of FTIR spectroscopic imaging where creatine microdeposits found in situ within thin sections from epileptic, Alzheimer’s (AD), and amlyoid lateral sclerosis (ALS) diseased brains were proposed to be disease specific markers and/or postulated to contribute to the brain pathogenesis. As such, a detailed investigation was undertaken, which has established that the creatine microdeposits exist as the highly soluble HCl salt or zwitterion and are an ex-vivo tissue processing artifact and, hence, have no effect on disease pathogenesis. They occur as a result of creatine crystallization during dehydration (i.e., air-drying) of thin sections of brain tissue. As ischemia and decreased aerobic (oxidative metabolism) are common to many brain disorders, regions of elevated creatine-to-phosphocreatine ratio are likely to promote crystal formation during tissue dehydration (due to the lower water solubility of creatine relative to phosphocreatine). The results of this study have demonstrated that

  6. Bilastine vs. hydroxyzine: occupation of brain histamine H1 -receptors evaluated by positron emission tomography in healthy volunteers.

    Science.gov (United States)

    Farré, Magí; Pérez-Mañá, Clara; Papaseit, Esther; Menoyo, Esther; Pérez, Marta; Martin, Soraya; Bullich, Santiago; Rojas, Santiago; Herance, José-Raúl; Trampal, Carlos; Labeaga, Luis; Valiente, Román

    2014-11-01

    A close correlation exists between positron emission tomography (PET)-determined histamine H1 -receptor occupancy (H1 RO) and the incidence of sedation. Antihistamines with H1 RO bilastine, a second generation antihistamine, with that of hydroxyzine. This randomized, double-blind, crossover study used PET imaging with [(11) C]-doxepin to evaluate H1 RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1 ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P bilastine and placebo. Overall H1 RO by bilastine was significantly lower than that by hydroxyzine (mean value -3.92% vs. 53.95%, P bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. A single oral dose of bilastine 20 mg had minimal H1 RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine. © 2014 The British Pharmacological Society.

  7. Evaluation of the binding characteristics of [5-{sup 11}C-methoxy]donepezil in the rat brain for in vivo visualization of acetylcholinesterase

    Energy Technology Data Exchange (ETDEWEB)

    Funaki, Yoshihito; Iwata, Ren; Ido, Tatsuo [Tohoku Univ., Sendai (Japan). Cyclotron and Radioisotope Center; Kato, Motohisa; Sakurai, Eiko; Tashiro, Manabu; Yanai, Kazuhiko [Tohoku Univ., Sendai (Japan). Graduate School of Medicine; Sakurai, Eiichi [Tohoku Coll. of Pharmacy, Sendai (Japan)

    2003-02-01

    Donepezil, an acetylcholinesterase (AChE) inhibitor, has not been evaluated for its binding characteristics using a radioactive tracer, although its inhibitory action on AChE has been studied. The aim of this research is to examine whether AChE can be visualized in vivo and in vitro with [{sup 11}C]donepezil. [5-{sup 11}C-methoxy]donepezil was synthesized by O-methylation using [{sup 11}C]methyl triflate. The binding of [{sup 11}C]donepezil to brain homogenates was higher in the brain stem and striatum, and it was lowest in the cerebellum. The in vitro autoradiographic study successfully demonstrated the specific binding of [{sup 11}C]donepezil to AChE in the rat brain. The IC{sub 50} value of binding was approximately 10 nM, which is comparable to the reported value for inhibiting enzyme activity (6 nM). Saturation experiments revealed that the B{sub max} and K{sub d} of [{sup 11}C]donepezil binding in vitro are 65 fmol/mg tissue and 39.8 nM, respectively. In accordance with the in vitro bindings, the in vivo distribution of [{sup 11}C]donepezil was heterogeneous in the rat brain. In the blocking experiments, the heterogeneous distribution disappeared in the presence of a large amount of unlabeled donepezil. These data suggest that [5-{sup 11}C-methoxy]donepezil can be potentially useful to image AChE non-invasively in the human brain by positron emission tomography. (author)

  8. Brain Activity of Thioctic Acid Enantiomers: In Vitro and in Vivo Studies in an Animal Model of Cerebrovascular Injury

    Directory of Open Access Journals (Sweden)

    Seyed Khosrow Tayebati

    2013-02-01

    Full Text Available Oxidative stress is an imbalance between the production of free radicals and antioxidant defense mechanisms, potentially leading to tissue damage. Oxidative stress has a key role in the development of cerebrovascular and/or neurodegenerative diseases. This phenomenon is mainly mediated by an enhanced superoxide production by the vascular endothelium with its consequent dysfunction. Thioctic, also known as alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid, is a naturally occurring antioxidant that neutralizes free radicals in the fatty and watery regions of cells. Both the reduced and oxidized forms of the compound possess antioxidant ability. Thioctic acid has two optical isomers designated as (+- and (−-thioctic acid. Naturally occurring thioctic acid is the (+-thioctic acid form, but the synthetic compound largely used in the market for stability reasons is a mixture of (+- and (−-thioctic acid. The present study was designed to compare the antioxidant activity of the two enantiomers versus the racemic form of thioctic acid on hydrogen peroxide-induced apoptosis in a rat pheochromocytoma PC12 cell line. Cell viability was evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay and free oxygen radical species (ROS production was assessed by flow cytometry. Antioxidant activity of the two enantiomers and the racemic form of thioctic acid was also evaluated in spontaneously hypertensive rats (SHR used as an in vivo model of increased oxidative stress. A 3-h exposure of PC12 cells to hydrogen peroxide (H2O2 significantly decreased cell viability and increased levels of intracellular ROS production. Pre-treatment with racemic thioctic acid or (+-enantiomer significantly inhibited H2O2-induced decrease in cell viability from the concentration of 50 μmol/L and 20 μmol/L, respectively. Racemic thioctic acid and (+-salt decreased levels of intracellular ROS, which were unaffected by (−-thioctic acid. In the brain of

  9. Six fucose-α(1-2) sugars and α-fucose assigned in the human brain using in vivo two-dimensional MRS.

    Science.gov (United States)

    Mountford, Carolyn; Quadrelli, Scott; Lin, Alexander; Ramadan, Saadallah

    2015-03-01

    A growing body of literature has indicated that fucose-α(1-2)-galactose sugars are implicated in the molecular mechanisms that underlie neuronal development, learning and memory in the human brain. An understanding of the in vivo roles played by these terminal fucose residues has been hampered by the lack of technology to non-invasively monitor their levels in the human brain. We have implemented in vivo two-dimensional MRS technology to examine the human brain in a 3-T clinical MR scanner, and report that six fucose-α(1-2)-galactose residues and free α-fucose are available for inspection. Fucose-α(1-3)-galactose residues cannot yet be assigned using this technology as they resonate under the water resonance. This new application offers an unprecedented insight into the molecular mechanisms by which fucosylated sugars contribute to neuronal processes and how they alter during development, ageing and disease. Copyright © 2014 John Wiley & Sons, Ltd.

  10. Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

    Directory of Open Access Journals (Sweden)

    Shaoling Wu

    2014-02-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB. In this study, GDNF conventional liposomes (GDNF-L and GDNF target sterically stabilized liposomes (GDNF-SSL-T were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC(0–1 h in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system.

  11. Melatonin reduces hypoxic-ischaemic (HI) induced autophagy and apoptosis: An in vivo and in vitro investigation in experimental models of neonatal HI brain injury.

    Science.gov (United States)

    Hu, Yingying; Wang, Zhouguang; Liu, Yanlong; Pan, Shulin; Zhang, Hao; Fang, Mingchu; Jiang, Huai; Yin, Jiayu; Zou, Shuangshuang; Li, Zhenmao; Zhang, Hongyu; Lin, Zhenlang; Xiao, Jian

    2017-07-13

    Melatonin has neuroprotective effects in many diseases, including neonatal hypoxic-ischaemic (HI) brain injury. The purpose of this study was to evaluate the neuroprotective effects of melatonin both in vivo and in vitro and associated molecular mechanisms behind these effects. Postnatal day 7 male and female rat pups were subjected to unilateral HI, melatonin was injected intraperitoneally 1h before HI and an additional six doses were administered at 24h intervals. The pups were sacrificed at 24h and 7 d after HI. Pre-treatment with melatonin significantly reduced brain damage at 7 d after HI, with 15mg/kg melatonin achieving over 30% recovery in tissue loss compared to vehicle-treated animals. Autophagy and apoptotic cell death as indicated by autophagy associated proteins, cleaved caspase 3 and Tunel staining, was significantly inhibited after melatonin treatment in vivo as well as in PC12 cells. Melatonin treatment also significantly increased the GAP43 in the cortex. In conclusion, melatonin treatment reduced neonatal rat brain injury after HI, and this appeared to be related to inhibiting autophagy as well as reducing apoptotic cell death. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T.

    Science.gov (United States)

    Stout, Jacques; Hanak, Anne-Sophie; Chevillard, Lucie; Djemaï, Boucif; Risède, Patricia; Giacomini, Eric; Poupon, Joël; Barrière, David André; Bellivier, Frank; Mégarbane, Bruno; Boumezbeur, Fawzi

    2017-11-01

    Lithium is the first-line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood-brain barrier remain poorly understood. The contribution of lithium-7 magnetic resonance imaging (7 Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo-spin-echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B1 inhomogeneities and differential T1 and T2 weighting. Our MRI-derived lithium concentrations were validated by comparison with inductively coupled plasma-mass spectrometry (ICP-MS) measurements ([Li]MRI  = 1.18[Li]MS , R = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain-to-plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90. Copyright © 2017 John Wiley & Sons, Ltd.

  13. In vivo optical microprobe imaging for intracellular Ca2+ dynamics in response to dopaminergic signaling in deep brain evoked by cocaine

    Science.gov (United States)

    Luo, Zhongchi; Pan, Yingtian; Du, Congwu

    2012-02-01

    Ca2+ plays a vital role as second messenger in signal transduction and the intracellular Ca2+ ([Ca2+]i) change is an important indicator of neuronal activity in the brain, including both cortical and subcortical brain regions. Due to the highly scattering and absorption of brain tissue, it is challenging to optically access the deep brain regions (e.g., striatum at >3mm under the brain surface) and image [Ca2+]i changes with cellular resolutions. Here, we present two micro-probe approaches (i.e., microlens, and micro-prism) integrated with a fluorescence microscope modified to permit imaging of neuronal [Ca2+]i signaling in the striatum using a calcium indicator Rhod2(AM). While a micro-prism probe provides a larger field of view to image neuronal network from cortex to striatum, a microlens probe enables us to track [Ca2+]i dynamic change in individual neurons within the brain. Both techniques are validated by imaging neuronal [Ca2+]i changes in transgenic mice with dopamine receptors (D1R, D2R) expressing EGFP. Our results show that micro-prism images can map the distribution of D1R- and D2R-expressing neurons in various brain regions and characterize their different mean [Ca2+]i changes induced by an intervention (e.g., cocaine administration, 8mg/kg., i.p). In addition, microlens images can characterize the different [Ca2+]i dynamics of D1 and D2 neurons in response to cocaine, including new mechanisms of these two types of neurons in striatum. These findings highlight the power of the optical micro-probe imaging for dissecting the complex cellular and molecular insights of cocaine in vivo.

  14. Occupational dermatosis

    National Research Council Canada - National Science Library

    Alchorne, Alice de Oliveira de Avelar; Alchorne, Maurício Mota de Avelar; Silva, Marzia Macedo

    2010-01-01

    Occupational Dermatosis is described as any alteration in the skin, mucosa or annexes that is directly or indirectly caused, conditioned, maintained or aggravated by agents present in the occupational...

  15. In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer.

    Science.gov (United States)

    Hamilton, Amanda M; Foster, Paula J

    2017-02-01

    Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

  16. Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

    Science.gov (United States)

    Devasthale, Pratik; Wang, Wei; Mignone, James; Renduchintala, Kishore; Radhakrishnan, Sridhar; Dhanapal, Jayanthi; Selvaraj, Jagannath; Kuppusamy, Rajesh; Pelleymounter, Mary Ann; Longhi, Daniel; Huang, Ning; Flynn, Neil; Azzara, Anthony V; Rohrbach, Kenneth; Devenny, James; Rooney, Suzanne; Thomas, Michael; Glick, Susan; Godonis, Helen; Harvey, Susan; Cullen, Mary Jane; Zhang, Hongwei; Caporuscio, Christian; Stetsko, Paul; Grubb, Mary; Huang, Christine; Zhang, Lisa; Freeden, Chris; Murphy, Brian J; Robl, Jeffrey A; Washburn, William N

    2015-10-15

    Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Holst, Klaus K; Adamsen, Dea

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address t...

  18. Staphylococcal α-hemolysin is neurotoxic and causes lysis of brain cells in vivo and in vitro.

    Science.gov (United States)

    Dahlberg, Daniel; Mariussen, Espen; Goverud, Ingeborg Løstegaard; Tønjum, Tone; Mæhlen, Jan; Antal, Ellen-Ann; Hassel, Bjørnar

    2015-05-01

    Formation of a bacterial brain abscess entails loss of brain cells and formation of pus. The mechanisms behind the cell loss are not fully understood. Staphylococcus aureus, a common cause of brain abscesses, produces various exotoxins, including α-hemolysin, which is an important factor in brain abscess formation. α-Hemolysin may cause cytolysis by forming pores in the plasma membrane of various eukaryotic cells. However, whether α-hemolysin causes lysis of brain cells is not known. Nor is it known whether α-hemolysin in the brain causes cell death through pore formation or by acting as a chemoattractant, recruiting leukocytes and causing inflammation. Here we show that α-hemolysin injected into rat brain causes cell damage and edema formation within 30 min. Cell damage was accompanied by an increase in extracellular concentrations of zinc, GABA, glutamate, and other amino acids, indicating plasma membrane damage, but leukocytic infiltration was not seen 0.5-12h after α-hemolysin injection. This was in contrast to injection of S. aureus, which triggered extensive infiltration with neutrophils within 8h. In vitro, α-hemolysin caused concentration-dependent lysis of isolated nerve endings and cultured astrocytes. We conclude that α-hemolysin contributes to the cell death inherent in staphylococcal brain abscess formation as a pore-forming neurotoxin. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. In vivo magnetic resonance imaging and 31P spectroscopy of large human brain tumours at 1.5 tesla

    DEFF Research Database (Denmark)

    Thomsen, C; Jensen, K E; Achten, E

    1988-01-01

    31P MR spectroscopy of human brain tumours is one feature of magnetic resonance imaging. Eight patients with large superficial brain tumours and eight healthy volunteers were examined with 31P spectroscopy using an 8 cm surface coil for volume selection. Seven frequencies were resolved in our spe...

  20. 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

    DEFF Research Database (Denmark)

    Ettrup, Anders; Mikkelsen, Jens D; Lehel, Szabolcs

    2011-01-01

    Small-molecule a(7) nicotinic acetylcholine receptor (a(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled a(7)nAChR PET tracer would be important for in vivo quantification of a(7)n...

  1. 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements

    DEFF Research Database (Denmark)

    Ettrup, Anders; Mikkelsen, Jens D; Lehel, Szabolcs

    2011-01-01

    Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)n...

  2. Peripheral SLC6A4 DNA Methylation Is Associated with In Vivo Measures of Human Brain Serotonin Synthesis and Childhood Physical Aggression

    Science.gov (United States)

    Wang, Dongsha; Szyf, Moshe; Benkelfat, Chawki; Provençal, Nadine; Turecki, Gustavo; Caramaschi, Doretta; Côté, Sylvana M.; Vitaro, Frank; Tremblay, Richard E.; Booij, Linda

    2012-01-01

    The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. PMID:22745770

  3. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.

    Directory of Open Access Journals (Sweden)

    Dongsha Wang

    Full Text Available The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET measures of brain serotonin (5-HT synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC. Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25 who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20 where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

  4. Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro.

    Directory of Open Access Journals (Sweden)

    O B Shevelev

    Full Text Available The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17 with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg. Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min. Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

  5. Acute pressure changes in the brain are correlated with MR elastography stiffness measurements: initial feasibility in an in vivo large animal model.

    Science.gov (United States)

    Arani, Arvin; Min, Hoon-Ki; Fattahi, Nikoo; Wetjen, Nicholas M; Trzasko, Joshua D; Manduca, Armando; Jack, Clifford R; Lee, Kendall H; Ehman, Richard L; Huston, John

    2018-02-01

    The homeostasis of intracranial pressure (ICP) is of paramount importance for maintaining normal brain function. A noninvasive technique capable of making direct measurements of ICP currently does not exist. MR elastography (MRE) is capable of noninvasively measuring brain tissue stiffness in vivo, and may act as a surrogate to measure ICP. The objective of this study was to investigate the impact of changing ICP on brain stiffness using MRE in a swine model. Baseline MRE measurements were obtained, and then catheters were surgically placed into the left and right lateral ventricles of three animals. ICP was systematically increased over the range of 0 to 55 millimeters mercury (mmHg), and stiffness measurements were made using brain MRE at vibration frequencies of 60 hertz (Hz), 90 Hz, 120 Hz, and 150 Hz. A significant linear correlation between stiffness and ICP in the cross-subject comparison was observed for all tested vibrational frequencies (P ≤ 0.01). The 120 Hz (0.030 ± 0.004 kilopascal (kPa)/mmHg, P Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

  6. Near-infrared oxymeter biosensor prototype for non-invasive in vivo analysis of rat brain oxygenation: effects of drugs of abuse

    Science.gov (United States)

    Crespi, F.; Donini, M.; Bandera, A.; Congestri, F.; Formenti, F.; Sonntag, V.; Heidbreder, C.; Rovati, L.

    2006-07-01

    The feasibility of non-invasive analysis of brain activities was studied in the attempt to overcome the major limitation of actual in vivo methodologies, i.e. invasiveness. Optic fibre probes were used as the optical head of a novel, highly sensitive near-infrared continuous wave spectroscopy (CW-NIR) instrument. This prototype was designed for non-invasive analysis of the two main forms of haemoglobin: oxy-haemoglobin (HbO2) and deoxy-haemoglobin (Hb), chromophores present in biological tissues. It was tested in peripheral tissue (human gastrocnemius muscle) and then reset to perform the measurement on rat brain. In animal studies, the optical head was firmly placed using stereotaxic apparatus upon the sagittal line of the head of anaesthetized adult rats, without any surgery. Then pharmacological treatments with saline (300 µl s.c.) amphetamine (2 mg kg-1) or nicotine (0.4 mg kg-1) were performed. Within 10-20 min amphetamine substantially increased HbO2 and reduced Hb control levels. Nicotine produced a rapid initial increase followed by a decrease in HbO2. In contrast to amphetamine, nicotine treatment also reduced Hb and blood volume. These results support the capacity of our CW-NIR prototype to measure non-invasively HbO2 and Hb levels in the rat brain, that are markers of the degree of tissue oxygenation, thus providing an index of blood levels and therefore of brain metabolism.

  7. Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability.

    Science.gov (United States)

    Tan, Suk Fei; Kirby, Brian P; Stanslas, Johnson; Basri, Hamidon Bin

    2017-11-01

    This study was aimed to investigate the potential of formulated valproic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavailability of valproic acid (VPA). Valproic acid-encapsulated nanoemulsions were formulated and physically characterised (osmolarity, viscosity, drug content, drug encapsulation efficiency). Further investigations were also conducted to estimate the drug release, cytotoxic profile, in-vitro blood-brain barrier (BBB) permeability, pharmacokinetic parameter and the concentration of VPA and VANE in blood and brain. Physical characterisation confirmed that VANE was suitable for parenteral administration. Formulating VPA into nanoemulsion significantly reduced the cytotoxicity of VPA. In-vitro drug permeation suggested that VANEs crossed the BBB as freely as VPA. Pharmacokinetic parameters of VANE-treated rats in plasma and brain showed F3 VANE had a remarkable improvement in AUC, prolongation of half-life and reduction in clearance compared to VPA. Given the same extent of in-vitro BBB permeation of VPA and VANE, the higher bioavailability of VANE in brain was believed to have due to higher concentration of VANE in blood. The brain bioavailability of VPA was improved by prolonging the half-life of VPA by encapsulating it within the nanoemulsion-T80. Nanoemulsion containing VPA has alleviated the cytotoxic effect of VPA and improved the plasma and brain bioavailability for parenteral delivery of VPA. © 2017 Royal Pharmaceutical Society.

  8. Neonatal domoic acid decreases in vivo binding of [11C]yohimbine to α2 adrenoceptors in adult rat brain

    DEFF Research Database (Denmark)

    Thomsen, Majken; Lillethorup, Thea Pinholt; Jakobsen, Steen

    treated rats. microPET data revealed that DOM60 rats had a 40-47 % reduction in [11C]yohimbine binding in limbic and cortical brain regions relative to saline treated rats. We conclude that neonatal administration of DOM combined with the potential stress associated with behavioural testing results...... in a significant decrease in [11C]yohimbine binding in limbic and cortical brain regions. We suggest that the observed downregulation of α2 adrenoceptors is a result of elevated extracellular noradrenaline which may represent a form of preconditioning to decrease seizure susceptibility of the brain....

  9. Optical properties of rabbit brain in the red and near-infrared: changes observed under in vivo, postmortem, frozen, and formalin-fixated conditions

    Science.gov (United States)

    Pitzschke, Andreas; Lovisa, Blaise; Seydoux, Olivier; Haenggi, Matthias; Oertel, Markus F.; Zellweger, Matthieu; Tardy, Yanik; Wagnières, Georges

    2015-02-01

    The outcome of light-based therapeutic approaches depends on light propagation in biological tissues, which is governed by their optical properties. The objective of this study was to quantify optical properties of brain tissue in vivo and postmortem and assess changes due to tissue handling postmortem. The study was carried out on eight female New Zealand white rabbits. The local fluence rate was measured in the VIS/NIR range in the brain in vivo, just postmortem, and after six weeks' storage of the head at -20°C or in 10% formaldehyde solution. Only minimal changes in the effective attenuation coefficient μeff were observed for two methods of sacrifice, exsanguination or injection of KCl. Under all tissue conditions, μeff decreased with increasing wavelengths. After long-term storage for six weeks at -20°C, μeff decreased, on average, by 15 to 25% at all wavelengths, while it increased by 5 to 15% at all wavelengths after storage in formaldehyde. We demonstrated that μeff was not very sensitive to the method of animal sacrifice, that tissue freezing significantly altered tissue optical properties, and that formalin fixation might affect the tissue's optical properties.

  10. Implanted, inductively-coupled, radiofrequency coils fabricated on flexible polymeric material: Application to in vivo rat brain MRI at 7 T

    Science.gov (United States)

    Ginefri, J.-C.; Rubin, A.; Tatoulian, M.; Woytasik, M.; Boumezbeur, F.; Djemaï, B.; Poirier-Quinot, M.; Lethimonnier, F.; Darrasse, L.; Dufour-Gergam, E.

    2012-11-01

    Combined with high-field MRI scanners, small implanted coils allow for high resolution imaging with locally improved SNR, as compared to external coils. Small flexible implantable coils dedicated to in vivo MRI of the rat brain at 7 T were developed. Based on the Multi-turn Transmission Line Resonator design, they were fabricated with a Teflon substrate using copper micromolding process and a specific metal-polymer adhesion treatment. The implanted coils were made biocompatible by PolyDimethylSiloxane (PDMS) encapsulation. The use of low loss tangent material achieves low dielectric losses within the substrate and the use of the PDMS layer reduces the parasitic coupling with the surrounding media. An implanted coil was implemented in a 7 T MRI system using inductive coupling and a dedicated external pick-up coil for signal transmission. In vivo images of the rat brain acquired with in plane resolution of (150 μm)2 thanks to the implanted coil revealed high SNR near the coil, allowing for the visualization of fine cerebral structures.

  11. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    OpenAIRE

    Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an i...

  12. Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

    Science.gov (United States)

    Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

    2016-11-01

    Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

  13. In vivo assessment of the permeability of the blood-brain barrier and blood-retinal barrier to fluorescent indoline derivatives in zebrafish

    Directory of Open Access Journals (Sweden)

    Watanabe Kohei

    2012-08-01

    Full Text Available Abstract Background Successful delivery of compounds to the brain and retina is a challenge in the development of therapeutic drugs and imaging agents. This challenge arises because internalization of compounds into the brain and retina is restricted by the blood–brain barrier (BBB and blood-retinal barrier (BRB, respectively. Simple and reliable in vivo assays are necessary to identify compounds that can easily cross the BBB and BRB. Methods We developed six fluorescent indoline derivatives (IDs and examined their ability to cross the BBB and BRB in zebrafish by in vivo fluorescence imaging. These fluorescent IDs were administered to live zebrafish by immersing the zebrafish larvae at 7-8 days post fertilization in medium containing the ID, or by intracardiac injection. We also examined the effect of multidrug resistance proteins (MRPs on the permeability of the BBB and BRB to the ID using MK571, a selective inhibitor of MRPs. Results The permeability of these barriers to fluorescent IDs administered by simple immersion was comparable to when administered by intracardiac injection. Thus, this finding supports the validity of drug administration by simple immersion for the assessment of BBB and BRB permeability to fluorescent IDs. Using this zebrafish model, we demonstrated that the length of the methylene chain in these fluorescent IDs significantly affected their ability to cross the BBB and BRB via MRPs. Conclusions We demonstrated that in vivo assessment of the permeability of the BBB and BRB to fluorescent IDs could be simply and reliably performed using zebrafish. The structure of fluorescent IDs can be flexibly modified and, thus, the permeability of the BBB and BRB to a large number of IDs can be assessed using this zebrafish-based assay. The large amount of data acquired might be useful for in silico analysis to elucidate the precise mechanisms underlying the interactions between chemical structure and the efflux transporters at the

  14. (131)I-trazodone: preparation, quality control and in vivo biodistribution study by intranasal and intravenous routes as a hopeful brain imaging radiopharmaceutical.

    Science.gov (United States)

    Motaleb, M A; Ibrahim, I T; Sayyed, M E; Awad, G A S

    The preparation of (131)I-trazodone hydrochloride and its biological evaluation as a promising brain imaging radiopharmaceutical using two routes of administration. Trazodone (TZ) was radiolabelled with (131)I using direct electrophilic substitution, and different factors affecting labelling yield were studied. Quality control of (131)I-TZ was carried out using ascending paper chromatography, paper electrophoresis, and high pressure liquid chromatography (HPLC). In vivo biodistribution of (131)I-TZ was evaluated in Swiss albino mice using 3 methods: intravenous (131)I-TZ solution (IVS), intranasal (131)I-TZ solution (INS), and intranasal (131)I-TZ microemulsion (INME). Optimum labelling yield of 91.23±2.12% was obtained with in vitro stability of (131)I-TZ up to 6h at room temperature. The biodistribution results showed a notably higher and sustained brain uptake for INME compared to IVS and INS at all time intervals. In addition, heart and blood uptake levels for INME were lower than those for IV solution which, in turn, could decrease the systemic side effects of trazodone. Also, the (131)I-trazodone INME brain uptake of 6.7±0.5%ID/g was higher than that of (99m)Tc-ECD and (99m)Tc-HMPAO (radiopharmaceuticals currently used for brain imaging). (131/123)I-trazodone formulated as INME could be used as a promising radiopharmaceutical for brain imaging. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  15. Toward an in Vivo Neurochemical Profile: Quantification of 18 Metabolites in Short-Echo-Time 1H NMR Spectra of the Rat Brain

    Science.gov (United States)

    Pfeuffer, Josef; Tkáč , Ivan; Provencher, Stephen W.; Gruetter, Rolf

    1999-11-01

    Localized in vivo1H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T1 than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-μL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in 1H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, γ-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

  16. In Vivo Imaging of Brain Aromatase in Female Baboons: [11C]Vorozole Kinetics and Effect of the Menstrual Cycle

    Directory of Open Access Journals (Sweden)

    Deborah Pareto

    2013-11-01

    Full Text Available The aim of this work was to quantify the brain distribution of the enzyme aromatase in the female baboon with positron emission tomography and the tracer [11C]vorozole using three different quantification methods for estimating the total distribution volume (VT: a graphical method, compartment modeling, and a tissue to plasma ratio. The graphical model and the compartment modeling gave similar estimates to the data and similar values (correlation R = .988; p = .0001. [11C]Vorozole shows a rapid uptake by the brain followed by a relatively constant accumulation, suggesting the possibility of using the tissue to plasma ratio as an estimate of VT. The highest uptake of [11C]vorozole in the baboon brain was measured in the amygdala, followed by the preoptic area and hypothalamus, basal ganglia, and cortical areas. Pretreatment studies with vorozole or letrozole showed a generalized decrease in brain accumulation and VT. The results suggested that the physiologic changes in gonadal hormone levels accompanying the menstrual cycle had a significant effect on brain aromatase VT.

  17. In vivo assessment of use-dependent brain plasticity--beyond the "one trick pony" imaging strategy.

    Science.gov (United States)

    Draganski, Bogdan; Kherif, Ferath

    2013-06-01

    This article has been written as a comment to Dr Thomas and Dr Baker's article "Teaching an adult brain new tricks: A critical review of evidence for training-dependent structural plasticity in humans". We deliberately expand on the key question about the biological substrates underlying use-dependent brain plasticity rather than reiterating the authors' main points of criticism already addressed in more general way by previous publications in the field. The focus here is on the following main issues: i) controversial brain plasticity findings in voxel-based morphometry studies are partially due to the strong dependency of the widely used T1-weighted imaging protocol on varying magnetic resonance contrast contributions; ii) novel concepts in statistical analysis allow one to directly infer topological specificity of structural brain changes associated with plasticity. We conclude that iii) voxel-based quantification of relaxometry derived parameter maps could provide a new perspective on use-dependent plasticity by characterisation of brain tissue property changes beyond the estimation of volume and cortical thickness changes. In the relevant sections we respond to the concerns raised by Dr Thomas and Dr Baker from the perspective of the proposed data acquisition and analysis strategy. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Xenon improves neurological outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury

    Science.gov (United States)

    Luh, Clara; Gruss, Marco; Radyushkin, Konstantin; Hirnet, Tobias; Werner, Christian; Engelhard, Kristin; Franks, Nicholas P; Thal, Serge C; Dickinson, Robert

    2015-01-01

    Objectives To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury, and to determine whether application of xenon has a clinically relevant therapeutic time window. Design Controlled animal study. Setting University research laboratory. Subjects Male C57BL/6N mice (n=196) Interventions 75% xenon, 50% xenon or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact. Measurements & Main Results Outcome following trauma was measured using: 1) functional neurological outcome score, 2) histological measurement of contusion volume, 3) analysis of locomotor function and gait. Our study shows that xenon-treatment improves outcome following traumatic brain injury. Neurological outcome scores were significantly (pxenon-treated groups in the early phase (24 hours) and up to 4 days after injury. Contusion volume was significantly (pxenon-treated groups. Xenon treatment significantly (pxenon was given 15 minutes after injury or when treatment was delayed 1 hour or 3 hours after injury. Neurological outcome was significantly (pxenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (pxenon-treated group, 1 month after trauma. Conclusions These results show for the first time that xenon improves neurological outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in brain trauma patients. PMID:25188549

  19. Hypertonic saline resuscitation of hemorrhagic shock does not decrease in vivo neutrophil interactions with endothelium in the blood-brain microcirculation.

    Science.gov (United States)

    Gong, Wanfeng; Marks, Joshua A; Sanati, Paymon; Sims, Carrie; Sarani, Babak; Smith, Douglas H; Pascual, Jose L

    2011-08-01

    Resuscitation of hemorrhagic shock with isotonic crystalloids has been shown to activate polymorphonuclear neutrophils (PMNs). Although hypertonic saline (HTS) can reduce PMN activation and interactions with endothelial cells (EC) in systemic microvascular beds, no data exist demonstrating that the same occurs in the unique blood-brain barrier microcirculation. We hypothesized that resuscitation of hemorrhagic shock with HTS would blunt brain in vivo PMN-EC interactions. Wistar rats (250-350 g) underwent craniotomy and placement of a window for live intravital viewing of pial vessels. Twenty animals were bled to a mean arterial pressure of 30 mm Hg to 35 mm Hg for 1 hour and resuscitated with shed blood and either 5% HTS (6 mL/kg) or Ringer's lactate (RL) (2× shed blood volume). Circulating rhodamine-6G-labeled PMN in pial venules were captured by videomicroscopy at baseline (preshock), end of the shock period, after resuscitation, and every 15 minutes to 30 minutes for 2 hours. Hemodynamics and arterial gases were monitored. Off-line footage analysis allowed comparisons of PMN-EC interactions between groups. Animals in both groups developed significant metabolic acidosis (p nature of the blood-brain interface.

  20. Differentiating pediatric epileptic brain tissue from normal brain tissue by using time-dependent diffuse reflectance spectroscopy in vivo: comprehensive data analysis method in the time domain

    Science.gov (United States)

    Oh, Sanghoon; Fernald, Bradley; Bhatia, Sanjiv; Ragheb, John; Sandberg, David; Johnson, Mahlon; Lin, Wei-Chiang

    2009-05-01

    This research investigated the feasibility of using time-dependent diffuse reflectance spectroscopy to differentiate pediatric epileptic brain tissue from normal brain tissue. The optical spectroscopic technique monitored the dynamic optical properties of the cerebral cortex that are associated with its physiological, morphological, and compositional characteristics. Due to the transient irregular epileptic discharge activity within the epileptic brain tissue it was hypothesized that the lesion would express abnormal dynamic optical behavior that would alter normal dynamic behavior. Thirteen pediatric epilepsy patients and seven pediatric brain tumor patients (normal controls) were recruited for this clinical study. Dynamic optical properties were obtained from the cortical surface intraoperatively using a timedependent diffuse reflectance spectroscopy system. This system consisted of a fiber-optic probe, a tungsten-halogen light source, and a spectrophotometer. It acquired diffuse reflectance spectra with a spectral range of 204 nm to 932 nm at a rate of 33 spectra per second for approximately 12 seconds. Biopsy samples were taken from electrophysiologically abnormal cortex and evaluated by a neuropathologist, which served as a gold standard for lesion classification. For data analysis, spectral intensity changes of diffuse reflectance in the time domain at two different wavelengths from each investigated site were compared. Negative correlation segment, defined by the periods where the intensity changes at the two wavelengths were opposite in their slope polarity, were extracted. The total duration of negative correlation, referred to as the "negative correlation time index", was calculated by integrating the negative correlation segments. The negative correlation time indices from all investigated sites were sub-grouped according to the corresponding histological classifications. The difference between the mean indices of two subgroups was evaluated by standard

  1. In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard

    DEFF Research Database (Denmark)

    Christiansen, P; Henriksen, O; Stubgaard, M

    1993-01-01

    in quantification of N-acetyl aspartate (NAA) concentration was about 1-2 mM (6-12%). Also in vivo a good linearity between water signal and selected voxel size was seen. The same was true for the studied metabolites, N-acetyl aspartate (NAA), creatine/phosphocreatine (Cr/PCr), and choline (Cho). Calculated average...

  2. An in Vivo Investigation of Brain Inflammation in Gulf War Illness with Integrated PET/MR Imaging

    Science.gov (United States)

    2015-10-01

    previously  pending)     R01  AT007550  (PI:  Harris/Napadow)    Neuroimaging  Approaches  to  Deconstructing   Acupuncture  for...Kreisl WC, Fujita M, Dustin I, Khan O, Appel S, et al. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy . J Nuclear Med

  3. The basic study on application of optical coherence tomography to monitoring of viability in vivo rat brain

    Science.gov (United States)

    Sato, Manabu; Nonaka, Ippei; Kitano, Tetushi; Takahashi, Toshihiro; Nishidate, Izumi

    2013-08-01

    The relations and correlation coefficients (CCs) between the OCT signal and the modified state entropy (MSE) of electroencephalogram (EEG) have been studied. Three dimensional (3D) OCT images of rat brains through the thinned skull and EEG have been measured simultaneously anesthetizing to reduce brain activity with the quadrature fringe widefield OCT. Measured 3D volumes are 4mm × 4mm × 2.8mm (Depth). MSE is the product of state entropy of EEG and its effective value. Depth profiles were obtained at the selected three points on the surface of thinned skull. For chosen each depth, the relative signal intensity (RSI) is defined as the ratios of signal intensity to first signal intensity. Deepening the anesthesia RSI increased and MSE decreased to show negative correlation and CCs from -0.31 to -0.56. These results indicate enhancements of the feasibility of OCT as a tool for monitoring/diagnosing the brain tissue viability.

  4. Nanotoxicity of poly(n-butylcyano-acrylate) nanoparticles at the blood-brain barrier, in human whole blood and in vivo.

    Science.gov (United States)

    Kolter, Marise; Ott, Melanie; Hauer, Christian; Reimold, Isolde; Fricker, Gert

    2015-01-10

    Therapy of diseases of the central nervous system is a major challenge since drugs have to overcome the blood-brain barrier (BBB). A powerful strategy to enhance cerebral drug concentration is administration of drug-loaded poly(n-butylcyano-acrylate) (PBCA) nanoparticles coated with polysorbate 80 (PS80). This study evaluates the toxicity of PBCA-nanoparticles at the BBB, representing the target organ, the inflammatory response in human whole blood, as the site of administration and in a rat model in vivo. PBCA-nanoparticles were prepared by a mini-emulsion method and characterized concerning size, surface charge, shape and PS80-adsorption. The influence on metabolic activity, cell viability and integrity of the BBB was analyzed in an in vitro model of the BBB. In ex vivo experiments in human whole blood the release of 12 inflammatory cytokines was investigated. In addition, the inflammatory response was studied in vivo in rats and complemented with the analysis of different organ toxicity parameters. PBCA-nanoparticles showed time- and concentration-dependent effects on metabolic activity, cell viability and BBB integrity. No cell death or loss of metabolic activity was observed for nanoparticle-concentrations ≤500μg/ml up to 3h of treatment. Within 12 tested inflammatory cytokines, only interleukin-8 displayed a significant release after nanoparticle exposure in human blood. No severe inflammatory processes or organ damages were identified in rats in vivo. Thus, PBCA-nanoparticles are a promising drug delivery system to overcome the BBB since they showed hardly any cytotoxic or inflammatory effect at therapeutic concentrations and incubation times. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Radiological-Pathological Correlations Following Blast-Related Traumatic Brain Injury in the Whole Human Brain Using ex Vivo Diffusion Tensor Imaging

    Science.gov (United States)

    2014-01-01

    injuries caused by non-blast related trauma (e.g. falls, motor vehicle accidents, etc.), post-mortem pathological analyses have revealed that...part of these advances is the use of high resolution imaging of blocks of human brain at 4.7 Tesla . This high resolution imaging has allowed...to noise Stereological methods: StereoInvestigator software coupled to a motorized stage on a Nikon 80i upright microscope. All tissue

  6. In vivo magnetic resonance imaging and 31P spectroscopy of large human brain tumours at 1.5 tesla

    DEFF Research Database (Denmark)

    Thomsen, C; Jensen, K E; Achten, E

    1988-01-01

    31P MR spectroscopy of human brain tumours is one feature of magnetic resonance imaging. Eight patients with large superficial brain tumours and eight healthy volunteers were examined with 31P spectroscopy using an 8 cm surface coil for volume selection. Seven frequencies were resolved in our...... and after chemotherapy. The spectra showed considerable changes during chemotherapy. It is concluded that 31P spectroscopy using surface coils is of limited value for tumour characterization, but may add useful information in monitoring the effect of chemotherapy....

  7. [{sup 11}C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Mingrong E-mail: zhang@nirs.go.jp; Kida, Takayo; Noguchi, Junko; Furutsuka, Kenji; Maeda, Jun; Suhara, Tetsuya; Suzuki, Kazutoshi

    2003-05-01

    DAA1106 (N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for peripheral benzodiazepine receptors (PBR) in mitochondrial fractions of rat (K{sub i}=0.043 nM) and monkey (K{sub i}=0.188 nM) brains. This compound was labeled by [{sup 11}C]methylation of a corresponding desmethyl precursor (DAA1123) with [{sup 11}C]CH{sub 3}I in the presence of NaH, with a 72{+-}16% (corrected for decay) incorporation yield of radioactivity. After HPLC purification, [{sup 11}C]DAA1106 was obtained with {>=}98% radiochemical purity and specific activity of 90-156 GBq/{mu}mol at the end of synthesis. After iv injection of [{sup 11}C]DAA1106 into mice, high accumulations of radioactivity were found in the olfactory bulb and cerebellum, the high PBR density regions in the brain. Coinjection of [{sup 11}C]DAA1106 with unlabeled DAA1106 and PBR-selective PK11195 displayed a significant reduction of radioactivity, suggesting a high specific binding of [{sup 11}C]DAA1106 to PBR. Although this tracer was rapidly metabolized in the plasma, only [{sup 11}C]DAA1106 was detected in the brain tissues, suggesting the specific binding in the brain due to the tracer itself. These findings revealed that [{sup 11}C]DAA1106 is a potential and selective positron emitting radioligand for PBR.

  8. Label-free, multi-scale imaging of ex-vivo mouse brain using spatial light interference microscopy

    Science.gov (United States)

    Min, Eunjung; Kandel, Mikhail E.; Ko, Chemyong J.; Popescu, Gabriel; Jung, Woonggyu; Best-Popescu, Catherine

    2016-12-01

    Brain connectivity spans over broad spatial scales, from nanometers to centimeters. In order to understand the brain at multi-scale, the neural network in wide-field has been visualized in detail by taking advantage of light microscopy. However, the process of staining or addition of fluorescent tags is commonly required, and the image contrast is insufficient for delineation of cytoarchitecture. To overcome this barrier, we use spatial light interference microscopy to investigate brain structure with high-resolution, sub-nanometer pathlength sensitivity without the use of exogenous contrast agents. Combining wide-field imaging and a mosaic algorithm developed in-house, we show the detailed architecture of cells and myelin, within coronal olfactory bulb and cortical sections, and from sagittal sections of the hippocampus and cerebellum. Our technique is well suited to identify laminar characteristics of fiber tract orientation within white matter, e.g. the corpus callosum. To further improve the macro-scale contrast of anatomical structures, and to better differentiate axons and dendrites from cell bodies, we mapped the tissue in terms of its scattering property. Based on our results, we anticipate that spatial light interference microscopy can potentially provide multiscale and multicontrast perspectives of gross and microscopic brain anatomy.

  9. A three-photon microscope with adaptive optics for deep-tissue in vivo structural and functional brain imaging

    Science.gov (United States)

    Tao, Xiaodong; Lu, Ju; Lam, Tuwin; Rodriguez, Ramiro; Zuo, Yi; Kubby, Joel

    2017-02-01

    We developed a three-photon adaptive optics add-on to a commercial two-photon laser scanning microscope. We demonstrated its capability for structural and functional imaging of neurons labeled with genetically encoded red fluorescent proteins or calcium indicators deep in the living mouse brain with cellular and subcellular resolution.

  10. Comparison of different pulse sequences for in vivo determination of T1 relaxation times in the human brain

    DEFF Research Database (Denmark)

    Kjaer, L; Henriksen, O

    1988-01-01

    ). T1 measurements were performed on the human brain using a whole body MR scanner operating at 1.5 tesla. Three different pulse sequences were compared including two 6-points inversion recovery (IR) sequences with TR = 2.0 s and 4.0, respectively, and a 12-points partial saturation inversion recovery...

  11. In vivo formation of natural HgSe nanoparticles in the liver and brain of pilot whales

    DEFF Research Database (Denmark)

    Gajdosechova, Z.; Lawan, M. M.; Urgast, D. S.

    2016-01-01

    Se) nanoparticles in the liver and brain of long-finned pilot whales are attached to Se-rich structures and possibly act as a nucleation point for the formation of large Se-Hg clusters, which can grow with age to over 5 μm in size. The detoxification mechanism is fully developed from the early age of the animals...

  12. Xenon improves neurologic outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury.

    Science.gov (United States)

    Campos-Pires, Rita; Armstrong, Scott P; Sebastiani, Anne; Luh, Clara; Gruss, Marco; Radyushkin, Konstantin; Hirnet, Tobias; Werner, Christian; Engelhard, Kristin; Franks, Nicholas P; Thal, Serge C; Dickinson, Robert

    2015-01-01

    To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury and to determine whether application of xenon has a clinically relevant therapeutic time window. Controlled animal study. University research laboratory. Male C57BL/6N mice (n = 196). Seventy-five percent xenon, 50% xenon, or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact. Outcome following trauma was measured using 1) functional neurologic outcome score, 2) histological measurement of contusion volume, and 3) analysis of locomotor function and gait. Our study shows that xenon treatment improves outcome following traumatic brain injury. Neurologic outcome scores were significantly (p < 0.05) better in xenon-treated groups in the early phase (24 hr) and up to 4 days after injury. Contusion volume was significantly (p < 0.05) reduced in the xenon-treated groups. Xenon treatment significantly (p < 0.05) reduced contusion volume when xenon was given 15 minutes after injury or when treatment was delayed 1 or 3 hours after injury. Neurologic outcome was significantly (p < 0.05) improved when xenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (p < 0.05) were observed in the xenon-treated group, 1 month after trauma. These results show for the first time that xenon improves neurologic outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in patients with brain trauma.

  13. Antisense in vivo knockdown of synaptotagmin I by HVJ-liposome mediated gene transfer attenuates ischemic brain damage in neonatal rats.

    Science.gov (United States)

    Omae, Tadaki; Yoshioka, Hiroshi; Tanaka, Taro; Nagai, Hideyuki; Saji, Makoto; Noda, Kazuko; Kobayashi, Shizuka; Sugimoto, Tohru

    2008-05-01

    Synaptic release of the excitatory amino acid glutamate is considered as an important mechanism in the pathogenesis of ischemic brain damage in neonates. Synaptotagmin I is one of exocytosis-related proteins at nerve terminals and considered to accelerate the exocytosis of synaptic vesicles by promoting fusion between the vesicles and plasma membrane. To test the possibility that antisense in vivo knockdown of synaptotagmin I modulates the exocytotic release of glutamate, thus suppressing the excitotoxic intracellular processes leading to neuronal death following ischemia in the neonatal brain, we injected antisense oligodeoxynucleotides (ODNs) targeting synaptotagmin I (0.3 (AS), 0.15 (0.5 AS), or 0.03 microg (0.1 AS), or vehicle) into the lateral ventricles of 7-day-old rats by using a hemagglutinating virus of Japan (HVJ)-liposome mediated gene transfer technique. At 10 days of age, these rats were subjected to an electrical coagulation of the right external and internal carotid arteries, then the insertion of a solid nylon thread into the right common carotid artery toward the ascending aorta up to 10-12 mm from the upper edge of the sternocleidomastoid muscle. Cerebral ischemia was induced by clamping the left external and internal carotid arteries with a clip, and ended by removing the clip 2h later. Twenty-four hours after the end of ischemia, the extent of ischemic brain damage was neuropathologically and quantitatively evaluated in the neocortex and striatum. While the relative volume of damage in the cerebral cortex and striatum of the vehicle group was extended to 40% and 13.7%, respectively, that in the AS group was significantly reduced to 4.8% and 0.6%. In the 0.5 AS group, the relative volume of ischemic damage in the cerebral cortex and striatum was reduced to 20.5% and 15.4%, respectively, and the difference between the 0.5 AS group and vehicle group was statistically significant in the neocortex, but not in the striatum. These results indicated

  14. Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy.

    Directory of Open Access Journals (Sweden)

    Julius O Enoru

    Full Text Available Parkinson's disease (PD is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®. We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioning to the brain. PP2A activity in mouse adrenal gland increased ~2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i crossed the blood-brain-barrier; (ii produced metabolites

  15. Ex vivo

    Science.gov (United States)

    Matsuda, Kant M; Lopes-Calcas, Ana; Honke, Michael L; O'Brien-Moran, Zoe; Buist, Richard; West, Michael; Martin, Melanie

    2017-07-01

    To advance magnetic resonance imaging (MRI) technologies further for in vivo tissue characterization with histopathologic validation, we investigated the feasibility of ex vivo tissue imaging of a surgically removed human brain tumor as a comprehensive approach for radiology-pathology correlation in histoanatomically identical fashion in a rare case of pigmented ganglioglioma with complex paramagnetic properties. Pieces of surgically removed ganglioglioma, containing melanin and hemosiderin pigments, were imaged with a small bore 7-T MRI scanner to obtain T1-, T2-, and T2*-weighted image and diffusion tensor imaging (DTI). Corresponding histopathological slides were prepared for routine hematoxylin and eosin stain and special stains for melanin and iron/hemosiderin to correlate with MRI signal characteristics. Furthermore, mean diffusivity (MD) maps were generated from DTI data and correlated with cellularity using image analysis. While the presence of melanin was difficult to interpret in in vivo MRI with certainty due to concomitant hemosiderin pigments and calcium depositions, ex vivo tissue imaging clearly demonstrated pieces of tissue exhibiting the characteristic MR signal pattern for melanin with pathologic confirmation in a histoanatomically identical location. There was also concordant correlation between MD and cellularity. Although it is still in an initial phase of development, ex vivo tissue imaging is a promising approach, which offers radiology-pathology correlation in a straightforward and comprehensive manner.

  16. Automated data processing of { 1H-decoupled} 13C MR spectra acquired from human brain in vivo

    Science.gov (United States)

    Shic, Frederick; Ross, Brian

    2003-06-01

    In clinical 13C infusion studies, broadband excitation of 200 ppm of the human brain yields 13C MR spectra with a time resolution of 2-5 min and generates up to 2000 metabolite peaks over 2 h. We describe a fast, automated, observer-independent technique for processing { 1H-decoupled} 13C spectra. Quantified 13C spectroscopic signals, before and after the administration of [1- 13C]glucose and/or [1- 13C]acetate in human subjects are determined. Stepwise improvements of data processing are illustrated by examples of normal and pathological results. Variation in analysis of individual 13C resonances ranged between 2 and 14%. Using this method it is possible to reliably identify subtle metabolic effects of brain disease including Alzheimer's disease and epilepsy.

  17. Depressed glucose consumption at reperfusion following brain ischemia does not correlate with mitochondrial dysfunction and development of infarction: an in vivo positron emission tomography study.

    Science.gov (United States)

    Martín, Abraham; Rojas, Santiago; Pareto, Deborah; Santalucia, Tomàs; Millán, Olga; Abasolo, Ibane; Gómez, Vanessa; Llop, Jordi; Gispert, Joan D; Falcon, Carles; Bargalló, Núria; Planas, Anna M

    2009-05-01

    Glucose consumption is severely depressed in the ischemic core, whereas it is maintained or even increased in penumbral regions during ischemia. Conversely, glucose utilization is severely reduced early after reperfusion in spite that glucose and oxygen are available. Experimental studies suggest that glucose hypometabolism might be an early predictor of brain infarction. However, the relationship between early glucose hypometabolism with later development of infarction remains to be further studied in the same subjects. Here, glucose consumption was assessed in vivo by positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) in a rat model of ischemia/reperfusion. Perfusion was evaluated by PET with (13)NH(3) during and after 2-hour (h) middle cerebral artery occlusion, and (18)F-FDG was given after 2h of reperfusion. Brain infarction was evaluated at 24h. Mitochondrial oxygen consumption was examined ex vivo using a biochemical method. Cortical (18)F-FDG uptake was reduced by 45% and 25% in the ischemic core and periphery, respectively. However, substantial alteration of mitochondrial respiration was not apparent until 24h, suggesting that mitochondria retained the ability to consume oxygen early after reperfusion. These results show reduced glucose use at early reperfusion in regions that will later develop infarction and, to a lesser extent, in adjacent regions. Depressed glucose metabolism in the ischemic core might be attributable to reduced metabolic requirement due to irreversible cellular injury. However, reduced glucose metabolism in peripheral regions suggests either an impairment of glycolysis or reduced glucose demand. Thus, our study supports that glycolytic depression early after reperfusion is not always related to subsequent development of infarction.

  18. In Vivo Brain Rosette Spectroscopic Imaging (RSI) with LASER Excitation, Constant Gradient Strength Readout, and Automated LCModel Quantification for all Voxels

    Science.gov (United States)

    Schirda, Claudiu V.; Zhao, Tiejun; Andronesi, Ovidiu C.; Lee, Yoojin; Pan, Jullie W.; Mountz, James M.; Hetherington, Hoby P.; Boada, Fernando E.

    2017-01-01

    Purpose To optimize the Rosette trajectories for high-sensitivity in vivo brain spectroscopic imaging and reduced gradient demands. Methods Using LASER localization, a rosette based sampling scheme for in vivo brain spectroscopic imaging data on a 3 Tesla (T) system is described. The two-dimensional (2D) and 3D rosette spectroscopic imaging (RSI) data were acquired using 20 × 20 in-plane resolution (8 × 8 mm2), and 1 (2D) −18 mm (1.1 cc) or 12 (3D) −8 mm partitions (0.5 cc voxels). The performance of the RSI acquisition was compared with a conventional spectroscopic imaging (SI) sequence using LASER localization and 2D or 3D elliptical phase encoding (ePE). Quantification of the entire RSI data set was performed using an LCModel based pipeline. Results The RSI acquisitions took 32 s for the 2D scan, and as short as 5 min for the 3D 20 × 20 × 12 scan, using a maximum gradient strength Gmax = 5.8 mT/m and slew-rate Smax = 45 mT/m/ms. The Bland-Altman agreement between RSI and ePE CSI, characterized by the 95% confidence interval for their difference (RSI-ePE), is within 13% of the mean (RSI+ePE)/2. Compared with the 3D ePE at the same nominal resolution, the effective RSI voxel size was three times smaller while the measured signal-to-noise ratio sensitivity, after normalization for differences in effective size, was 43% greater. Conclusion 3D LASER-RSI is a fast, high-sensitivity spectroscopic imaging sequence, which can acquire medium-to-high resolution SI data in clinically acceptable scan times (5–10 min), with reduced stress on the gradient system. PMID:26308482

  19. In vivo measure of neonate brain optical properties and hemodynamic parameters by time-domain near-infrared spectroscopy.

    Science.gov (United States)

    Spinelli, Lorenzo; Zucchelli, Lucia; Contini, Davide; Caffini, Matteo; Mehler, Jacques; Fló, Ana; Ferry, Alissa L; Filippin, Luca; Macagno, Francesco; Cattarossi, Luigi; Torricelli, Alessandro

    2017-10-01

    By exploiting a multichannel portable instrument for time-domain near-infrared spectroscopy (TD-NIRS), we characterized healthy neonates' brains in term of optical properties and hemodynamic parameters. In particular, we assessed the absolute values of the absorption and reduced scattering coefficients at two wavelengths, together with oxy-, deoxy- and total hemoglobin concentrations, and the blood oxygen saturation of the neonates' brains. In this study, 33 healthy full-term neonates were tested, obtaining the following median values: 0.28 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; 5.8 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; 72% for [Formula: see text]. In general, the agreement of these values with the sparse existing literature appears not always consistent. These findings demonstrate the first measurements of optical properties of the healthy neonate brain using TD-NIRS and show the need for clarification of optical properties across methods and populations.

  20. In vivo optical reflectance imaging of spreading depression waves in rat brain with and without focal cerebral ischemia.

    Science.gov (United States)

    Chen, Shangbin; Feng, Zhe; Li, Pengcheng; Jacques, Steven L; Zeng, Shaoqun; Luo, Qingming

    2006-01-01

    Spreading depression (SD) waves occur in focal cerebral ischemia of the brain. Optical reflectance imaging at 550 +/- 10-nm wavelength using a charge-coupled device (CCD) camera, called optical intrinsic signal imaging (OISI) in the neuroscience community, provides high resolution imaging of SD waves based on changes in blood perfusion. We present optical images of SD waves in normal rat brain induced by a pinprick, and the spontaneous SD waves that follow middle cerebral artery occlusion (MCAO). The images of change in reflectance are calculated as A = (I-I(o))I(o), where I is pixel intensity as some timepoint and I(o) is the initial intensity just prior to an SD wave. Difference images B = [I(i)-I(i-1)]I(o), where I(i) is the image at time i and I(i-1) is the previous image at time i-1 (a 6.4-s interval), significantly sharpen the boundaries between leading and trailing edges of the SD wave. Maximum rate-of-change images C = max(B) display the maximum pixel value of B within the duration of a single SD wave, and provide an image that visualizes the entire penumbra. The penumbra appear bright due to a rapid drop in perfusion, while the normal brain and infarct area appear dark.

  1. In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET

    Energy Technology Data Exchange (ETDEWEB)

    Conti, Peter S. [PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033 (United States)], E-mail: pconti@usc.edu; Bading, James R. [PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033 (United States); Mouton, Peter P. [Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21218 (United States); Links, Jonathan M. [Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21218 (United States); Alauddin, Mian M.; Fissekis, John D. [PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, CA 90033 (United States); Ravert, Hayden T.; Hilton, John; Wong, Dean F.; Anderson, James H. [Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21218 (United States)

    2008-01-15

    Introduction: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of {sup 11}C 2'-fluoro-5-methyl-1-{beta}-D-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model. Methods: Adult beagles (n=8) with implanted brain tumors received [{sup 11}C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m{sup 2}) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomography-defined regions of interest were corrected for partial volume effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor volume occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[{sup 11}C]FMAU and BUdR were compared by linear regression analysis and analysis of variance, as well as by a nonparametric rank correlation test. Results: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6{+-}0.4 and 5.5{+-}1.2 (n=8; mean{+-}S.E.M.), respectively. No {sup 11}C-labeled metabolites were observed in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k{sub 4}=0) and by Patlak analysis. Parametric statistical analysis showed that FMAU clearance from plasma into tumor Compartment 3 (K{sub FMAU}) was significantly correlated with S-phase percent volume (P=.03), while tumor SUV was significantly correlated with both S-phase percent volume and cell percent volume (P=.02 and .03, respectively). Patlak slope, K{sub FMAU} and tumor SUV were equivalent with regard to rank correlation analysis, which showed that tumor uptake and trapping of FMAU were correlated with the volume density of dividing cells (P=.0003) rather than nondividing cells (P=.3). Conclusions: Trapping of

  2. Multispectral reflectance imaging of brain activation in rodents: methodological study of the differential path length estimations and first in vivo recordings in the rat olfactory bulb

    Science.gov (United States)

    Renaud, Rémi; Martin, Claire; Gurden, Hirac; Pain, Frédéric

    2012-01-01

    Dynamic maps of relative changes in blood volume and oxygenation following brain activation are obtained using multispectral reflectance imaging. The technique relies on optical absorption modifications linked to hemodynamic changes. The relative variation of hemodynamic parameters can be quantified using the modified Beer-Lambert Law if changes in reflected light intensities are recorded at two wavelengths or more and the differential path length (DP) is known. The DP is the mean path length in tissues of backscattered photons and varies with wavelength. It is usually estimated using Monte Carlo simulations in simplified semi-infinite homogeneous geometries. Here we consider the use of multilayered models of the somatosensory cortex (SsC) and olfactory bulb (OB), which are common physiological models of brain activation. Simulations demonstrate that specific DP estimation is required for SsC and OB, specifically for wavelengths above 600 nm. They validate the hypothesis of a constant path length during activation and show the need for specific DP if imaging is performed in a thinned-skull preparation. The first multispectral reflectance imaging data recorded in vivo during OB activation are presented, and the influence of DP on the hemodynamic parameters and the pattern of oxymetric changes in the activated OB are discussed.

  3. MCNPx computational estimation of the calibration factor of an In vivo counter for {sup 18}F-FDG activity incorporated in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Melo M, B.; Ferreira F, T. C.; Duarte V, K.; Da Silva, T. A. [Centro de Desenvolvimento da Tecnologia Nuclear / CNEN, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil); Ribeiro de C, T. P., E-mail: bmm@cdtn.br [Universidade Federal de Minas Gerais, Departamento de Engenharia Nuclear, Programa de Pos-graduacao em Ciencias e Tecnicas, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil)

    2016-10-15

    In previous work, the computational modeling of the Centro de Desenvolvimento da Tecnologia Nuclear in vivo counter for estimation of {sup 18}F-FGD activity incorporated into workers brains was validated. Here, we studied the calibration factor (Cf) for seven distinct voxelized computational phantoms including the reference models from ICRP 110. Computational simulations were also carried out to study the effect of increasing the distance between the detector and the brain up to 100 cm. The degree of correlation among geometric and anatomical parameters of the computational models and the calibration factors were also evaluated. The morphological diversity of the computational phantoms resulted Cf variations greater than 38% (39.8 ± 0.2 to 64.6 ± 0.5 Bq.CPS{sup -1}). Despite the variations, Cf has been reduced by the increasing distance, although the remarkable decrease in counting efficiency makes prohibitive this geometry. These findings suggest that head anatomic parameters can be used to improve Cf estimation. (Author)

  4. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  5. Quantitative, noninvasive, in vivo longitudinal monitoring of gene expression in the brain by co-AAV transduction with a PET reporter gene

    Directory of Open Access Journals (Sweden)

    Sea Young Yoon

    2014-01-01

    Full Text Available In vivo imaging of vector transgene expression would be particularly valuable for repetitive monitoring of therapy in the brain, where invasive tissue sampling is contraindicated. We evaluated adeno-associated virus vector expression of a dopamine-2 receptor (D2R mutant (D2R80A by positron emission tomography in the brains of mice and cats. D2R80A is inactivated for intracellular signaling and binds subphysiologic amounts of the radioactive [18F]-fallypride analog of dopamine. The [18F]-fallypride signal bound to D2R80A in the injection site was normalized to the signal from endogenous D2R in the striatum and showed stable levels of expression within individual animals. A separate adeno-associated virus type 1 vector with identical gene expression control elements, expressing green fluorescent protein or a therapeutic gene, was coinjected with the D2R80A vector at equal doses into specific sites. Both transgenes had similar levels of gene expression by immunohistochemistry, in situ hybridization, and quantitative PCR assays, demonstrating that D2R80A is a faithful surrogate measure for expression of a gene of interest. This dual vector approach allows the D2R80A gene to be used with any therapeutic gene and to be injected into a single site for monitoring while the therapeutic gene can be distributed more widely as needed in each disease.

  6. Occupational health

    CERN Document Server

    Fingret, Dr Ann

    2013-01-01

    Offers a comprehensive view of health and safety issues at work. An invaluable resource for managers, personnel professionals and occupational health practitioners. Recommended by the Institute of Personnel Management.

  7. Occupational Therapists

    Science.gov (United States)

    ... bachelor’s degree and specific coursework, including biology and physiology. Many programs also require applicants to have volunteered ... of many conditions and ailments commonly associated with aging, such as arthritis and stroke. Occupational therapists also ...

  8. Occupational Health

    Science.gov (United States)

    Occupational health problems occur at work or because of the kind of work you do. These problems can include ... by exposure to radiation Exposure to germs in health care settings Good job safety and prevention practices ...

  9. Occupational Asthma

    Science.gov (United States)

    ... the enzymes of the bacteria Bacillus subtilis, while bakers may develop an allergy and occupational asthma symptoms ... counts Continuing education center Find an allergist / immunologist Journals Login / My membership Search your symptoms Shop the ...

  10. An In Vivo Microdialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson’s Disease Model Rats

    Directory of Open Access Journals (Sweden)

    Jinfeng Hou

    2014-01-01

    Full Text Available FLZ (N-[2-(4-hydroxy-phenyl-ethyl]-2-(2,5-dimethoxy-phenyl-3-(3-methoxy-4-hydroxy-phenyl-acrylamide is a novel synthetic squamosamide derivative and a potential anti-Parkinson’s disease (PD agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v. drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl. A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

  11. An In Vivo Microdialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson's Disease Model Rats

    Science.gov (United States)

    Hou, Jinfeng; Liu, Qian; Li, Yingfei; Sun, Hua; Zhang, Jinlan

    2014-01-01

    FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances. PMID:25045708

  12. Early metabolite changes after melatonin treatment in neonatal rats with hypoxic-ischemic brain injury studied by in-vivo1H MR spectroscopy.

    Science.gov (United States)

    Berger, Hester Rijkje; Nyman, Axel K G; Morken, Tora Sund; Vettukattil, Riyas; Brubakk, Ann-Mari; Widerøe, Marius

    2017-01-01

    Melatonin is a promising neuroprotective agent after perinatal hypoxic-ischemic (HI) brain injury. We used in-vivo 1H magnetic resonance spectroscopy to investigate effects of melatonin treatment on brain metabolism after HI. Postnatal day 7 Sprague-Dawley rats with unilateral HI brain injury were treated with either melatonin 10 mg/kg dissolved in phosphate-buffered saline (PBS) with 5% dimethyl sulfoxide (DMSO) or vehicle (5% DMSO and/or PBS) directly and at 6 hours after HI. 1H MR spectra from the thalamus in the ipsilateral and contralateral hemisphere were acquired 1 day after HI. Our results showed that injured animals had a distinct metabolic profile in the ipsilateral thalamus compared to sham with low concentrations of total creatine, choline, N-acetyl aspartate (NAA), and high concentrations of lipids. A majority of the melatonin-treated animals had a metabolic profile characterized by higher total creatine, choline, NAA and lower lipid levels than other HI animals. When comparing absolute concentrations, melatonin treatment resulted in higher glutamine levels and lower lipid concentrations compared to DMSO treatment as well as higher macromolecule levels compared to PBS treatment day 1 after HI. DMSO treated animals had lower concentrations of glucose, creatine, phosphocholine and macromolecules compared to sham animals. In conclusion, the neuroprotective effects of melatonin were reflected in a more favorable metabolic profile including reduced lipid levels that likely represents reduced cell injury. Neuroprotective effects may also be related to the influence of melatonin on glutamate/glutamine metabolism. The modulatory effects of the solvent DMSO on cerebral energy metabolism might have masked additional beneficial effects of melatonin.

  13. Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain.

    Science.gov (United States)

    Ribeiro, Rafael Teixeira; Zanatta, Ângela; Amaral, Alexandre Umpierrez; Leipnitz, Guilhian; de Oliveira, Francine Hehn; Seminotti, Bianca; Wajner, Moacir

    2018-02-06

    Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2',7'-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.

  14. Test-retest reliability of (11)C-ORM-13070 in PET imaging of α2C-adrenoceptors in vivo in the human brain.

    Science.gov (United States)

    Lehto, Jussi; Virta, Jere R; Oikonen, Vesa; Roivainen, Anne; Luoto, Pauliina; Arponen, Eveliina; Helin, Semi; Hietamäki, Johanna; Holopainen, Aila; Kailajärvi, Marita; Peltonen, Juha M; Rouru, Juha; Sallinen, Jukka; Virtanen, Kirsi; Volanen, Iina; Scheinin, Mika; Rinne, Juha O

    2015-01-01

    α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes. PET imaging with the specific α2C-adrenoceptor antagonist tracer [(11)C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also 0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [(11)C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. The results of this study support the use of [(11)C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios.

  15. Test-retest reliability of {sup 11}C-ORM-13070 in PET imaging of α{sub 2C}-adrenoceptors in vivo in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Lehto, Jussi; Peltonen, Juha M.; Volanen, Iina; Scheinin, Mika [University of Turku, Clinical Research Services Turku CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); Virta, Jere R. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); Oikonen, Vesa; Roivainen, Anne; Luoto, Pauliina; Arponen, Eveliina; Helin, Semi; Virtanen, Kirsi [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Turku (Finland); Kailajaervi, Marita [Turku Imanet, GE Healthcare, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku, Clinical Research Services Turku CRST, Turku (Finland)

    2015-01-15

    α{sub 2C}-Adrenoceptors share inhibitory presynaptic functions with the more abundant α{sub 2A}-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α{sub 2}-adrenoceptor subtypes. PET imaging with the specific α{sub 2C}-adrenoceptor antagonist tracer [{sup 11}C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [{sup 11}C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. The results of this study support the use of [{sup 11}C]ORM-13070 PET in the quantitative assessment of α{sub 2C}-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios. (orig.)

  16. Mechanistic evaluation of tapentadol in reducing the pain perception using in-vivo brain and spinal cord microdialysis in rats.

    Science.gov (United States)

    Benade, Vijay; Nirogi, Ramakrishna; Bhyrapuneni, Gopinadh; Daripelli, Saivishal; Ayyanki, Ganesh; Irappanavar, Shantaveer; Ponnamaneni, Ranjithkumar; Manoharan, Arunkumar

    2017-08-15

    Role of monoamine neurotransmitters in the modulation of emotional and pain processing in spinal cord and brain regions is not well known. Tapentadol, a norepinephrine reuptake inhibitor with µ-opioid receptor agonistic activity has recently been introduced for the treatment of moderate to severe pain. The objective of the present study was to examine the effects of tapentadol on modulation of monoamines in the prefrontal cortex and dorsal horn using brain microdialysis. Tapentadol was administered intraperitoneally at 4.64-21.5mg/kg to male Wistar rats. Based on these results, 10mg/kg i.p. was chosen for spinal microdialysis in freely moving rats. Tapentadol produced significant and dose-dependent increase in cortical dopamine and norepinephrine levels with mean maximum increase of 600% and 300%, respectively. Treatment had no effect on cortical serotonin levels. In the dorsal horn, serotonin, dopamine and norepinephrine levels were significantly increased with mean maximum increases of 220%, 190% and 280%, respectively. Although the density of dopamine transporter is low in cortex, the increase of dopamine and norepinephrine levels in cortex could be mediated through the inhibition of norepinephrine transporter. In the dorsal horn, increase in norepinephrine levels could be due to inhibition of norepinephrine transporter in the spinal cord. Whereas, activation of opioids receptors in non-spinal regions might be responsible for increase in dopamine and serotonin levels. The results from current investigation suggest that clinical efficacy of tapentadol in neuropathic pain is mediated through the enhanced monoaminergic neurotransmission in the spinal cord and regions involved with emotional processing in brain. Copyright © 2017. Published by Elsevier B.V.

  17. Comparison of different pulse sequences for in vivo determination of T1 relaxation times in the human brain

    DEFF Research Database (Denmark)

    Kjaer, L; Henriksen, O

    1988-01-01

    ). T1 measurements were performed on the human brain using a whole body MR scanner operating at 1.5 tesla. Three different pulse sequences were compared including two 6-points inversion recovery (IR) sequences with TR = 2.0 s and 4.0, respectively, and a 12-points partial saturation inversion recovery...... (PSIR) sequence with TR varying between 0.24 and 8.0 s. The median T1 relaxation times obtained in cortical grey matter and cerebrospinal fluid were significantly shorter in the IR experiments at TR = 2 s than in those carried out at TR = 4 s. Concerning white matter the discrepancy was much less...

  18. Ex-vivo diffusion MRI reveals microstructural alterations in stress-sensitive brain regions: A chronic mild stress recovery study

    DEFF Research Database (Denmark)

    Khan, Ahmad Raza; Hansen, Brian; Wiborg, Ove

    Depression is a leading cause of disability worldwide and causes significant microstructural alterations in stress-sensitive brain regions. However, the potential recovery of these microstructural alterations has not previously been investigated, which we, therefore, set out to do using diffusion...... MRI (d-MRI) in the chronic mild stress (CMS) rat model of depression. This study reveals significant microstructural alterations after 8 weeks of recovery, in the opposite direction to change induced by stress in the acute phase of the experiment. Such findings may be useful in the prognosis...

  19. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Directory of Open Access Journals (Sweden)

    Udvardi PT

    2013-12-01

    Full Text Available Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip] or saline (0.9%, ip for 21 consecutive days on postnatal days (PND 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR, mesencephalon (MES, and hippocampus (HC was analyzed either directly after treatment (PND 42 or 2 months after termination of treatment (PND 101 to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects

  20. Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology.

    Science.gov (United States)

    Frigerio, Federica; Frasca, Angelisa; Weissberg, Itai; Parrella, Sara; Friedman, Alon; Vezzani, Annamaria; Noé, Francesco M

    2012-11-01

      Dysfunction of the blood-brain barrier (BBB) is a common finding during seizures or following epileptogenic brain injuries, and experimentally induced BBB opening promotes seizures both in naive and epileptic animals. Brain albumin extravasation was reported to promote hyperexcitability by inducing astrocytes dysfunction. To provide in vivo evidence for a direct role of extravasated serum albumin in seizures independently on the pathologic context, we did the following: (1) quantified the amount of serum albumin extravasated in the rat brain parenchyma during status epilepticus (SE); (2) reproduced a similar concentration in the hippocampus by intracerebroventricular (i.c.v.) albumin injection in naive rats; (3) measured electroencephalography (EEG) activity in these rats, their susceptibility to kainic acid (KA)-induced seizures, and their hippocampal afterdischarge threshold (ADT).   Brain albumin concentration was measured in the rat hippocampus and other forebrain regions 2 and 24 h after SE by western blot analysis. Brain distribution of serum albumin or fluorescein isothiocyanate (FITC)-albumin was studied by immunohistochemistry and immunofluorescence, respectively. Naive rats were injected with rat albumin or FITC-albumin, i.c.v., to mimic the brain concentration attained after SE, or with dextran used as control. Inflammation was evaluated by immunohistochemistry by measuring glial induction of interleukin (IL)-1β. Western blot analysis was used to measure inward rectifying potassium channel subunit Kir4.1 protein levels in the hippocampus. Seizures were induced in rats by intrahippocampal injection of 80 ng KA and quantified by EEG analysis, 2 or 24 h after rat albumin or dextran administration. ADT was measured by electrical stimulation of the hippocampus 3 months after albumin injection. In these rats, EEG was continuously monitored for 2 weeks to search for spontaneous seizures.   The hippocampal serum albumin concentration 24

  1. Functional Anatomy of the Thalamus as a Model of Integrated Structural and Functional Connectivity of the Human Brain In Vivo.

    Science.gov (United States)

    Mastropasqua, Chiara; Bozzali, Marco; Spanò, Barbara; Koch, Giacomo; Cercignani, Mara

    2015-07-01

    While methods of measuring non-invasively both, functional and structural brain connectivity are available, the degree of overlap between them is still unknown. In this paper this issue is addressed by investigating the connectivity pattern of a brain structure with many, well characterized structural connections, namely the thalamus. Diffusion-weighted and resting state (RS) functional MRI (fMRI) data were collected in a group of 38 healthy participants. Probabilistic tractography was performed to parcellate the thalamus into regions structurally connected to different cortical areas. The resulting regions were used as seeds for seed-based analysis of RS fMRI data. The tractographic parcellation was thus cross-validated against functional connectivity data by evaluating the overlap between the functional and structural thalamo-cortical connections originating from the parcellated regions. Our data show only a partial overall correspondence between structural and functional connections, in the same group of healthy individuals, thus suggesting that the two approaches provide complementary and not overlapping information. Future studies are warranted to extend the results we obtained in the thalamus to other structures, and to confirm that the mechanisms behind functional connectivity are more complex than just expressing structural connectivity.

  2. In vivo measurement of volumetric strain in the human brain induced by arterial pulsation and harmonic waves.

    Science.gov (United States)

    Hirsch, Sebastian; Klatt, Dieter; Freimann, Florian; Scheel, Michael; Braun, Jürgen; Sack, Ingolf

    2013-09-01

    Motion-sensitive phase contrast magnetic resonance imaging and magnetic resonance elastography are applied for the measurement of volumetric strain and tissue compressibility in human brain. Volumetric strain calculated by the divergence operator using a biphasic effective-medium model is related to dilatation and compression of fluid spaces during harmonic stimulation of the head or during intracranial passage of the arterial pulse wave. In six volunteers, phase contrast magnetic resonance imaging showed that the central cerebrum expands at arterial pulse wave to strain values of (2.8 ± 1.9)·10(-4). The evolution of volumetric strain agrees well with the magnitude of the harmonic divergence measured in eight volunteers by magnetic resonance elastography using external activation of 25 Hz vibration frequency. Intracranial volumetric strain was proven sensitive to venous pressure altered by abdominal muscle contraction. In eight volunteers, an increase in volumetric strain due to abdominal muscle contraction of approximately 45% was observed (P = 0.0001). The corresponding compression modulus in the range of 9.5-13.5 kPa demonstrated that the compressibility of brain tissue at 25 Hz stimulation is much higher than that of water. This pilot study provides the background for compression-sensitive magnetic resonance imaging with or without external head stimulation. Volumetric strain may be sensitive to fluid flow abnormalities or pressure imbalances between vasculature and parenchyma as seen in hydrocephalus. Copyright © 2012 Wiley Periodicals, Inc.

  3. Nitric oxide monitoring in brain extracellular fluid: characterisation of Nafion-modified Pt electrodes in vitro and in vivo.

    Science.gov (United States)

    Brown, Finbar O; Finnerty, Niall J; Lowry, John P

    2009-10-01

    A Nafion(5 pre-coats/2 dip-coats)-modified Pt sensor developed for real-time neurochemical monitoring has now been characterised in vitro for the sensitive and selective detection of nitric oxide (NO). A potentiodynamic profile at bare Pt established +0.9 V (vs. SCE) to be the most appropriate applied potential for NO oxidation. The latter was confirmed using oxyhaemoglobin and N(2), both of which reduced the NO signal to baseline levels. Results indicated enhanced NO sensitivity at the Nafion(5/2) sensor (1.67 +/- 0.08 nA microM(-1)) compared to bare Pt (1.08 +/- 0.20 nA microM(-1)) and negligible interference from a wide range of endogenous electroactive interferents such as ascorbic acid, dopamine and its metabolites, NO(2)(-) and H(2)O(2). The response time of 33.7 +/- 2.7 s was found to improve (19.0 +/- 3.4 s) when the number of Nafion layers was reduced to 2/1 and an insulating outer layer of poly(o-phenylenediamine) added. When tested under physiological conditions of 37 degrees C the response time of the Nafion(5/2) sensor improved to 14.00 +/- 2.52 s. In addition, the NO response was not affected by physiological concentrations of O(2) despite the high reactivity of the two species for each other. The limit of detection (LOD) was estimated to be 5 nM while stability tests in lipid (phosphatidylethanolamine; PEA) and protein (bovine serum albumin; BSA) solutions (10%) found an initial ca. 38% drop in sensitivity in the first 24 h which remained constant thereafter. Preliminary in vivo experiments involving systemic administration of NO and L-arginine produced increases in the signals recorded at the Nafion(5/2) sensor implanted in the striatum of freely-moving rats, thus supporting reliable in vivo recording of NO.

  4. In vivo high angular resolution diffusion-weighted imaging of mouse brain at 16.4 Tesla.

    Directory of Open Access Journals (Sweden)

    Othman I Alomair

    Full Text Available Magnetic Resonance Imaging (MRI of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T1 and shorter T2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces. The Stejskal-Tanner spin echo diffusion-weighted imaging (DWI sequence is often used in high-field rodent brain MRI due to its immunity to these artefacts. To accurately determine diffusion-tensor or fibre-orientation distribution, high angular resolution diffusion imaging (HARDI with strong diffusion weighting (b >3000 s/mm2 and at least 30 diffusion-encoding directions are required. However, this results in long image acquisition times unsuitable for live animal imaging. In this study, we describe the optimization of HARDI acquisition parameters at 16.4T using a Stejskal-Tanner sequence with echo-planar imaging (EPI readout. EPI segmentation and partial Fourier encoding acceleration were applied to reduce the echo time (TE, thereby minimizing signal decay and distortion artefacts while maintaining a reasonably short acquisition time. The final HARDI acquisition protocol was achieved with the following parameters: 4 shot EPI, b = 3000 s/mm2, 64 diffusion-encoding directions, 125×150 μm2 in-plane resolution, 0.6 mm slice thickness, and 2h acquisition time. This protocol was used to image a cohort of adult C57BL/6 male mice, whereby the quality of the acquired data was assessed and diffusion tensor imaging (DTI derived parameters were measured. High-quality images with high spatial and angular resolution, low distortion and low variability in DTI-derived parameters were obtained, indicating that EPI-DWI is feasible at 16.4T to study animal models of white

  5. In vivo high angular resolution diffusion-weighted imaging of mouse brain at 16.4 Tesla.

    Science.gov (United States)

    Alomair, Othman I; Brereton, Ian M; Smith, Maree T; Galloway, Graham J; Kurniawan, Nyoman D

    2015-01-01

    Magnetic Resonance Imaging (MRI) of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla) offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T1 and shorter T2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces. The Stejskal-Tanner spin echo diffusion-weighted imaging (DWI) sequence is often used in high-field rodent brain MRI due to its immunity to these artefacts. To accurately determine diffusion-tensor or fibre-orientation distribution, high angular resolution diffusion imaging (HARDI) with strong diffusion weighting (b >3000 s/mm2) and at least 30 diffusion-encoding directions are required. However, this results in long image acquisition times unsuitable for live animal imaging. In this study, we describe the optimization of HARDI acquisition parameters at 16.4T using a Stejskal-Tanner sequence with echo-planar imaging (EPI) readout. EPI segmentation and partial Fourier encoding acceleration were applied to reduce the echo time (TE), thereby minimizing signal decay and distortion artefacts while maintaining a reasonably short acquisition time. The final HARDI acquisition protocol was achieved with the following parameters: 4 shot EPI, b = 3000 s/mm2, 64 diffusion-encoding directions, 125×150 μm2 in-plane resolution, 0.6 mm slice thickness, and 2h acquisition time. This protocol was used to image a cohort of adult C57BL/6 male mice, whereby the quality of the acquired data was assessed and diffusion tensor imaging (DTI) derived parameters were measured. High-quality images with high spatial and angular resolution, low distortion and low variability in DTI-derived parameters were obtained, indicating that EPI-DWI is feasible at 16.4T to study animal models of white matter (WM

  6. In vivo

    Science.gov (United States)

    Berkowitz, Bruce A; Lenning, Jacob; Khetarpal, Nikita; Tran, Catherine; Wu, Johnny Y; Berri, Ali M; Dernay, Kristin; Haacke, E Mark; Shafie-Khorassani, Fatema; Podolsky, Robert H; Gant, John C; Maimaiti, Shaniya; Thibault, Olivier; Murphy, Geoffrey G; Bennett, Brian M; Roberts, Robin

    2017-09-01

    Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/ T 1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. © FASEB.

  7. Imaging the dopamine uptake site with ex vivo [18F]GBR 13119 binding autoradiography in rat brain.

    Science.gov (United States)

    Ciliax, B J; Kilbourn, M R; Haka, M S; Penney, J B

    1990-08-01

    We studied the binding of [18F]GBR 13119 (1-[[(4-[18F]fluorophenyl) (phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) to rat brain with autoradiography after intravenous injection. The rank order of binding was dorsal striatum greater than nucleus accumbens = olfactory tubercle greater than substantia nigra = ventral tegmental area greater than other areas. Binding was blocked by prior injection of dopamine uptake blockers but not by injection of dopamine receptor antagonists or drugs that bind to the dialkylpiperazine site. Unilateral 6-hydroxy-dopamine lesions of dopamine neurons caused a marked decrease in striatal and nigral binding on the side of the lesion. We conclude that intravenous injection of [18F]GBR 13119 provides a useful marker of presynaptic dopamine uptake sites.

  8. Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy.

    Science.gov (United States)

    Duarte, João M N; Do, Kim Q; Gruetter, Rolf

    2014-07-01

    Alterations to brain homeostasis during development are reflected in the neurochemical profile determined noninvasively by (1)H magnetic resonance spectroscopy. We determined longitudinal biochemical modifications in the cortex, hippocampus, and striatum of C57BL/6 mice aged between 3 and 24 months . The regional neurochemical profile evolution indicated that aging induces general modifications of neurotransmission processes (reduced GABA and glutamate), primary energy metabolism (altered glucose, alanine, and lactate) and turnover of lipid membranes (modification of choline-containing compounds and phosphorylethanolamine), which are all probably involved in the frequently observed age-related cognitive decline. Interestingly, the neurochemical profile was different in male and female mice, particularly in the levels of taurine that may be under the control of estrogen receptors. These neurochemical profiles constitute the basal concentrations in cortex, hippocampus, and striatum of healthy aging male and female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders.

    Directory of Open Access Journals (Sweden)

    Donna C Davidson

    Full Text Available Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND, indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1 positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.

  10. Three-dimensional histological imaging of primate brain and correlation with in vivo medical device images Imagerie histologique tri-dimensionnelle du cerveau de primate et corrélation avec l'imagerie médicale in vivo

    Directory of Open Access Journals (Sweden)

    Julien Dauguet

    2011-02-01

    Full Text Available The 3D reconstruction of series of histological slices is an imaging technique that appeared about 25 years ago but that is only starting now to become recognized as an imaging modality per se. Thanks to this technique, it becomes possible to restore the spatial consistency of the brain and to match accurately histological slices with an in vivo medical device image such as an MRI or a PET scan. This is of high interest since it allows direct comparison between the histology, often considered as the gold standard in terms of information, and the same medical devices used in clinical routine to image human patients. Thanks to the similarity of their brain with humans and the disease models widely developed for them, non-human primates are privileged species to benefit from this possibility of 3D analysis and in vivo - post mortem correlation. We present in this article a state of the art review of the main techniques proposed to achieve this original imaging technique, followed by a set of some particularly promising neuroimaging applications.La reconstruction 3D de séries de coupes histologiques est une technique d'imagerie qui est apparue il y a 25 ans environ mais qui commence seulement à être reconnue comme une modalité d'imagerie à part entière. Grâce à cette technique, la cohérence 3D du cerveau est rétablie et il devient notamment possible de mettre en correspondance précisément des coupes histologiques avec un examen issu d'un imageur médical comme une IRM ou une TEP. C'est d'un intérêt majeur car cela permet une comparaison directe entre l'histologie, souvent considérée comme la référence étalon en termes d'information fournie, et les mêmes imageurs médicaux que ceux utilisés en routine clinique pour suivre les patients humains. Grâce à leur similarité avec les humains et aux nombreux modèles animaux de maladies développés pour eux, les primates non-humains sont une espèce privilégiée pour bénéficier de

  11. Effect of Physical Exercise and Acute Escitalopram on the Excitability of Brain Monoamine Neurons: In Vivo Electrophysiological Study in Rats.

    Science.gov (United States)

    Dremencov, Eliyahu; Csatlósová, Kristína; Durišová, Barbora; Moravcíková, Lucia; Lacinová, Lubica; Ježováv, Daniela

    2017-07-01

    The antidepressant effect of physical exercise has been reported in several clinical and animal studies. Since serotonin, norepinephrine, and dopamine play a central role in depression, it is possible that the beneficial effects of physical exercise are mediated via monoamine pathways. This study investigates the effects of voluntary wheel running on the excitability of monoamine neurons. Male Sprague-Dawley rats were used in the study. Voluntary wheel running (VWR) rats were housed in individual cages with free access to a running wheel, while control animals were housed in standard laboratory cages. After three weeks, the rats were anesthetized, and in vivo electrophysiological recordings were taken from dorsal raphe nucleus serotonin neurons, locus coeruleus norepinephrine neurons, and ventral tegmental dopamine neurons. VWR stimulated activity in serotonin, but not in norepinephrine or dopamine neurons. Subsequently, acute administration of the selective serotonin reuptake inhibitor escitalopram in control rats led to complete suppression of serotonin neurons; this suppression was reversed by subsequent administration of selective antagonist of serotonin-1A receptors, WAY100135. Escitalopram induced only partial inhibition of serotonin neurons in the VWR rats while WAY100135 increased the firing activity of serotonin neurons above the baseline value. The beneficial effect of physical exercise on mood is mediated, at least in part, via activation of serotonin neurons. Physical exercise can potentiate the response to selective serotonin reuptake inhibitors by increasing the basal firing activity and diminishing selective serotonin reuptake inhibitor-induced inhibition of serotonin neurons.

  12. Diffusion MRI microstructure models with in vivo human brain Connectom data: results from a multi-group comparison

    CERN Document Server

    Ferizi, Uran; Schneider, Torben; Alipoor, Mohammad; Eufracio, Odin; Fick, Rutger H J; Deriche, Rachid; Nilsson, Markus; Loya-Olivas, Ana K; Rivera, Mariano; Poot, Dirk H J; Ramirez-Manzanares, Alonso; Marroquin, Jose L; Rokem, Ariel; Pötter, Christian; Dougherty, Robert F; Sakaie, Ken; Wheeler-Kingshott, Claudia; Warfield, Simon K; Witzel, Thomas; Wald, Lawrence L; Raya, José G; Alexander, Daniel C

    2016-01-01

    A large number of mathematical models have been proposed to describe the measured signal in diffusion-weighted (DW) magnetic resonance imaging (MRI) and infer properties about the white matter microstructure. However, a head-to-head comparison of DW-MRI models is critically missing in the field. To address this deficiency, we organized the "White Matter Modeling Challenge" during the International Symposium on Biomedical Imaging (ISBI) 2015 conference. This competition aimed at identifying the DW-MRI models that best predict unseen DW data. in vivo DW-MRI data was acquired on the Connectom scanner at the A.A.Martinos Center (Massachusetts General Hospital) using gradients strength of up to 300 mT/m and a broad set of diffusion times. We focused on assessing the DW signal prediction in two regions: the genu in the corpus callosum, where the fibres are relatively straight and parallel, and the fornix, where the configuration of fibres is more complex. The challenge participants had access to three-quarters of t...

  13. Occupational mortality

    DEFF Research Database (Denmark)

    Lynge, Elsebeth

    2011-01-01

    INTRODUCTION: This paper aims to present the methods and main results from the Danish occupational mortality studies, and to set the Danish studies into the international context of occupational mortality studies. RESEARCH TOPICS: The first Danish occupational mortality study from 1970......-1975 revealed a considerable social class gradient in male mortality where university teachers and farmers had a 40% lower mortality and waiters and seamen had an about 100% higher mortality than the average for economically active men. The social class gradient was less steep for women. A similar pattern...... was found in 1996- 2005. CONCLUSION: In view of the considerable societal changes which have taken place from the beginning of the 1970s to the turn of the century, surprisingly small changes have taken place in the mortality pattern across social groups....

  14. Non-uniformly weighted sampling for faster localized two-dimensional correlated spectroscopy of the brain in vivo

    Science.gov (United States)

    Verma, Gaurav; Chawla, Sanjeev; Nagarajan, Rajakumar; Iqbal, Zohaib; Albert Thomas, M.; Poptani, Harish

    2017-04-01

    Two-dimensional localized correlated spectroscopy (2D L-COSY) offers greater spectral dispersion than conventional one-dimensional (1D) MRS techniques, yet long acquisition times and limited post-processing support have slowed its clinical adoption. Improving acquisition efficiency and developing versatile post-processing techniques can bolster the clinical viability of 2D MRS. The purpose of this study was to implement a non-uniformly weighted sampling (NUWS) scheme for faster acquisition of 2D-MRS. A NUWS 2D L-COSY sequence was developed for 7T whole-body MRI. A phantom containing metabolites commonly observed in the brain at physiological concentrations was scanned ten times with both the NUWS scheme of 12:48 duration and a 17:04 constant eight-average sequence using a 32-channel head coil. 2D L-COSY spectra were also acquired from the occipital lobe of four healthy volunteers using both the proposed NUWS and the conventional uniformly-averaged L-COSY sequence. The NUWS 2D L-COSY sequence facilitated 25% shorter acquisition time while maintaining comparable SNR in humans (+0.3%) and phantom studies (+6.0%) compared to uniform averaging. NUWS schemes successfully demonstrated improved efficiency of L-COSY, by facilitating a reduction in scan time without affecting signal quality.

  15. Long-term Neuroglial Cocultures as a Brain Aging Model: Hallmarks of Senescence, MicroRNA Expression Profiles, and Comparison With In Vivo Models.

    Science.gov (United States)

    Bigagli, Elisabetta; Luceri, Cristina; Scartabelli, Tania; Dolara, Piero; Casamenti, Fiorella; Pellegrini-Giampietro, Domenico E; Giovannelli, Lisa

    2016-01-01

    Our purpose was to evaluate long-term neuroglial cocultures as a model for investigating senescence in the nervous system and to assess its similarities with in vivo models. To this aim, we maintained the cultures from 15 days in vitro (mature cultures) up to 27 days in vitro (senescent cultures), measuring senescence-associated, neuronal, dendritic, and astrocytic markers. Whole microRNA expression profiles were compared with those measured in the cortex of 18- and 24-month-old C57Bl/6J aged mice and of transgenic TgCRND8 mice, a model of amyloid-β deposition. Neuroglial cocultures displayed features of cellular senescence (increased senescence-associated-β-galactosidase activity, oxidative stress, γ-H2AX expression, IL-6 production, astrogliosis) that were concentration dependently counteracted by the antiaging compound resveratrol (1-5 µM). Among the 1,080 microRNAs analyzed, 335 were downregulated or absent in 27 compared with 15 days in vitro and resveratrol reversed this effect. A substantial overlapping was found between age-associated changes in microRNA expression profiles in vitro and in TgCRND8 mice but not in physiologically aged mice, indicating that this culture model displays more similarities with pathological than physiological brain aging. Our results demonstrate that neuroglial cocultures aged in vitro can be useful for investigating the cellular and molecular mechanisms of brain aging and for preliminary testing of protective compounds. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Development of an imaging system for in vivo real-time monitoring of neuronal activity in deep brain of free-moving rats.

    Science.gov (United States)

    Iijima, Norio; Miyamoto, Shinji; Matsumoto, Keisuke; Takumi, Ken; Ueta, Yoichi; Ozawa, Hitoshi

    2017-09-01

    We have newly developed a system that allows monitoring of the intensity of fluorescent signals from deep brains of rats transgenically modified to express enhanced green fluorescent protein (eGFP) via an optical fiber. One terminal of the optical fiber was connected to a blue semiconductor laser oscillator/green fluorescence detector. The other terminal was inserted into the vicinity of the eGFP-expressing neurons. Since the optical fiber was vulnerable to twisting stresses caused by animal movement, we also developed a cage in which the floor automatically turns, in response to the turning of the rat's head. This relieved the twisting stress on the optical fiber. The system then enabled real-time monitoring of fluorescence in awake and unrestrained rats over many hours. Using this system, we could continuously monitor eGFP-expression in arginine vasopressin-eGFP transgenic rats. Moreover, we observed an increase of eGFP-expression in the paraventricular nucleus under salt-loading conditions. We then performed in vivo imaging of eGFP-expressing GnRH neurons in the hypothalamus, via a bundle consisting of 3000 thin optical fibers. With the combination of the optical fiber bundle connection to the fluorescence microscope, and the special cage system, we were able to capture and retain images of eGFP-expressing neurons from free-moving rats. We believe that our newly developed method for monitoring and imaging eGFP-expression in deep brain neurons will be useful for analysis of neuronal functions in awake and unrestrained animals for long durations.

  17. Mapping of electrophysiological response to transcranial infrared laser stimulation on the human brain in vivo measured by electroencephalography (Conference Presentation)

    Science.gov (United States)

    Wang, Xinlong; Reddy, Divya Dhandapani; Gonzalez-Lima, F.; Liu, Hanli

    2017-02-01

    Transcranial infrared laser stimulation (TILS) is a non-destructive and non-thermal photobiomodulation therapy or process on the human brain; TILS uses infrared light from lasers or LEDs and has gained increased recognition for its beneficial effects on a variety of neurological and psychological conditions. While the mechanism of TILS has been assumed to stem from cytochrome-c-oxidase (CCO), which is the last enzyme in the electron transportation chain and is the primary photoacceptor, no literature is found to report electrophysiological response to TILS. In this study, a 64-channel electroencephalography (EEG) system was employed to monitor electrophysiological activities from 15 healthy human participants before, during and after TILS. A placebo experimental protocol was also applied for rigorous comparison. After recording a 3-minute baseline, we applied a 1064-nm laser with a power of 3.5W on the right forehead of each human participant for 8 minutes, followed by a 5-minute recovery period. In 64-channel EEG data analysis, we utilized several methods (root mean square, principal component analysis followed by independent component analysis, permutation conditional mutual information, and time-frequency wavelet analysis) to reveal differences in electrophysiological response to TILS between the stimulated versus placebo group. The analyzed results were further investigated using general linear model and paired t-test to reveal statistically meaningful responses induced by TILS. Moreover, this study will provide spatial mapping of human electrophysiological and possibly neural network responses to TILS for first time, indicating the potential of EEG to be an effective method for monitoring neurological improvement induced by TILS.

  18. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    Science.gov (United States)

    Choi, Woo June; Wang, Ruikang K.

    2015-10-01

    We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll.

  19. Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

    Directory of Open Access Journals (Sweden)

    Kavelaars Annemieke

    2010-08-01

    Full Text Available Abstract Background Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior. Methods Sickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs. Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC with electrochemical detection. Results Intracerebroventricular (i.c.v. administration of LPS (100 ng increased steady-state transcripts of TNFα, IL-6 and the inducible isoform of nitric oxide synthase (iNOS in the hippocampus in the absence of any change in IFNγ mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFα and IL-6 protein and activation of iNOS while IFNγ expression was undetectable. Conclusion These data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce

  20. Quantitative assessment of hemodynamic and structural characteristics of in vivo brain tissue using total diffuse reflectance spectrum measured in a non-contact fashion.

    Science.gov (United States)

    Song, Yinchen; Garcia, Sarahy; Frometa, Yisel; Ramella-Roman, Jessica C; Soltani, Mohammad; Almadi, Mohamed; Riera, Jorge J; Lin, Wei-Chiang

    2017-01-01

    Here we present a new methodology that investigates the intrinsic structural and hemodynamic characteristics of in vivo brain tissue, in a non-contact fashion, and can be easily incorporated in an intra-operative environment. Within this methodology, relative total diffuse reflectance spectra (RTD(λ)) were acquired from targets using a hybrid spectroscopy imaging system. A spectral interpretation algorithm was subsequently applied to RTD(λ) to retrieve optical properties related to the compositional and structural characteristics of each target. Estimation errors of the proposed methodology were computationally evaluated using a Monte Carlo simulation model for photon migration under various conditions. It was discovered that this new methodology could handle moderate noise and achieve very high accuracy, but only if the refractive index of the target is known. The accuracy of the technique was also validated using a series of tissue phantom studies, and consistent and accurate estimates of μs'(λ)/μa(λ) were obtained from all the phantoms tested. Finally, a small-scale animal study was conducted to demonstrate the clinical utility of the reported method, wherein a forepaw stimulation model was utilized to induce transient hemodynamic responses in somatosensory cortices. With this approach, significant stimulation-related changes (p < 0.001) in cortical hemodynamic and structural characteristics were successfully measured.

  1. Enhanced in-vivo optical coherence tomography of live mouse brain by the use of implanted micro-lens (Presentation Recording)

    Science.gov (United States)

    Hassani Nia, Iman; Dombeck, Daniel; Mohseni, Hooman

    2015-08-01

    Near-infrared optical coherence tomography (OCT) has gained a lot of attention due to the fact that it is relatively cheap, non-invasive and provides high resolution and fast method of imaging. However the main challenge of this technique is the poor signal to noise ratio of the images of the tissue at large depths due to optical scattering. The signal to noise ratio can be improved by increasing the source power, however the laser safety standards (ANSI Z136.1) restricts the maximum amount of power that can be used safely to characterize the biological tissue. In this talk, we discuss the advantage of implanting a micro-lens inside the tissue to have a higher signal to noise ratio for confocal and OCT measurements. We explain the theoretical background, experimental setup and the method of implanting the micro lens at arbitrary depths within a live mouse brain. The in-vivo 3D OCT and two-photon microscopy images of live mouse with implanted micro-lens are presented and significant enhancement of signal to noise ratio is observed. The confocal and OCT measurements have been performed with super-luminescent LEDs emitting at 1300 nm. We believe that the high resolution and high sensitivity of this technique is of fundamental importance for characterization of neural activity, monitoring the hemodynamic responses, tumors and for performing image guided surgeries.

  2. In vivo receptor binding of opioid drugs at the mu site

    Energy Technology Data Exchange (ETDEWEB)

    Rosenbaum, J.S.; Holford, N.H.; Sadee, W.

    1985-06-01

    The in vivo receptor binding of a series of opioid drugs was investigated in intact rats after s.c. administration of (/sup 3/H)etorphine tracer, which selectively binds to mu sites in vivo. Receptor binding was determined by a membrane filtration assay immediately after sacrifice of the animals and brain homogenization. Coadministration of unlabeled opioid drugs together with tracer led to a dose-dependent decrease of in vivo tracer binding. Estimates of the doses required to occupy 50% of the mu sites in vivo established the following potency rank order: diprenorphine, naloxone, buprenorphine, etorphine, levallorphan, cyclazocine, sufentanil, nalorphine, ethylketocyclazocine, ketocyclazocine, pentazocine, morphine. In vivo-in vitro differences among the relative receptor binding potencies were only partially accounted for by differences in their access to the brain and the regulatory effects of Na+ and GTP, which are expected to reduce agonist affinities in vivo. The relationship among mu receptor occupancy in vivo and pharmacological effects of the opioid drugs is described.

  3. About Occupational Therapy

    Science.gov (United States)

    ... if}} {{{tweet}}} About Occupational Therapy What Is Occupational Therapy? Occupational therapy practitioners ask, "What matters to you?" not, " ... about our science-driven and evidence-based profession. Occupational Therapy: Improving Function While Controlling Costs 4 4 The ...

  4. Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment

    Directory of Open Access Journals (Sweden)

    Yufei Mei

    2016-02-01

    Full Text Available Individuals afflicted with occupational formaldehyde (FA exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m3 for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.

  5. Occupational epidemiology.

    Science.gov (United States)

    Guidotti, T L

    2000-02-01

    The epidemiological literature for assessing risk in many, if not most, modern occupations has now become sufficiently obsolete that it can no longer be depended upon to guide either prevention or adjudication of compensation. This obsolescence must be dealt with by developing new sources of information pertinent to occupational hazards and the risks associated with most occupations. Ideally, a comprehensive surveillance mechanism that would be automatically updated for the changing risk in a changing economy would be ideal and may be attainable with further developments in health information technology. The characteristics of such a system are described. However, there are many obstacles to such a system which appear insurmountable in the short term. A more eclectic plan for cooperation and data-sharing would help in the short term and would establish a pattern of collaboration that could both place adjudication on a more solid foundation and avoid allegations of collusion in business. The general outline for a practical programme of collaboration along these lines is presented.

  6. Who among patients with acquired brain injury returned to work after occupational rehabilitation? : The rapid-return-to-work-cohort-study

    NARCIS (Netherlands)

    Aas, R.W.; Haveraaen, L.A.; Brouwers, E.P.M.; Skarpaas, L.S.

    2017-01-01

    Acquired brain injury (ABI) is known to be severely disabling. On average, 40% of employeesreturn to work (RTW) within two years after injury. There is, however, limited research on what might con-tribute to successful RTW. To examine factors that might impact the time-to first RTW for patients with

  7. Occupation: nurse; occupational hazard: radiation

    Energy Technology Data Exchange (ETDEWEB)

    Nickson, K.

    1984-03-01

    The work of the occupational health nurses at the Pickering Generating Station is described. A staff of two nurses teach first aid and safety, practice an emergency plan, and monitor personnel for minimum health standards for radiation workers. Special attention is paid to problems which might be aggravated by radiation, such as skin complaints, respiratory diseases, emotional stability, or phobias regarding heights, plastic suits, or radiation itself. Procedures used in treating contaminated personnel are outlined.

  8. Occupational physiology

    CERN Document Server

    Toomingas, Allan; Tornqvist, Ewa Wigaeus

    2011-01-01

    In a clear and accessible presentation, Occupational Physiology focuses on important issues in the modern working world. Exploring major public health problems-such as musculoskeletal disorders and stress-this book explains connections between work, well-being, and health based on up-to-date research in the field. It provides useful methods for risk assessment and guidelines on arranging a good working life from the perspective of the working individual, the company, and society as a whole.The book focuses on common, stressful situations in different professions. Reviewing bodily demands and r

  9. In Vivo

    Science.gov (United States)

    Lau, Melissa; Li, Jianli; Cline, Hollis T

    2017-01-01

    The neurovascular niche is a specialized microenvironment formed by the interactions between neural progenitor cells (NPCs) and the vasculature. While it is thought to regulate adult neurogenesis by signaling through vascular-derived soluble cues or contacted-mediated cues, less is known about the neurovascular niche during development. In Xenopus laevis tadpole brain, NPCs line the ventricle and extend radial processes tipped with endfeet to the vascularized pial surface. Using in vivo labeling and time-lapse imaging in tadpoles, we find that intracardial injection of fluorescent tracers rapidly labels Sox2/3-expressing NPCs and that vascular-circulating molecules are endocytosed by NPC endfeet. Confocal imaging indicates that about half of the endfeet appear to appose the vasculature, and time-lapse analysis of NPC proliferation and endfeet-vascular interactions suggest that proliferative activity does not correlate with stable vascular apposition. Together, these findings characterize the neurovascular niche in the developing brain and suggest that, while signaling to NPCs may occur through vascular-derived soluble cues, stable contact between NPC endfeet and the vasculature is not required for developmental neurogenesis.

  10. Who among patients with acquired brain injury returned to work after occupational rehabilitation? The rapid-return-to-work-cohort-study.

    Science.gov (United States)

    Aas, Randi Wågø; Haveraaen, Lise Aasen; Brouwers, Evelien P M; Skarpaas, Lisebet Skeie

    2017-07-20

    Acquired brain injury (ABI) is known to be severely disabling. On average, 40% of employees return to work (RTW) within two years after injury. There is, however, limited research on what might contribute to successful RTW. To examine factors that might impact the time-to first RTW for patients with ABI, participating in a RTW-program. The study was designed as a cohort study of patients on sick leave due to mild or moderate ABI (n = 137). The mean age of the patients was 51 years, and 58% were men. The most common diagnoses were stroke (75%) and traumatic brain injury (12%). Data were collected through questionnaires, and combined with register data on sickness absence. Survival analyses were used to analyse the effect of different variables on time to first RTW (full or partial), at one- and two-year follow-up. Generally, women (HR = 0.447; CI: 0.239-0.283) had higher RTW-rates than men, and patients with non-comorbid impairments returned to work earlier than patients with multiple impairments. Although not statistically significant, receiving individual consultations and participating in group-sessions were generally associated with a delayed RTW at both follow-up-times. The only service-related factor significantly associated with delayed RTW was meetings with the social insurance office (HR = 0.522; CI: 0.282-0.965), and only at one-year follow-up. Women and patients with non-comorbid impairments returned to work earlier than men and patients with multiple impairments. There seems to be an association between intense and long-lasting participation in the RTW program and prolonged time-to first-RTW, even after controlling for level of cognitive impairments and comorbidity. Implications for Rehabilitation Acquired brain injury (ABI) is known to be severely disabling, and persons with ABI often experience difficulties in regard to returning to work. This study provides information on prognostic factors that might contribute to return to work (RTW

  11. Comparison of in vivo and ex vivo imaging of the microvasculature with 2-photon fluorescence microscopy

    Science.gov (United States)

    Steinman, Joe; Koletar, Margaret; Stefanovic, Bojana; Sled, John G.

    2016-03-01

    This study evaluates 2-Photon fluorescence microscopy of in vivo and ex vivo cleared samples for visualizing cortical vasculature. Four mice brains were imaged with in vivo 2PFM. Mice were then perfused with a FITC gel and cleared in fructose. The same regions imaged in vivo were imaged ex vivo. Vessels were segmented automatically in both images using an in-house developed algorithm that accounts for the anisotropic and spatially varying PSF ex vivo. Through non-linear warping, the ex vivo image and tracing were aligned to the in vivo image. The corresponding vessels were identified through a local search algorithm. This enabled comparison of identical vessels in vivo/ex vivo. A similar process was conducted on the in vivo tracing to determine the percentage of vessels perfused. Of all the vessels identified over the four brains in vivo, 98% were present ex vivo. There was a trend towards reduced vessel diameter ex vivo by 12.7%, and the shrinkage varied between specimens (0% to 26%). Large diameter surface vessels, through a process termed 'shadowing', attenuated in vivo signal from deeper cortical vessels by 40% at 300 μm below the cortical surface, which does not occur ex vivo. In summary, though there is a mean diameter shrinkage ex vivo, ex vivo imaging has a reduced shadowing artifact. Additionally, since imaging depths are only limited by the working distance of the microscope objective, ex vivo imaging is more suitable for imaging large portions of the brain.

  12. Occupational Therapy (For Parents)

    Science.gov (United States)

    ... Late for the Flu Vaccine? Eating Disorders Arrhythmias Occupational Therapy KidsHealth > For Parents > Occupational Therapy Print A A ... for some kids. continue Kids Who Might Need Occupational Therapy According to the AOTA, kids with these medical ...

  13. Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Shuichi; Kurosaki, Kunihiko; Kuriiwa, Fumi; Endo, Takahiko [Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 (Japan); Mukai, Toshiji [Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-0015 (Japan)

    2002-10-01

    Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na{sup +} channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na{sup +}-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species

  14. Image processing occupancy sensor

    Science.gov (United States)

    Brackney, Larry J.

    2016-09-27

    A system and method of detecting occupants in a building automation system environment using image based occupancy detection and position determinations. In one example, the system includes an image processing occupancy sensor that detects the number and position of occupants within a space that has controllable building elements such as lighting and ventilation diffusers. Based on the position and location of the occupants, the system can finely control the elements to optimize conditions for the occupants, optimize energy usage, among other advantages.

  15. Comparison of occupational exposure assessment methods in a case-control study of lead, genetic susceptibility and risk of adult brain tumors

    Science.gov (United States)

    Bhatti, Parveen; Stewart, Patricia A.; Linet, Martha S.; Blair, Aaron; Inskip, Peter D.; Rajaraman, Preetha

    2013-01-01

    Objectives There is great interest in evaluating gene-environment interactions with chemical exposures, but exposure assessment poses a unique challenge in case-control studies. Expert assessment of detailed work history data is usually considered the best approach, but it is a laborious and time-consuming process. We set out to determine if a less intensive method of exposure assessment (a job exposure matrix [JEM]) would produce similar results to a previous analysis that found evidence of effect modification between expert assessed-lead exposure and risk of brain tumors by a single nucleotide polymorphism in the ALAD gene (rs1800435). Methods We used data from a study of 355 patients with glioma, 151 patients with meningioma and 505 controls. Logistic regression models were used to examine associations between brain tumor risk and lead exposure and effect modification by genotype. We evaluated Cohen’s kappa, sensitivity and specificity for the JEM compared to the expert-assessed exposure metrics. Results Although effect estimates were imprecise and driven by a small number of cases, we found evidence of effect modification between lead exposure and ALAD genotype when using expert- but not JEM-derived lead exposure estimates. Kappa values indicated only modest agreement (exposure metrics, with the JEM indicating high specificity (~0.9) but poor sensitivity (~0.5). Disagreement between the two methods was generally due to having additional information in the detailed work history. Conclusion These results provide preliminary evidence suggesting that high quality exposure data are likely to improve the ability to detect genetic effect modification. PMID:20798009

  16. Occupational therapy students' perceptions of occupational therapy.

    Science.gov (United States)

    Turpin, Merrill June; Rodger, Sylvia; Hall, Anna R

    2012-10-01

    An understanding of students' perceptions of occupational therapy on entry is required to recognise how professional socialisation occurs through curriculum. Findings pertain to a qualitative study investigating students' perceptions of occupational therapy upon entry to two occupational therapy programmes in Australia. Students commencing Bachelor of Occupational Therapy and Masters of Occupational Therapy Studies programmes participated in the study (n = 462). A purpose-designed questionnaire was distributed to students in the first lecture of each programme. Preliminary analysis comprised identification of keywords/phrases and coding categories were generated from patterns of keywords. Frequency counts and percentages of keywords/phrases within categories were completed. Students' responses were categorised as 'what' occupational therapists do; 'how' they do it; 'why' they do it; and 'who' they work with. In 'what' occupational therapists do students frequently described 'helping' people. Both undergraduate and graduate entry masters students used the term 'rehabilitation' to describe how occupational therapy is done, with graduate entry students occasionally responding with 'through occupation' and 'modifying the environment'. Students perceived the 'why' of occupational therapy as getting back to 'everyday activities', with some students emphasising returning to 'normal' activities or life. Regarding the 'who' category, students also thought occupational therapists worked with people with an 'injury' or 'disability'. Students entered their occupational therapy programmes with perceptions consistent with the general public's views of occupational therapy. However, graduate entry students exposed to a pre-reading package prior to entry had more advanced occupational therapy concepts than undergraduate students. © 2011 The Authors. Australian Occupational Therapy Journal © 2011 Occupational Therapy Australia.

  17. Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

    Science.gov (United States)

    Machida, Takashi; Takata, Fuyuko; Matsumoto, Junichi; Miyamura, Tomoyuki; Hirata, Ryosuke; Kimura, Ikuya; Kataoka, Yasufumi; Dohgu, Shinya; Yamauchi, Atsushi

    2017-01-01

    Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood-brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin-treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte-thrombin interaction may play a key role in causing BBB dysfunction in obesity

  18. In vivo measurements of blood-brain barrier permeability using micro-dialysis: radiobiological application; Etude in vivo des effets de l'irradiation gamma sur la permeabilite de la barriere hemato-encephalique

    Energy Technology Data Exchange (ETDEWEB)

    Agin, A.; Diserbo, M.; Mauris, J.; Martin, C

    1998-07-01

    The effects of total-body irradiation on the permeability of striatal blood-brain barrier (BBB) to [{sup 3}H] amino-isobutyric acid (AIBA) and [{sup 14}C] sucrose were investigated. Six weeks, three and five months after gamma exposure at the dose of 4.5 Gy, no modification of the transport of AIB or of the diffusion of sucrose from blood to brain was observed. (authors)

  19. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig: comparison with results in vivo

    DEFF Research Database (Denmark)

    Minuzzi, Luciano; Alstrup, Aage Kristian Olsen; Bender, Dirk

    2006-01-01

    in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain...

  20. "Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.

    Science.gov (United States)

    Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe

    2016-04-22

    A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug

  1. Effectiveness of functional hand splinting and the cognitive orientation to occupational performance (CO-OP) approach in children with cerebral palsy and brain injury: two randomised controlled trial protocols.

    Science.gov (United States)

    Jackman, Michelle; Novak, Iona; Lannin, Natasha

    2014-07-15

    Cerebral palsy (CP) and brain injury (BI) are common conditions that have devastating effects on a child's ability to use their hands. Hand splinting and task-specific training are two interventions that are often used to address deficits in upper limb skills, both in isolation or concurrently. The aim of this paper is to describe the method to be used to conduct two randomised controlled trials (RCT) investigating (a) the immediate effect of functional hand splints, and (b) the effect of functional hand splints used concurrently with task-specific training compared to functional hand splints alone, and to task-specific training alone in children with CP and BI. The Cognitive Orientation to Occupational Performance (CO-OP) approach will be the task-specific training approach used. Two concurrent trials; a two group, parallel design, RCT with a sample size of 30 participants (15 per group); and a three group, parallel design, assessor blinded, RCT with a sample size of 45 participants (15 per group). age 4-15 years; diagnosis of CP or BI; Manual Abilities Classification System (MACS) level I - IV; hand function goals; impaired hand function; the cognitive, language and behavioural ability to participate in CO-OP. Participants will be randomly allocated to one of 3 groups; (1) functional hand splint only (n=15); (2) functional hand splint combined with task-specific training (n=15); (3) task-specific training only (n=15). Allocation concealment will be achieved using sequentially numbered, sealed opaque envelopes opened by an off-site officer after baseline measures. Treatment will be provided for a period of 2 weeks, with outcome measures taken at baseline, 1 hour after randomisation, 2 weeks and 10 weeks. The functional hand splint will be a wrist cock-up splint (+/- thumb support or supination strap). Task-specific training will involve 10 sessions of CO-OP provided in a group of 2-4 children. Primary outcome measures will be the Canadian Occupational Performance

  2. Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

    Directory of Open Access Journals (Sweden)

    Takashi Machida

    Full Text Available Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood-brain barrier (BBB exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS. We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin-treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1 and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte-thrombin interaction may play a key role in causing BBB dysfunction in

  3. Demonstration of in vivo synthesis of pro-opiomelanocortin-, beta- endorphin-, and alpha-melanotropin-like species in the adult rat brain

    National Research Council Canada - National Science Library

    Liotta, AS; Advis, JP; Krause, JE; McKelvy, JF; Krieger, DT

    1984-01-01

    ...)-, beta-endorphin- and alpha- melanotropin (MSH)-like molecular species in rat brain. Unrestrained adult female rats were bilaterally cannulated in the hypothalamic arcuate nuclear region; [35S...

  4. Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

    Science.gov (United States)

    Fang, Jen-Hung; Chiu, Tsung-Lang; Huang, Wei-Chen; Lai, Yen-Ho; Hu, Shang-Hsiu; Chen, You-Yin; Chen, San-Yuan

    2016-03-01

    Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Main effect and interactions of brain regions and gender in the calculation of volumetric asymmetry indices in healthy human brains: ANCOVA analyses of in vivo 3T MRI data.

    Science.gov (United States)

    Roldan-Valadez, Ernesto; Rios, Camilo; Suarez-May, Marcela A; Favila, Rafel; Aguilar-Castañeda, Erika

    2013-12-01

    Macroanatomical right-left hemispheric differences in the brain are termed asymmetries, although there is no clear information on the global influence of gender and brain-regions. The aim of this study was to evaluate the main effects and interactions of these variables on the measurement of volumetric asymmetry indices (VAIs). Forty-seven healthy young-adult volunteers (23 males, 24 females) agreed to undergo brain magnetic resonance imaging in a 3T scanner. Image post processing using voxel-based volumetry allowed the calculation of 54 VAIs from the frontal, temporal, parietal and occipital lobes, limbic system, basal ganglia, and cerebellum for each cerebral hemisphere. Multivariate ANCOVA analysis calculated the main effects and interactions on VAIs of gender and brain regions controlling the effect of age. The only significant finding was the main effect of brain regions (F (6, 9373.605) 44.369, P power of 1.0), with no significant interaction between gender and brain regions (F (6, 50.517) .239, P = .964). Volumetric asymmetries are present across all brain regions, with larger values found in the limbic system and parietal lobe. The absence of a significant influence of gender and age in the evaluation of the numerous measurements generated by multivariate analyses in this study should not discourage researchers to report and interpret similar results, as this topic still deserves further assessment. Copyright © 2013 Wiley Periodicals, Inc.

  6. Brain refractive index measured in vivo with high-NA defocus-corrected full-field OCT and consequences for two-photon microscopy.

    Science.gov (United States)

    Binding, Jonas; Ben Arous, Juliette; Léger, Jean-François; Gigan, Sylvain; Boccara, Claude; Bourdieu, Laurent

    2011-03-14

    Two-photon laser scanning microscopy (2PLSM) is an important tool for in vivo tissue imaging with sub-cellular resolution, but the penetration depth of current systems is potentially limited by sample-induced optical aberrations. To quantify these, we measured the refractive index n' in the somatosensory cortex of 7 rats in vivo using defocus optimization in full-field optical coherence tomography (ff-OCT). We found n' to be independent of imaging depth or rat age. From these measurements, we calculated that two-photon imaging beyond 200 µm into the cortex is limited by spherical aberration, indicating that adaptive optics will improve imaging depth.

  7. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  8. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole.

    Science.gov (United States)

    Biegon, Anat; Kim, Sung Won; Alexoff, David L; Jayne, Millard; Carter, Pauline; Hubbard, Barbara; King, Payton; Logan, Jean; Muench, Lisa; Pareto, Deborah; Schlyer, David; Shea, Colleen; Telang, Frank; Wang, Gene-Jack; Xu, Youwen; Fowler, Joanna S

    2010-11-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-(11)C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ∼70% blocking in thalamus andpreoptic area to ∼10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  9. In vitro and in vivo evidence for active brain uptake of the GHB analogue HOCPCA by the monocarboxylate transporter subtype 1

    DEFF Research Database (Denmark)

    Thiesen, Louise; Kehler, Jan; Clausen, Rasmus P

    2015-01-01

    γ-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance which binds to both high and low affinity sites in the brain. For studying the molecular mechanisms and the biological role of the GHB high-affinity b......γ-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance which binds to both high and low affinity sites in the brain. For studying the molecular mechanisms and the biological role of the GHB high...

  10. Determination of methylphenidate in Calliphorid larvae by liquid-liquid extraction and liquid chromatography mass spectrometry - Forensic entomotoxicology using an in vivo rat brain model

    DEFF Research Database (Denmark)

    Bushby, Sarah K.; Thomas, Nicky; Priemel, Petra A.

    2012-01-01

    The aim of this study was to examine the potential forensic utilisation of blowfly larvae (Diptera: Calliphoridae) as an alternative toxicological specimen for the detection of the psychotropic model drug methylphenidate (MPH). MPH was extracted from biological matrices (rat brain, serum and Call......The aim of this study was to examine the potential forensic utilisation of blowfly larvae (Diptera: Calliphoridae) as an alternative toxicological specimen for the detection of the psychotropic model drug methylphenidate (MPH). MPH was extracted from biological matrices (rat brain, serum...

  11. A simple method for assessing free brain/free plasma ratios using an in vitro model of the blood brain barrier.

    Directory of Open Access Journals (Sweden)

    Maxime Culot

    Full Text Available Historically, the focus has been to use in vitro BBB models to optimize rate of drug delivery to the CNS, whereas total in vivo brain/plasma ratios have been used for optimizing extent. However, these two parameters do not necessarily show good correlations with receptor occupancy data or other pharmacological readouts. In line with the free drug hypothesis, the use of unbound brain concentrations (Cu,br has been shown to provide the best correlations with pharmacological data. However, typically the determination of this parameter requires microdialysis, a technique not ideally suited for screening in early drug development. Alternative, and less resource-demanding methodologies to determine Cu,br employ either equilibrium dialysis of brain homogenates or incubations of brain slices in buffer to determine fraction unbound brain (fu,br, which is subsequently multiplied by the total brain concentration to yield Cu,br. To determine Cu,br/Cu,pl ratios this way, still requires both in vitro and in vivo experiments that are quite time consuming. The main objective of this study was to explore the possibility to directly generate Cu,br/Cu,pl ratios in a single in vitro model of the BBB, using a co-culture of brain capillary endothelial and glial cells in an attempt to mimick the in vivo situation, thereby greatly simplifying existing experimental procedures. Comparison to microdialysis brain concentration profiles demonstrates the possibility to estimate brain exposure over time in the BBB model. A stronger correlation was found between in vitro Cu,br/Cu,pl ratios and in vivo Cu,br/Cu,pl obtained using fu,br from brain slice than with fu,br from brain homogenate for a set of 30 drugs. Overall, Cu,br/Cu,pl ratios were successfully predicted in vitro for 88% of the 92 studied compounds. This result supports the possibility to use this methodology for identifying compounds with a desirable in vivo response in the CNS early on in the drug discovery

  12. Occupational therapy evaluation

    DEFF Research Database (Denmark)

    Nielsen, Kristina Tomra; Wæhrens, Eva Ejlersen

    2015-01-01

    Background: The Occupational Therapy Intervention Process Model (OTIPM) serves to guide occupational therapists in their professional reasoning. The OTIPM prescribes evaluation of task performance based on both self-report and observation. Although this approach seems ideal, many clinicians raise...

  13. Different early effect of irradiation in brain and small cell lung cancer examined by in vivo 31P-magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Kristjansen, P E; Pedersen, A G; Quistorff, B

    1992-01-01

    -MRS. No effect was observed in brain at any dose level. In contrast, 40 Gy induced a statistically significant reduction in ATP/Pi ratio during the 12-h post-irradiation period. This effect was more pronounced in 54A than in 54B. Some reduction was observed following 10 Gy, whereas 2.5 Gy induced no changes...

  14. IN-VIVO PROTEIN-SYNTHESIS RATE DETERMINATION IN PRIMARY OR RECURRENT BRAIN-TUMORS USING L-[1-C-11]-TYROSINE AND PET

    NARCIS (Netherlands)

    WILLEMSEN, ATM; VANWAARDE, A; PAANS, AMJ; PRUIM, J; LUURTSEMA, G; GO, KG; VAALBURG, W

    The applicability of protein synthesis rate (PSR) determination with L-[1-C-11]tyrosine (C-11-TYR) and PET was assessed in patients suspected of a primary or recurrent brain tumor. Methods: Simultaneous to intravenous injection of 265 MBq of C-11-TYR, dynamic PET acquisition was started and

  15. Radioligand binding analysis of α 2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

    DEFF Research Database (Denmark)

    Phan, Jenny-Ann; Landau, Anne M.; Jakobsen, Steen

    2017-01-01

    Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50-60% in the presence of unlabeled...

  16. Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery.

    Science.gov (United States)

    Rashed, Hassan M; Shamma, Rehab N; Basalious, Emad B

    2016-11-01

    Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5-13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with (99m)Tc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of (99m)Tc-NM loaded LPM were lower compared with that following administration of (99m)Tc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of (99m)Tc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of (99m)Tc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.

  17. In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice.

    Directory of Open Access Journals (Sweden)

    Jose Morales-Corraliza

    2009-09-01

    Full Text Available The metabolism of the amyloid precursor protein (APP and tau are central to the pathobiology of Alzheimer's disease (AD. We have examined the in vivo turnover of APP, secreted APP (sAPP, Abeta and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Abeta degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Abeta40 and Abeta42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a beta-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the beta-amyloid depositing Tg2576 mice may represent a neuroprotective response.

  18. Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

    KAUST Repository

    Tong, Jing

    2013-01-07

    Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the enzyme was conjugated with poly(2-oxazoline) (POx) block copolymers, P(MeOx-b-BuOx) or P(EtOx-b-BuOx), composed of (1) hydrophilic 2-methyl-2-oxazoline (MeOx) or 2-ethyl-2-oxazoline (EtOx) and (2) hydrophobic 2-butyl-2-oxazoline (BuOx) repeating units. The conjugates contained from 2 to 3 POx chains joining the protein amino groups via cleavable -(ss)- or noncleavable -(cc)- linkers at the BuOx block terminus. They retained 30% to 50% of initial SOD1 activity, were conformationally and thermally stable, and assembled in 8 or 20 nm aggregates in aqueous solution. They had little if any toxicity to CATH.a neurons and displayed enhanced uptake in these neurons as compared to native or PEGylated SOD1. Of the two conjugates, SOD1-(cc)-P(MeOx-b-BuOx) and SOD1-(cc)-P(EtOx-b-BuOx), compared, the latter was entering cells 4 to 7 times faster and at 6 h colocalized predominantly with endoplasmic reticulum (41 ± 3%) and mitochondria (21 ± 2%). Colocalization with endocytosis markers and pathway inhibition assays suggested that it was internalized through lipid raft/caveolae, also employed by the P(EtOx-b-BuOx) copolymer. The SOD activity in cell lysates and ability to attenuate angiotensin II (Ang II)-induced superoxide in live cells were increased for this conjugate compared to SOD1 and PEG-SOD1. Studies in mice showed that SOD1-POx had ca. 1.75 times longer half-life in blood than native SOD1 (28.4 vs 15.9 min) and after iv administration penetrated the BBB significantly faster than albumin to accumulate in brain parenchyma. The conjugate maintained high stability both in serum and in brain (77% vs 84% at 1 h postinjection). Its amount taken up by the brain

  19. Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

    Directory of Open Access Journals (Sweden)

    Susann Schröder

    2015-05-01

    Full Text Available Phosphodiesterase 2A (PDE2A is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET. Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2–4 and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4 and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.

  20. Analysis of brain metabolism changes induced by acute potassium cyanide intoxication by 31P NMR in vivo using chronically implanted surface coils.

    Science.gov (United States)

    Decorps, M; Lebas, J F; Leviel, J L; Confort, S; Remy, C; Benabid, A L

    1984-03-12

    Chronic implantation of surface coils on the skull has been developed to record 31P NMR spectra of the brain in unanesthetized rats. Intraperitoneal sublethal potassium cyanide doses induce strong and reversible changes in high-energy phosphate compounds in the brain, similar in part to those induced by ischemia. These effects are dose-dependent as far as phosphocreatine, inorganic orthophosphates and pH are concerned; ATP does not seem to be altered by KCN doses ranging from 3 to 5 mg/kg but starts decreasing at a dose of 6 mg/kg. The fraction of Mg2+ complexed ATP which could be estimated as about 90% was not affected by KCN intoxication. For high doses (6 mg/kg) a new peak, appearing on the upfield side of the inorganic phosphate peak, may correspond to an acidic compartment, the significance of which is discussed.

  1. Alleviation of Kainic Acid-Induced Brain Barrier Dysfunction by 4-O-Methylhonokiol in In Vitro and In Vivo Models

    Directory of Open Access Journals (Sweden)

    Jin-Yi Han

    2015-01-01

    Full Text Available This experiment was designed to investigate whether 4-O-methylhonokiol (MH, a principal ingredient of Magnolia (M. officinalis bark, alleviated acute intraperitoneal (i.p. kainic acid- (KA- induced brain blood barrier dysfunction (BBBD via pathological examination and cytological analyses of the brain tissues of mice. KA (10–30 mg/kg time- and dose-dependently increased the water content of brain tissues and induced edema and encephalopathy. However, pretreatment with MH (5 and 20 mg/kg, i.p. significantly reduced the water content of the brain compared to that observed in the KA control group. Furthermore, MH significantly and dose-dependently reversed the remarkable variations in evan’s blue dye (EBD staining and malondialdehyde (MDA levels that were induced by KA (10 mg/kg, i.p.. MH also decreased the elevated seizure scores that were induced by KA (10 mg/kg, i.p. in mice in a manner similar to scavengers such as DMTU and trolox. Additionally, MH significantly scavenged intracellular ROS and Ca2+ within hippocampal cells. The tight junction seals mediated by claudin (Cld-5 were also found to be modulated by MH. MH efficiently reduced 1,1-diphenyl-2-picrylhydrazyl (DPPH (IC50, 52.4 mM and •OH with an electron spin resonance (ESR signal rate constant of 4×109 M-1·S-1, which is close to the reactivity of the vitamin E analog trolox. Taken together, these results suggest that MH may enhance radical scavenging in lipid and hydrophobic environments, which may be important for the physiological activity of the barrier.

  2. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Swami, Rajan; Singh, Indu [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India); Kulhari, Hitesh [CSIR-Indian Institute of Chemical Technology, Medicinal Chemistry & Pharmacology Division (India); Jeengar, Manish Kumar [National Institute of Pharmaceutical Education & Research (NIPER), Departmentof Pharmacology (India); Khan, Wahid, E-mail: wahid@niperhyd.ac.in; Sistla, Ramakrishna, E-mail: sistla@iict.res.in, E-mail: rksistla@yahoo.com [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India)

    2015-06-15

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by {sup 1}HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere{sup ®}). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors.

  3. Macrophage Polarization and Utility of in Vivo Therapy with a Brain-Permeable Anti-TNF Agent in Models of Autism

    Science.gov (United States)

    2017-10-01

    of Autism PRINCIPAL INVESTIGATOR: MariadeLourdes Tansey, PhD CONTRACTING ORGANIZATION: Emory University Atlanta, GA 30322-4250 REPORT DATE... Autism 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) MariadeLourdes Tansey, PhD 5d. PROJECT NUMBER 5e. TASK...response in the gut and do not make IL-17 which signals at receptors in the brain to mediate the autism -like behavior deficits. For this reason, we

  4. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    Energy Technology Data Exchange (ETDEWEB)

    Purger, David; McNutt, Todd; Wong, John; Ford, Eric [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, 401 North Broadway, Suite 1440, Baltimore, MD 21231 (United States); Achanta, Pragathi; Quinones-Hinojosa, Alfredo [Department of Neurosurgery, Johns Hopkins University, Cancer Research Building II, 1550 Orleans Street, Room 247, Baltimore, MD 21231 (United States)], E-mail: eric.ford@jhmi.edu

    2009-12-21

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  5. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    Science.gov (United States)

    Purger, David; McNutt, Todd; Achanta, Pragathi; Quiñones-Hinojosa, Alfredo; Wong, John; Ford, Eric

    2009-12-01

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  6. Correlation between lactate and neuronal cell damage in the rat brain after focal ischemia: An in vivo 1H magnetic resonance spectroscopic (1H-MRS) study.

    Science.gov (United States)

    Woo, Chul-Woong; Lee, Byong Sop; Kim, Sang Tae; Kim, Ki-Soo

    2010-04-01

    Increased levels of lactate are observed by (1)H magnetic resonance spectroscopy ((1)H-MRS) in rat brains after stroke. However, it is not known whether the changes in lactate levels are predictive of the degree of neuronal damage. To investigate the correlation between changes in lactate and lipid levels measured by (1)H-MRS and neuronal cell damage in the rat brain. A middle cerebral artery occlusion (MCAO) model was used to evaluate focal ischemia in rats (n=36). After MCAO for 90 min T2-weighted images (T2WIs), diffusion-weighted images (DWIs), and (1)H-MRS data were obtained from brains immediately, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 3 days, and 7 days after reperfusion. Infarct volumes were measured in T2WIs obtained 4 weeks after reperfusion. The degree of neuronal damage was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining in three rats from each group at the same time as brain images were collected. Creatine (Cr)-normalized lactate + lipid levels ([Lac+Lip]/Cr) were negatively correlated with Cr-normalized N-acetyl-L-aspartate levels (NAA/Cr) and positively correlated with TUNEL-positive cell numbers up to 24 hours after reperfusion. (Lac+Lip)/Cr at 6 hours and 9 hours was significantly correlated with NAA/Cr at 7 days, but there was no significant correlation between (Lac+Lip)/Cr during the first 24 hours and infarct volume at 4 weeks. Up to 24 hours after reperfusion, (Lac+Lip)/Cr was strongly negatively correlated with NAA/Cr, and was a good predictor of neuronal damage at 7 days; however, it was not predictive of final infarct volume at 4 weeks.

  7. In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury

    DEFF Research Database (Denmark)

    Sommer, Jens Bak; Bach, Anders; Rytter, Hana Malá

    2017-01-01

    PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a nov...... studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration....

  8. 2-acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats.

    Science.gov (United States)

    Kobayashi, Toshitake; Sasaki, Satoshi; Tomita, Naoki; Fukui, Seiji; Nakayama, Masaharu; Kiba, Atsushi; Kusaka, Masami; Matsumoto, Shin-ichi; Yamaguchi, Masashi; Itoh, Fumio; Baba, Atsuo

    2010-07-15

    GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  9. The distribution of radioactivity in brains of rats given (N-methyl- sup 11 C)PK 11195 in vivo after induction of a cortical ischaemic lesion

    Energy Technology Data Exchange (ETDEWEB)

    Cremer, J.E.; Hume, S.P.; Cullen, B.M.; Myers, R.; Manjil, L.G.; Turton, D.R.; Luthra, S.K.; Bateman, D.M.; Pike, V.W. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit)

    1992-02-01

    PK 11195 is a selective ligand for the peripheral-type benzodiazepine bindings site (PTBBS). There are few sites in normal brain but their number increases in association with tissue necrosis. The time-course of appearance of PTBBS around a focally induced ischaemic lesion in frontal cortex of rat brain was established by autoradiography using (N-methyl-{sup 3} H )PK 11195. Using this information and the same experimental model of ischaemia, the distribution of radioactivity after injection of carbon-11 labelled PK 11195 was studied. The purpose was to synthesize (N-methyl-{sup 11}C)PK 11195 and to test its suitability as a tracer for depicting the presence of PTBB in ischaemic lesions. The time-profiles of distribution of radioactivity in brain regions after intravenous injection of tracer and the ratio of radioactivity in lesioned compared with unlesioned cortex were determined. Data for the temporal (days after lesion induction) and for the regional retention of radioactivity were consistent with independent evidence (autoradiographic and immunohistochemical) for the occurence of increased numbers of PTBBS, predominantly in association with macrophages, in areas undergoing necrosis. (Author).

  10. A History of In Vivo Neutron Activation Analysis in Measurement of Aluminum in Human Subjects.

    Science.gov (United States)

    Mohseni, Hedieh K; Chettle, David R

    2016-01-01

    Aluminum, as an abundant metal, has gained widespread use in human life, entering the body predominantly as an additive to various foods and drinking water. Other major sources of exposure to aluminum include medical, cosmetic, and occupational routes. As a common environmental toxin, with well-known roles in several medical conditions such as dialysis encephalopathy, aluminum is considered a potential candidate in the causality of Alzheimer's disease. Aluminum mostly accumulates in the bone, which makes bone an indicator of the body burden of aluminum and an ideal organ as a proxy for the brain. Most of the techniques developed for measuring aluminum include bone biopsy, which requires invasive measures, causing inconvenience for the patients. There has been a considerable effort in developing non-invasive approaches, which allow for monitoring aluminum levels for medical and occupational purposes in larger populations. In vivo neutron activation analysis, a method based on nuclear activation of isotopes of elements in the body and their subsequent detection, has proven to be an invaluable tool for this purpose. There are definite challenges in developing in vivo non-invasive techniques capable of detecting low levels of aluminum in healthy individuals and aluminum-exposed populations. The following review examines the method of in vivo neutron activation analysis in the context of aluminum measurement in humans focusing on different neutron sources, interference from other activation products, and the improvements made in minimum detectable limits and patient dose over the past few decades.

  11. Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels-An Ex Vivo Study.

    Science.gov (United States)

    Śmieszek, Agnieszka; Stręk, Zuzanna; Kornicka, Katarzyna; Grzesiak, Jakub; Weiss, Christine; Marycz, Krzysztof

    2017-04-20

    Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined the role of metformin on mouse olfactory ensheathing cells (mOECs) derived from animals receiving metformin for eight weeks at a concentration equal to 2.8 mg/day. The mOECs expanded ex vivo were characterized in terms of their cellular phenotype, morphology, proliferative activity, viability and accumulation of oxidative stress factors. Moreover, we determined the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), distinguishing the secretion of BDNF by mOECs in cultures and circulating serum levels of BDNF. The mOECs used in the experiment were glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor (p75 NTR ) positive and exhibited both astrocyte-like and non-myelin Schwann cell-like morphologies. Our results revealed that the proliferation of OECs derived from mice treated with metformin was lowered, when compared to control group. Simultaneously, we noted increased cell viability, reduced expression of markers associated with cellular senescence and a decreased amount of reactive oxygen species. We observed increased mRNA expression of BDNF and its down-stream genes. Obtained results indicate that metformin may exert antioxidant, anti-apoptotic and senolytic action on OECs expanded ex vivo.

  12. Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

    Science.gov (United States)

    Śmieszek, Agnieszka; Stręk, Zuzanna; Kornicka, Katarzyna; Grzesiak, Jakub; Weiss, Christine; Marycz, Krzysztof

    2017-01-01

    Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined the role of metformin on mouse olfactory ensheathing cells (mOECs) derived from animals receiving metformin for eight weeks at a concentration equal to 2.8 mg/day. The mOECs expanded ex vivo were characterized in terms of their cellular phenotype, morphology, proliferative activity, viability and accumulation of oxidative stress factors. Moreover, we determined the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), distinguishing the secretion of BDNF by mOECs in cultures and circulating serum levels of BDNF. The mOECs used in the experiment were glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor (p75NTR) positive and exhibited both astrocyte-like and non-myelin Schwann cell-like morphologies. Our results revealed that the proliferation of OECs derived from mice treated with metformin was lowered, when compared to control group. Simultaneously, we noted increased cell viability, reduced expression of markers associated with cellular senescence and a decreased amount of reactive oxygen species. We observed increased mRNA expression of BDNF and its down-stream genes. Obtained results indicate that metformin may exert antioxidant, anti-apoptotic and senolytic action on OECs expanded ex vivo. PMID:28425952

  13. The Role of the Occupational Therapist in the Treatment of Patients with Huntington's Disease

    OpenAIRE

    Sýkorová, Jitka

    2016-01-01

    The Role of the Occupational Therapist in the Treatment of Patients with Huntington's Disease Abstract: This thesis is focused on the possible potential of occupational therapy in patients with Huntington's disease, a neurodegenerative brain disease. Currently, Huntington's disease is incurable, but there are some therapeutic methods and approaches which have positive influence on a progress of the disease. Also, early intervention of occupational therapy is needed and the occupational therap...

  14. Disruption of redox homeostasis and brain damage caused in vivo by methylmalonic acid and ammonia in cerebral cortex and striatum of developing rats.

    Science.gov (United States)

    Viegas, C M; Zanatta, Â; Grings, M; Hickmann, F H; Monteiro, W O; Soares, L E; Sitta, Â; Leipnitz, G; de Oliveira, F H; Wajner, M

    2014-06-01

    Hyperammonemia is a common finding in children with methylmalonic acidemia and propionic acidemia, but its contribution to the development of the neurological symptoms in the affected patients is poorly known. Considering that methylmalonic acid (MMA) and propionic acid (PA) predominantly accumulate in these disorders, we investigated the effects of hyperammonemia induced by urease treatment in 30-day-old rats receiving an intracerebroventricular (ICV) injection of MMA or PA on important parameters of redox homeostasis in cerebral cortex and striatum. We evaluated glutathione (GSH) concentrations, sulfhydryl content, nitrate and nitrite concentrations, 2',7'-dichlorofluorescein (DCFH) oxidation, and the activity of antioxidant enzymes. MMA decreased GSH concentrations and sulfhydryl content and increased nitrate and nitrite concentrations in cerebral cortex and striatum from hyperammonemic rats, whereas MMA or ammonia per se did not alter these parameters. MMA plus hyperammonemia also decreased glutathione reductase activity in rat cerebral cortex, but did not affect catalase, superoxide dismutase and glutathione peroxidase activities, neither DCFH oxidation. Furthermore, ICV PA administration alone or combined with hyperammonemia did not alter any of the evaluated parameters. We also found that pre-treatment with antioxidants prevented GSH reduction and sulfhydryl oxidation, whereas N(ω)-nitro-L-arginine methyl ester (L-NAME) prevented the increased nitrate and nitrite concentrations provoked by MMA plus ammonia treatments. Histological alterations, including vacuolization, ischemic neurons, and pericellular edema, were observed in brain of hyperammonemic rats injected with MMA. The data indicate a synergistic effect of MMA and ammonia disturbing redox homeostasis and causing morphological brain abnormalities in rat brain.

  15. In vivo diagnostic imaging using micro-CT: sequential and comparative evaluation of rodent models for hepatic/brain ischemia and stroke.

    Directory of Open Access Journals (Sweden)

    Naoto Hayasaka

    Full Text Available BACKGROUND: There is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report. METHODOLOGY: We performed contrast-enhanced CT (CECT on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA, indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT. PRINCIPAL FINDINGS: In the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data. CONCLUSIONS: This study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is

  16. In vivo measurement of intracellular pH in human brain during different tensions of carbon dioxide in arterial blood. A 31P-NMR study

    DEFF Research Database (Denmark)

    Jensen, K E; Thomsen, C; Henriksen, O

    1988-01-01

    The effect of changes in carbon dioxide tension in arterial blood upon intracellular pH in brain tissue was studied in seven healthy volunteers, aged 22-45 years. The pH changes were monitored by use of 31P nuclear magnetic resonance spectroscopy, performed on a whole-body 1.5 Tesla Siemens imaging...... system. The measurements were carried out during hyperventilation and with the subject breathing atmospheric air containing 5 vol. % and 7 vol. % carbon dioxide. Intracellular pH increased significantly during 15 min of hyper-ventilation and decreased significantly during 18 min respiration of air...

  17. In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Yuan-Yuan [Huazhong University of Science and Technology, Department of Radiology, Tongji Hospital, Tongji Medical College, Wuhan (China); The Johns Hopkins University School of Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States); Li, Mu-Wei; Oishi, Kenichi [The Johns Hopkins University School of Medicine, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States); Zhang, Shun; Zhang, Yan; Zhao, Ling-Yun; Zhu, Wen-Zhen [Huazhong University of Science and Technology, Department of Radiology, Tongji Hospital, Tongji Medical College, Wuhan (China); Lei, Hao [Chinese Academy of Sciences, Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Wuhan (China)

    2013-08-15

    Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model. VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy. Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p < 0.05, corrected). The average kappa value between manual and atlas-based structure delineation was approximately 0.8, and there was no significant difference between APP/PS1 and WT mice (p > 0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single-slice histological specimen. This study demonstrated the structure-specific nature of pathological changes in APP/PS1 mouse, and also showed the

  18. Microcystin-LR acute exposure does not alter in vitro and in vivo ATP, ADP and AMP hydrolysis in adult zebrafish (Danio rerio brain membranes

    Directory of Open Access Journals (Sweden)

    Luiza Wilges Kist

    2012-10-01

    Full Text Available Microcystins (MCs are toxins produced by cyanobacteria during the blooms that could accumulate in aquatic animals and be relocated to higher trophic levels. Adenosine triphosphate (ATP acts as an excitatory neurotransmitter and/or a neuromodulator in the extracellular space playing important roles in physiological and pathological conditions. The aim of this study was, therefore, to evaluate the acute effects of different concentrations of MC-LR on nucleoside triphosphate diphosphohydrolases and 5’-nucleotidade in adult zebrafish (Danio rerio brain membranes. The results have shown no significant changes in ATP, adenosine diphosphate (ADP and adenosine monophosphate (AMP hydrolysis in zebrafish brain membranes. MC-LR in vitro also did not alter ATP, ADP and AMP hydrolysis in the concentrations tested. These findings show that acute exposure to MC-LR did not modulate ectonucleotidase activity in the conditions tested. However, additional studies including chronic exposure should be performed in order to achieve a better understanding about MC-LR toxicity mechanisms in the central nervous system.

  19. Advanced In vivo Use of CRISPR/Cas9 and Anti-sense DNA Inhibition for Gene Manipulation in the Brain.

    Science.gov (United States)

    Walters, Brandon J; Azam, Amber B; Gillon, Colleen J; Josselyn, Sheena A; Zovkic, Iva B

    2015-01-01

    Gene editing tools are essential for uncovering how genes mediate normal brain-behavior relationships and contribute to neurodegenerative and neuropsychiatric disorders. Recent progress in gene editing technology now allows neuroscientists unprecedented access to edit the genome efficiently. Although many important tools have been developed, here we focus on approaches that allow for rapid gene editing in the adult nervous system, particularly CRISPR/Cas9 and anti-sense nucleotide-based techniques. CRISPR/Cas9 is a flexible gene editing tool, allowing the genome to be manipulated in diverse ways. For instance, CRISPR/Cas9 has been successfully used to knockout genes, knock-in mutations, overexpress or inhibit gene activity, and provide scaffolding for recruiting specific epigenetic regulators to individual genes and gene regions. Moreover, the CRISPR/Cas9 system may be modified to target multiple genes at one time, affording simultaneous inhibition and overexpression of distinct genetic targets. Although many of the more advanced applications of CRISPR/Cas9 have not been applied to the nervous system, the toolbox is widely accessible, such that it is poised to help advance neuroscience. Anti-sense nucleotide-based technologies can be used to rapidly knockdown genes in the brain. The main advantage of anti-sense based tools is their simplicity, allowing for rapid gene delivery with minimal technical expertise. Here, we describe the main applications and functions of each of these systems with an emphasis on their many potential applications in neuroscience laboratories.

  20. The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat.

    Science.gov (United States)

    Donovan, Maria D; O'Brien, Fionn E; Boylan, Geraldine B; Cryan, John F; Griffin, Brendan T

    2015-04-01

    Recent data highlight the potential of bumetanide as a treatment for neonatal seizures and autism, as it facilitates the excitatory to inhibitory switch in gamma-aminobutyric acid signalling. This study examines the extent of blood-brain barrier (BBB) permeation of bumetanide, a key determinant of the efficacy of centrally acting drugs. Furthermore, the impact of efflux transporter organic anion transporter 3 (oat3) inhibition on bumetanide pharmacokinetics was investigated. Bumetanide levels in extracellular fluid (ECF) and plasma in the presence and absence of oat3 inhibitor probenecid were monitored using integrated microdialysis. Following a bumetanide bolus/continuous infusion of 10 mg/kg and 6 mg/kg/h, bumetanide was detected in hippocampal ECF at the estimated concentration of 131 ± 55 ng/ml. Plasma bumetanide levels were ∼20 mg/l at steady state. Coadministration of probenecid resulted in an increase in bumetanide levels in both ECF and plasma, indicating that oat3 inhibition influences the pharmacokinetics of bumetanide primarily in the periphery. Although bumetanide reached detectable levels in hippocampal ECF, bumetanide concentration in ECF was low relative to systemic concentration. Oat3 inhibition by probenecid resulted in increased bumetanide concentrations in brain and plasma. As an acute treatment in neonatal seizures, the bumetanide/probenecid combination may hold therapeutic potential. © 2014 Royal Pharmaceutical Society.

  1. In vitro and in vivo effect of the nootropic agent adafenoxate on the 5-HT1 sites in different rat brain structures.

    Science.gov (United States)

    Hadjiivanova, C I; Stancheva, S L

    1994-09-01

    1. The effect of the nootropic agent adafenoxate (a structural analogue of meclofenoxate) on the binding parameters of 5-HT1 receptors in vitro and in vivo in rat cerebral cortex, striatum, hippocampus and hypothalamus was studied. 2. The chronic (100 mg/kg per os for 7 days) adafenoxate treatment produced a significant (24.6%) decrease in the density of 5-HT1 sites in the hippocampus. 3. In vitro adafenoxate inhibited specific [3H]5-HT binding with equal potency in all the regions studied with IC50s in the microM range. 4. It is suggested that the decrease in the density of the 5-HT1 sites in rat hippocampus might contribute to the nootropic action of adafenoxate.

  2. Occupant Controlled Lighting

    DEFF Research Database (Denmark)

    Logadóttir, Ásta

    2011-01-01

    The studies presented in this thesis explore opportunities and limitations of using the method of adjustment for occupant controlled lighting. The method of adjustment is studied with respect to occupant preferences and energy efficiency. The work presents three types of studies using the method...... of adjustment. Firstly, there was preliminary laboratory study exploring the influence of daylight on occupant controlled dynamic lighting in a laboratory office environment. Secondly, there was non-daylit laboratory study on occupant preferences for illuminance, and thirdly a scale model study on occupant...... preferences for correlated colour temperature (CCT). The results suggest that the method of adjustment, previously used in the lighting literature, is not adequate to generalize about occupant preferences for illuminance or CCT. Factors that influence occupants’ lighting preference when applying the method...

  3. OCCUPATIONAL EXPOSURE AND COPD

    DEFF Research Database (Denmark)

    Würtz, Else Toft

    Chronic Obstructive Pulmonary Disease (COPD) is a common disease. The main risk factor is smoking although 15% of the COPD cases are expected to be preventable if the occupational exposures from vapour, gas, dust, and fume were eliminated; the population attributable fraction (PAF). The thesis...... addresses the association between occupational exposure and COPD in a population-based cohort of Danes aged 45-84-years. 4717 participants were included at baseline and 2624 at the four year follow-up. COPD was defined by spirometry and the occupational exposure was based on specialist defined jobs...... and questionnaires. The main occupational exposure was organic dust and 49% reported no lifetime occupational exposure. The results suggest occupational exposures to be associated to COPD also in never smokers and women. We found an exposure-response relation in the cross sectional analyses. The results...

  4. Essential Occupational Health Services.

    Directory of Open Access Journals (Sweden)

    Yucel Demiral,Ali Naci Yildiz

    2010-12-01

    Full Text Available Coverage of the occupational health services varies between 15%-90% of the workforce. Available services do not always fit the requirements of the occupational health necessities. Moreover, the need for the occupational health services has been growing while the working life has changed in the globalization era. International Labor Office instruments and World Health Organisation primary health care approach and health for all strategy have suggested universal and comprehensive occupational health services. From this point of view, World Health Organisation / International Labor Office and International Commission on Occupational Health jointly developed and proposed basic occupational health services to tackle this challenge. [TAF Prev Med Bull 2010; 9(6.000: 673-676

  5. In vivo functional brain mapping in a conditional mouse model of human tauopathy (tauP301L) reveals reduced neural activity in memory formation structures.

    Science.gov (United States)

    Perez, Pablo D; Hall, Gabrielle; Kimura, Tetsuya; Ren, Yan; Bailey, Rachel M; Lewis, Jada; Febo, Marcelo; Sahara, Naruhiko

    2013-02-04

    Tauopathies are characterized by intracellular deposition of the microtubule-associated protein tau as filamentous aggregates. The rTg4510 mouse conditionally expresses mutant human tau protein in various forebrain areas under the Tet-off expression system. Mice develop neurofibrillary tangles, with significant neuronal loss and cognitive deficits by 6 months of age. Previous behavioral and biochemical work has linked the expression and aggregates of mutant tau to functional impairments. The present work used manganese-enhanced magnetic resonance imaging (MEMRI) to investigate basal levels of brain activity in the rTg4510 and control mice. Our results show an unmistakable curtailment of neural activity in the amygdala and hippocampus, two regions known for their role in memory formation, but not the cortex, cerebellum, striatum and hypothalamus in tau expressing mice. Behavioral impairments associated with changes in activity in these areas may correspond to age progressive mutant tau(P301L)-induced neurodegeneration.

  6. Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [18F]-FEPPA

    Science.gov (United States)

    Mizrahi, Romina; Rusjan, Pablo M; Kennedy, James; Pollock, Bruce; Mulsant, Benoit; Suridjan, Ivonne; De Luca, Vincenzo; Wilson, Alan A; Houle, Sylvain

    2012-01-01

    [18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands. PMID:22472607

  7. Teacher's Guide to Occupational Orientation.

    Science.gov (United States)

    National Evaluation Systems, Inc., Amherst, MA.

    This guide is specifically designed to accompany materials developed for occupational orientation (particularly in Illinois) in the following five cluster areas: Applied biological and agricultural occupations; personal and public service occupations; health occupations; business, marketing, and management occupations; and industrial oriented…

  8. Evaluation of stereoisomers of 4-fluoroalkyl analogues of 3-quinuclidinyl benzilate in in vivo competition studies for the M1, M2, and M3 muscarinic receptor subtypes in brain

    Energy Technology Data Exchange (ETDEWEB)

    Kiesewetter, Dale O.; Eckelman, William C.; Jaetae, Lee; Paik, Chang H.; Park, Seok G

    1995-08-01

    To develop a subtype selective muscarinic acetylcholine receptor (mAChR) antagonist for PET, fluorine-19 labeled alkyl analogues of quinuclidinyl benzilate (QNB) were synthesized by stereoselective reactions. To investigate these analogues for tissue subtype specificity, in vivo competitive binding studies were performed in rat brain using (R)-3-quinuclidinyl (R)-4-[{sup 125}I]Iodobenzilate (IQNB). Five, fifty, or five-hundred nmol of the non-radioactive ligands were coinjected intravenously with 8 pmol of the radioligand. Cold (R,R)-IQNB blocked (R,R)-[{sup 125}I]IQNB in a dose-dependent manner, without showing regional specificity. For the (R,S)-fluoromethyl, -fluoroethyl, and -fluoropropyl derivatives, a higher percent blockade was seen at 5 and 50 nmol levels in M2 predominant tissues (medulla, pons, and cerebellum) than in M1 predominant tissues (cortex, striatum and hippocampus). The blockade pattern of the radioligand also correlated qualitatively with the percentage of M2 receptors in the region. The S-quinuclidinyl analogues showed M2 selectivity but less efficient blockade of the radioligand, indicating lower affinities. Radioligand bound to the medulla was inversely correlated to the M2 relative binding affinity of the fluoroalkyl analogues. These results indicate that the nonradioactive ligand blocks the radioligand based on the affinity of the nonradioactive ligand for a particular receptor subtype compared to the affinity of the radioligand for the same receptor subtype. Of the seven compounds evaluated, (R,S)-fluoromethyl-QNB appears to show the most selectivity for the M2 subtypes in competition studies in vivo.

  9. Leadership and Occupational Stress

    Science.gov (United States)

    Stickle, Fred E.; Scott, Kelly

    2016-01-01

    In a leadership position, it is important to understand what stress is and how it affects others. In an occupational setting, stressors vary according to personality types, gender, and occupational rank. The purpose of this manuscript is to review the foundations of stress and to explore how personality characteristics influence stress.…

  10. [Hand and occupational diseases].

    Science.gov (United States)

    Bensefa-Colas, Lynda; Choudat, Dominique

    2013-12-01

    Hand is frequently the site of work accidents or occupational diseases. The musculoskeletal upper limb is the first recognized occupational disease and carpal tunnel syndrome is the most common of them. The most common location of occupational dermatoses is the hand. Their causes are often multifactorial, involving chemical irritants, physical, allergens and endogenous factors (mainly atopic dermatitis). Occupational exposure to microtrauma and iterative use of vibrating tools may also be the cause of hypothenar hammer syndrome and acrosyndromes. The frequent chronicity and functional impairment induced by these attacks can cause lasting disabilities, an inability to source workstation. Occupational physician is a focal point for helping to maintain the position and the prevention of socioprofessional disinsertion. Many pathologies of the hand related to professional activity may benefit from a statement in occupational disease and thus allow the patient to obtain compensation and employment protection. Prevention of occupational hand diseases should be made by all health actors, especially in occupations and industries at risk. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Occupational Mortality, Background on

    DEFF Research Database (Denmark)

    Lynge, Elsebeth

    2016-01-01

    The study of occupational mortality involves the systematic tabulation of mortality by occupational or socioeconomic groups. Three main methods are used to conduct these studies: cross-sectional studies, death certificate studies, and follow-up studies. Cross-sectional studies were undertaken in ...... the mortality rates of blue- and white-collar workers....

  12. The American Occupational Structure.

    Science.gov (United States)

    Blau, Peter M.; Duncan, Otis Dudley

    The objective of this book is to present a systematic analysis of the American occupational structure, and, thus, of the major foundation of the stratification system in this society. Processes of social mobility from one generation to the next and from career beginnings to occupational destinations are considered to reflect the dynamics of the…

  13. Dimensions of Occupational Prestige

    Science.gov (United States)

    Haug, Marie R.; Widdison, Harold A.

    1975-01-01

    Eight dimensions of occupational prestige are examined for their effect on the general prestige ratings accorded various occupations within the medical profession. Stepwise multiple regression analyzes the relative weight of these dimension among 410 persons. The findings suggested that public stereotypes exert a normative pressure on individual…

  14. In vivo functional brain mapping in a conditional mouse model of human tauopathy (taup301l reveals reduced neural activity in memory formation structures

    Directory of Open Access Journals (Sweden)

    Perez Pablo D

    2013-02-01

    Full Text Available Abstract Background Tauopathies are characterized by intracellular deposition of the microtubule-associated protein tau as filamentous aggregates. The rTg4510 mouse conditionally expresses mutant human tau protein in various forebrain areas under the Tet-off expression system. Mice develop neurofibrillary tangles, with significant neuronal loss and cognitive deficits by 6 months of age. Previous behavioral and biochemical work has linked the expression and aggregates of mutant tau to functional impairments. The present work used manganese-enhanced magnetic resonance imaging (MEMRI to investigate basal levels of brain activity in the rTg4510 and control mice. Results Our results show an unmistakable curtailment of neural activity in the amygdala and hippocampus, two regions known for their role in memory formation, but not the cortex, cerebellum, striatum and hypothalamus in tau expressing mice. Conclusion Behavioral impairments associated with changes in activity in these areas may correspond to age progressive mutant tauP301L-induced neurodegeneration.

  15. 31P nuclear magnetic resonance in vivo spectroscopy of the metabolic changes induced in the awake rat brain during KCN intoxication and its reversal by hydroxocobalamine.

    Science.gov (United States)

    Benabid, A L; Decorps, M; Remy, C; Le Bas, J F; Confort, S; Leviel, J L

    1987-03-01

    Radiofrequency surface coils were chronically implanted in rats, which were subsequently subjected to 31P nuclear magnetic resonance (NMR) investigations at 4.7 T. The implanted coil allowed study of the animals without need for anesthesia, which is a prerequisite for studies of normal brain metabolism. The animals may be kept in the NMR probe for several hours. During subsequent experiments, they may be placed in the same position, therefore allowing follow-up studies for periods as long as 2 months. This method has been used in the study of sublethal KCN intoxication. KCN, a cytochrome c oxidase inhibitor, induces a blockade of cell respiratory processes, which is reflected, in a dose-dependent manner, by a decrease in phosphocreatine content and pH and an increase in inorganic phosphate content, whereas ATP levels remain constant until high doses of KCN (6 mg/kg i.p.) are reached. 31P NMR allows the time course of these metabolic changes to be followed. For high KCN doses, a new peak, termed X, is observed, which is interpreted as being due to a pool of inorganic phosphate at very low pH (5.65), corresponding to a subset of cells that did not survive KCN injury. Hydroxocobalamine, a specific antidote of KCN, suppresses the metabolic changes due to 6 mg/kg of KCN.

  16. Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Waldman, A.D.; Cordery, R.J.; Godbolt, A.; Rossor, M.N. [University College London, Dementia Research Group, Department of Neurodegenerative Disease, Institute of Neurology, London (United Kingdom); Imperial College of Science, Technology and Medicine, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, London (United Kingdom); MacManus, D.G. [University College London, NMR Research Unit, Department of Clinical Neurology, Institute of Neurology, London (United Kingdom); Collinge, J. [University College London, MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, London (United Kingdom)

    2006-06-15

    Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Straeussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease. (orig.)

  17. In vivo three-photon activity imaging of GCaMP6-labeled neurons in deep cortex and the hippocampus of the mouse brain

    Science.gov (United States)

    Wang, Tianyu; Ouzounov, Dimitre G.; Wang, Mengran; Feng, Danielle; Cruz-Hernandez, Jean C.; Reimer, Jacob; Tolias, Andreas; Nishimura, Nozomi; Xu, Chris

    2017-02-01

    We demonstrate that three-photon microscopy (3PM) with 1300-nm excitation enables functional imaging of GCaMP6s labeled neurons beyond the depth limit of two-photon microscopy (2PM) with 920-nm excitation. We quantitatively compared 2PM and 3PM imaging of calcium indicator GCaMP6s by measuring correlation between activity traces, absolute signal level, excitation attenuation with depth, and signal-to-background ratio (SBR). Compared to 2PM imaging of GCaMP6s-labeled neurons, 3PM imaging has increasingly larger advantages in signal strength and SBR as the imaging depth increases in densely labeled mouse brain, given the same pulse energy, pulse width, and repetition rate at the sample surface. For example, 3PM has comparable signal strength as 2PM and up to two orders of magnitude higher SBR as 2PM in mouse cortex around 700-800um. We also demonstrate 3PM activity recording of 150 neurons in the hippocampal stratum pyramidale (SP) at 1mm depth, which is inaccessible to non-invasive 2PM imaging. Our work establishes 3PM as a powerful tool for calcium imaging at the depth beyond 2PM limits.

  18. In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: an 18F-fluorodeoxyglucose-small animal positron emission tomography study.

    Science.gov (United States)

    Guo, Y; Gao, F; Wang, S; Ding, Y; Zhang, H; Wang, J; Ding, M-P

    2009-09-15

    Cerebral glucose hypometabolism is common in temporal lobe epilepsy (TLE). The temporospatial evolution of these metabolic changes during epileptogenesis remains to be determined. We measured the regional normalized cerebral metabolic rate for glucose (nCMRglc) with (18)F-fluorodeoxyglucose (FDG)-small animal positron emission tomography (microPET) in animals receiving systemic pilocarpine application. The microPET scan was performed on day 2 (early), day 7 (latent) and 42 days (chronic phase) after the initial status epilepticus. We found specific temporospatial changes in glucose utilization in rats during the course of epileptogenesis. In the early phase, the limbic structures underwent the largest decrease in glucose utilization. Most brain structures were still hypometabolic in the latent phase and recovered in the chronic phase. Conversely, the hippocampus and thalamus presented with persistent hypometabolism during epileptogenesis. The cerebellum and pons maintained normal glucose utilization during this process. We also found that severe glucose hypometabolism in the entorhinal cortex during the early phase was correlated with epileptogenesis, indicating the critical role of the entorhinal cortex in the early stages of TLE.

  19. Occupational stress among dentists

    DEFF Research Database (Denmark)

    Moore, Rod

    2011-01-01

    Dentists report a high degree of occupational stress.(Cooper, Mallinger, and Kahn, 1978;Coster, Carstens, and Harris, 1987;DiMatteo, Shugars, and Hays, 1993;Hakeberg et al., 1992;Möller and Spangenberg, 1996;Moore, 2000;Myers and Myers, 2004;O'Shea, Corah, and Ayer, 1984) This chapter reviews...... the literature of studies that elaborate on the circumstances of occupational stress of dentists. These will include the frequency of occurrence of occupational stress among dentists in several countries, frequency and intensity of identified stressors specific to dentistry, as well as the consequences...... of this occupational stress. The literature on consequences includes effects on dentists' physical health, personal and occupational performance, including "burnout" phenomena, as well as topics of alcohol or substance abuse and reports of suicidal behaviour among dentists. One specific and less conventionally...

  20. Occupational medicine and toxicology

    Directory of Open Access Journals (Sweden)

    Fischer Axel

    2006-02-01

    Full Text Available Abstract This editorial is to announce the Journal of Occupational Medicine and Toxicology, a new Open Access, peer-reviewed, online journal published by BioMed Central. Occupational medicine and toxicology belong to the most wide ranging disciplines of all medical specialties. The field is devoted to the diagnosis, prevention, management and scientific analysis of diseases from the fields of occupational and environmental medicine and toxicology. It also covers the promotion of occupational and environmental health. The complexity of modern industrial processes has dramatically changed over the past years and today's areas include effects of atmospheric pollution, carcinogenesis, biological monitoring, ergonomics, epidemiology, product safety and health promotion. We hope that the launch of the Journal of Occupational Medicine and Toxicology will aid in the advance of these important areas of research bringing together multi-disciplinary research findings.

  1. Near-Infrared Emitting PbS Quantum Dots for in Vivo Fluorescence Imaging of the Thrombotic State in Septic Mouse Brain

    Directory of Open Access Journals (Sweden)

    Yukio Imamura

    2016-08-01

    Full Text Available Near-infrared (NIR fluorescent imaging is a powerful tool for the non-invasive visualization of the inner structure of living organisms. Recently, NIR fluorescence imaging at 1000–1400 nm (second optical window has been shown to offer better spatial resolution compared with conventional NIR fluorescence imaging at 700–900 nm (first optical window. Here we report lead sulfide (PbS quantum dots (QDs and their use for in vivo NIR fluorescence imaging of cerebral venous thrombosis in septic mice. Highly fluorescent PbS QDs with a 1100 nm emission peak (QD1100 were prepared from lead acetate and hexamethyldisilathiane, and the surface of QD1100 was coated with mercaptoundecanoic acid so as to be soluble in water. NIR fluorescence imaging of the cerebral vessels of living mice was performed after intravascular injection (200–300 μL of QD1100 (3 μM from a caudal vein. By detecting the NIR fluorescence of QD1100, we achieved non-invasive NIR fluorescence imaging of cerebral blood vessels through the scalp and skull. We also achieved NIR fluorescence imaging of cerebral venous thrombosis in septic mice induced by the administration of lipopolysaccharide (LPS. From the NIR fluorescence imaging, we found that the number of thrombi in septic mice was significantly increased by the administration of LPS. The formation of thrombi in cerebral blood vessels in septic mice was confirmed by enzyme-linked immunosorbent assay (ELISA. We also found that the number of thrombi significantly decreased after the administration of heparin, an inhibitor of blood coagulation. These results show that NIR fluorescence imaging with QD1100 is useful for the evaluation of the pathological state of cerebral blood vessels in septic mice.

  2. In vivo intracellular oxygen dynamics in murine brain glioma and immunotherapeutic response of cytotoxic T cells observed by fluorine-19 magnetic resonance imaging.

    Directory of Open Access Journals (Sweden)

    Jia Zhong

    Full Text Available Noninvasive biomarkers of anti-tumoral efficacy are of great importance to the development of therapeutic agents. Tumor oxygenation has been shown to be an important indicator of therapeutic response. We report the use of intracellular labeling of tumor cells with perfluorocarbon (PFC molecules, combined with quantitative ¹⁹F spin-lattice relaxation rate (R₁ measurements, to assay tumor cell oxygen dynamics in situ. In a murine central nervous system (CNS GL261 glioma model, we visualized the impact of Pmel-1 cytotoxic T cell immunotherapy, delivered intravenously, on intracellular tumor oxygen levels. GL261 glioma cells were labeled ex vivo with PFC and inoculated into the mouse striatum. The R₁ of ¹⁹F labeled cells was measured using localized single-voxel magnetic resonance spectroscopy, and the absolute intracellular partial pressure of oxygen (pO₂ was ascertained. Three days after tumor implantation, mice were treated with 2×10⁷ cytotoxic T cells intravenously. At day five, a transient spike in pO₂ was observed indicating an influx of T cells into the CNS and putative tumor cell apoptosis. Immunohistochemistry and quantitative flow cytometry analysis confirmed that the pO₂ was causally related to the T cells infiltration. Surprisingly, the pO₂ spike was detected even though few (∼4×10⁴ T cells actually ingress into the CNS and with minimal tumor shrinkage. These results indicate the high sensitivity of this approach and its utility as a non-invasive surrogate biomarker of anti-cancer immunotherapeutic response in preclinical models.

  3. The Occupations of Literacy: Occupational Therapy's Role

    Science.gov (United States)

    Frolek Clark, Gloria

    2016-01-01

    Nationally, student proficiency in reading and writing is very low and requires ongoing focus from state and local agencies. With almost 25% of occupational therapists working in early intervention and school settings (AOTA, 2015), their role of facilitating literacy (e.g., reading, writing, speaking and listening) is critical. Occupational…

  4. In Vivo Evaluation of Blood Based and Reference Tissue Based PET Quantifications of [11C]DASB in the Canine Brain.

    Directory of Open Access Journals (Sweden)

    Nick Van Laeken

    Full Text Available This first-in-dog study evaluates the use of the PET-radioligand [11C]DASB to image the density and availability of the serotonin transporter (SERT in the canine brain. Imaging the serotonergic system could improve diagnosis and therapy of multiple canine behavioural disorders. Furthermore, as many similarities are reported between several human neuropsychiatric conditions and naturally occurring canine behavioural disorders, making this tracer available for use in dogs also provide researchers an interesting non-primate animal model to investigate human disorders. Five adult beagles underwent a 90 minutes dynamic PET scan and arterial whole blood was sampled throughout the scan. For each ROI, the distribution volume (VT, obtained via the one- and two- tissue compartment model (1-TC, 2-TC and the Logan Plot, was calculated and the goodness-of-fit was evaluated by the Akaike Information Criterion (AIC. For the preferred compartmental model BPND values were estimated and compared with those derived by four reference tissue models: 4-parameter RTM, SRTM2, MRTM2 and the Logan reference tissue model. The 2-TC model indicated in 61% of the ROIs a better fit compared to the 1-TC model. The Logan plot produced almost identical VT values and can be used as an alternative. Compared with the 2-TC model, all investigated reference tissue models showed high correlations but small underestimations of the BPND-parameter. The highest correlation was achieved with the Logan reference tissue model (Y = 0.9266 x + 0.0257; R2 = 0.9722. Therefore, this model can be put forward as a non-invasive standard model for future PET-experiments with [11C]DASB in dogs.

  5. Identification of in vivo brain-derived neurotrophic factor-stimulated autophosphorylation sites on the TrkB receptor tyrosine kinase by site-directed mutagenesis.

    Science.gov (United States)

    Guiton, M; Gunn-Moore, F J; Stitt, T N; Yancopoulos, G D; Tavaré, J M

    1994-12-02

    Brain-derived neurotrophic factor (BDNF) interacts with the TrkB receptor tyrosine kinase, the tyrosine kinase domain of which has homology with the insulin receptor subfamily of protein kinases. This includes the conservation of three regulatory tyrosines (residues 670, 674, and 675) known to play a crucial role in signal transmission by the insulin receptor (tyrosines 1158, 1162, and 1163). Wild-type TrkB and TrkB mutants with Y670F, Y674F/Y675F, Y751F (the tyrosine reported to be important in phosphatidylinositol 3-kinase binding (Obermeier, A., Lammers, R., Wiesmuller, K. H., June, G., Schlessinger, J., and Ullrich, A. (1993) J. Biol. Chem. 268, 22963-22966)), and K540R (consensus ATP binding lysine) substitutions were transiently expressed in COS cells for analysis of phosphorylation sites by two-dimensional phosphopeptide mapping. TrkB phosphorylation sites were also studied in MG86 cells stably expressing wild-type TrkB. In addition, the mutants were expressed in Chinese hamster ovary cells for analysis of the ability of the receptor to mediate BDNF-stimulated transcription from a 12-O-tetradecanoylphorbol-13-acetate response element (TRE). BDNF stimulated the phosphorylation of wild-type TrkB on multiple tyrosine and serine residues. This phosphorylation occurred on tyrosines 670, 674, and 675 plus two other tyrosines and at least two serines that were not unequivocally identified. Wild-type TrkB mediated a pronounced stimulation of TRE-dependent transcription. A Y674F/Y675F, but not Y670F, substitution dramatically inhibited this response. Surprisingly, in COS cells, a Y751F substitution induced dramatically lower tyrosine and serine phosphorylation at all sites but mediated a normal BDNF-stimulated activation of a TRE. Our results demonstrate a critical role for the phosphorylation of tyrosines 674 and 675 in BDNF-dependent signaling by wild-type TrkB.

  6. Combining whole-brain voxel-wise analysis with in vivo tractography of diffusion behavior after sports-related concussion in adolescents: a preliminary report.

    Science.gov (United States)

    Borich, Michael; Makan, Nadia; Boyd, Lara; Virji-Babul, Naznin

    2013-07-15

    We have previously shown that sports-related concussion in adolescents is associated with changes in whole-brain properties of white-matter pathways. Here, we assess local changes within these pathways. Twelve adolescents with a clinical diagnosis of subacute concussion and 10 healthy adolescents matched for age, gender, and physical activity completed magnetic resonance imaging scanning. Voxel-wise tract-based spatial statistics and tractography were performed to assess local changes in diffusion-based measures of microstructural properties of white-matter pathways (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity) between the two groups. Fractional anisotropy values were higher for the concussed group in multiple cluster regions using tract-based spatial statistics, primarily in frontal white-matter regions, including the anterior corona radiata bilaterally. Using these regions of altered diffusion characteristics to seed fiber tractography, significantly reduced axial diffusivity in tracts passing through these areas were detected in the concussed group (p=0.04). A trend toward reduced mean and radial diffusivity in the concussed group was also observed within the same reconstructed tracts. Diffusion behavior within these tracts was significantly correlated with an assessment of concussion status (Sports Concussion Assessment Tool 2). Fractional anisotropy within the reconstructed tracts was not significantly different between the two groups. These results suggest that subacute concussion in adolescents is associated with altered diffusion properties within regional white-matter tissue and along reconstructed fiber pathways. Combining voxel-wise analysis with fiber tractography provides an alternative objective approach to evaluate and identify subtle changes in white-matter fiber integrity after concussion.

  7. Brain Basics

    Medline Plus

    Full Text Available ... About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain Brain ... called the hypothalamic-pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain Basics in Real Life— ...

  8. Occupational Accidents Aboard Merchant Ships

    National Research Council Canada - National Science Library

    H. L. Hansen; D. Nielsen; M. Frydenberg

    2002-01-01

    Objectives: To investigate the frequency, circumstances, and causes of occupational accidents aboard merchant ships in international trade, and to identify risk factors for the occurrence of occupational...

  9. Alcoholism and occupation.

    Science.gov (United States)

    Olkinuora, M

    1984-12-01

    Occupational roles are a dominant force in many aspects of social life. Occupation signifies a complex of social and psychological factors that reflect intelligence, education, personality, ambition, social status, and life-style. The consumption of alcohol and alcoholism have many correlations with occupational roles. Mortality from cirrhosis of the liver reflects the per capita consumption of alcohol. In certain occupations such mortality rates are clearly above average. The highest risk is found in occupations associated with the serving of food and beverages. A Finnish study has shown that the alcohol-related use of health services among males is the highest among unskilled workers, painters, seamen, and construction workers and the lowest among executives and farmers. Many population studies have shown that blue-collar workers and laborers have the highest level of drinking. This pattern is not necessarily true among females. The risk factors associated with occupation include the availability of alcohol at work, social pressure to drink on the job, separation from normal social relationships, and freedom from supervision. The opportunity to obtain alcoholic beverages relatively inexpensively, when combined with social pressure by peers to drink heavily, is an especially powerful explanation for high rates of alcoholism within an occupation.

  10. Occupational skin cancers

    Energy Technology Data Exchange (ETDEWEB)

    Gawkrodger, D.J. [Royal Hallamshire Hospital, Sheffield (United Kingdom). Dept. of Dermatology

    2004-10-01

    Skin cancer due to occupation is more common than is generally recognized, although it is difficult to obtain an accurate estimate of its prevalence. Over the past two centuries, occupational skin cancers have particularly been due to industrial exposure of men (it seems more so than women) to chemical carcinogens such as polycyclic hydrocarbons (e.g. from coal tar products) or to arsenic. Industrial processes have improved in most Western countries to limit this type of exposure, but those with outdoor occupations are still exposed to solar ultraviolet irradiation without this being widely recognized as an industrial hazard. Ionizing radiation such as X-rays can also cause skin cancer. Occupational skin cancers often resemble skin tumours found in non-occupational subjects, e.g. basal cell carcinoma, squamous cell carcinoma and malignant melanoma, but some pre-malignant lesions can be more specific and point to an occupational origin, e.g. tar keratoses or arsenical keratoses. An uncommon but well-recognized cause of occupational skin cancer is that which results from scar formation following an industrial burn. In the future it will be necessary to focus on preventative measures, e.g. for outdoor workers, the need to cover up in the sun and use sun protective creams and a campaign for earlier recognition of skin cancers, which are usually curable if treated in their early stages.

  11. One-step construction of a molybdenum disulfide/multi-walled carbon nanotubes/polypyrrole nanocomposite biosensor for the ex-vivo detection of dopamine in mouse brain tissue.

    Science.gov (United States)

    Vijayaraj, Kathiresan; Dinakaran, Thirumalai; Lee, Yujeong; Kim, Suhkmann; Kim, Hyung Sik; Lee, Jaewon; Chang, Seung-Cheol

    2017-12-09

    We developed a new strategy for construction of a biosensor for the neurotransmitter dopamine. The biosensor was constructed by one-step electrochemical deposition of a nanocomposite in aqueous solution at pH 7.0, consisting of molybdenum disulfide, multi-walled carbon nanotubes, and polypyrrole. A series of analytical methods was performed to investigate the surface characteristics and the improved electrocatalytic effect of the nanocomposite, including cyclic voltammetry, electrochemical impedance spectroscopy, field-emission scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. The constructed biosensor showed high sensitivity (1.130 μAμM-1cm-2) with a dynamic linearity range of 25-1000 nM and a detection limit of 10 nM. Additionally, the designed sensor exhibited strong anti-interference ability and satisfactory reproducibility. The practical application of the sensor was manifested for the ex vivo determination of dopamine neurotransmitters using brain tissue samples of a mouse Parkinson's disease model. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Occupational cancer in Britain

    Science.gov (United States)

    Chen, Yiqun; Osman, John

    2012-01-01

    Although only a relatively small proportion of cancer is attributable to occupational exposure to carcinogenic agents, the estimated number of deaths due to occupational cancer is high when compared to other deaths due to work-related ill health and injury. However, risk from occupational exposure to carcinogens can be minimised through proportionate but effective risk management. The Health and Safety Executive (HSE) is the regulator of workplace health and safety in Great Britain. As part of its aim to reduce ill health arising from failures to control properly exposure to hazards at work, HSE commissioned the research presented elsewhere in this supplement to enable it to identify priorities for preventing occupational cancer. The research has shown that occupational cancer remains a key health issue and that low-level exposure of a large number of workers to carcinogens is important. The finding that a small number of carcinogens have been responsible for the majority of the burden of occupational cancer provides key evidence in the development of priorities for significant reduction of occupational cancer. Although the research presented in this supplement reflects the consequences of past exposures to carcinogens, occupational cancer remains a problem. The potential for exposure to the agents considered in this research is still present in the workplace and the findings are relevant to prevention of future disease. In this article, the principle approaches for risk reduction are described. It provides supporting information on some of the initiatives already being undertaken, or those being put in place, to reduce occupational cancer in Great Britain. The need also for systematic collection of exposure information and the importance of raising awareness and changing behaviours are discussed. PMID:22710673

  13. Evaluation of [11C]Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy and receptor crosstalk.

    Science.gov (United States)

    Krämer, Stefanie D; Betzel, Thomas; Mu, Linjing; Haider, Ahmed; Herde Müller, Adrienne; Boninsegni, Anna K; Keller, Claudia; Szermerski, Marina; Schibli, Roger; Wünsch, Bernhard; Ametamey, Simon M

    2017-11-30

    Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [11C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator. Methods: [11C]Me-NB1 was synthesized and characterized by in vitro displacement binding experiments with rat brain membranes, in vitro autoradiography, blocking and displacement experiments by PET and PET kinetic modeling with an arterial input function. Receptor occupancy by eliprodil was studied in vivo by PET with [11C]Me-NB1. Results: [11C]Me-NB1 was synthesized at 290±90 GBq/µmol specific activity, 7.4±1.9 GBq total activity at the end of synthesis and >99% radiochemical purity. [11C]Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. In vivo, half maximal receptor occupancy by eliprodil occurred at 1.5 μg/kg. At 1 mg/kg eliprodil, a dose with reported neuroprotective effects, >99.5% binding sites were occupied. In vitro, [11C]Me‑NB1 binding was independent of sigma 1 receptor (Sigma1R) and the Sigma1R agonist (+)‑pentazocine did not compete for high affinity binding. In vivo, 2.5 mg/kg (+)‑pentazocine abolished [11C]Me-NB1 specific binding, indicating an indirect effect of Sigma1R on [11C]Me-NB1 binding. Conclusion: [11C]Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assessment of the receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, [11C]Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor crosstalk. Copyright © 2017 by the Society of Nuclear Medicine

  14. Gossip and Occupational Ideology

    Science.gov (United States)

    Rysman, Alexander R.

    1976-01-01

    Defines the transmission of gossip as an essential social process reflecting a shared group membership and discusses the ways in which gossip supports ideologies held by members of a specific occupation. (MH)

  15. Occupants' window opening behaviour

    DEFF Research Database (Denmark)

    Fabi, Valentina; Andersen, Rune Korsholm; Corgnati, Stefano

    2012-01-01

    and office buildings. The analysis of the literature highlights how a shared approach on identifying the driving forces for occupants' window opening and closing behaviour has not yet been reached. However, the reporting of variables found not to be drivers may reveal contradictions in the obtained results......Energy consumption in buildings is influenced by several factors related to the building properties and the building controls, some of them highly connected to the behaviour of their occupants.In this paper, a definition of items referring to occupant behaviour related to the building control...... systems is proposed, based on studies presented in literature and a general process leading to the effects on energy consumptions is identified.Existing studies on the topic of window opening behaviour are highlighted and a theoretical framework to deal with occupants' interactions with building controls...

  16. Occupational Noise Exposure

    Science.gov (United States)

    Powered by Translate UNITED STATES DEPARTMENT OF LABOR Facebook Twitter Instagram RSS Subscribe Search A TO Z INDEX UNITED STATES DEPARTMENT OF LABOR Facebook Twitter Instagram RSS Subscribe Occupational Safety and Health Administration English | ...

  17. Occupational health in Mexico.

    Science.gov (United States)

    Carreón, Tania; Santos-Burgoa, Carlos; Baron, Sherry; Hernández, Sendy

    2002-01-01

    The authors discuss the maquiladoras and child labor, and offer an overview of the history of occupational safety and health in Mexico that covers laws and regulations, social security, unions, and enforcement of legislation. The organization and structure of the various institutions responsible for occupational safety and health (OSH), as well as administrative procedures, are described. This article concludes with a list of the new challenges for OSH in Mexico.

  18. Occupancy in continuous habitat

    Science.gov (United States)

    Efford, Murray G.; Dawson, Deanna K.

    2012-01-01

    The probability that a site has at least one individual of a species ('occupancy') has come to be widely used as a state variable for animal population monitoring. The available statistical theory for estimation when detection is imperfect applies particularly to habitat patches or islands, although it is also used for arbitrary plots in continuous habitat. The probability that such a plot is occupied depends on plot size and home-range characteristics (size, shape and dispersion) as well as population density. Plot size is critical to the definition of occupancy as a state variable, but clear advice on plot size is missing from the literature on the design of occupancy studies. We describe models for the effects of varying plot size and home-range size on expected occupancy. Temporal, spatial, and species variation in average home-range size is to be expected, but information on home ranges is difficult to retrieve from species presence/absence data collected in occupancy studies. The effect of variable home-range size is negligible when plots are very large (>100 x area of home range), but large plots pose practical problems. At the other extreme, sampling of 'point' plots with cameras or other passive detectors allows the true 'proportion of area occupied' to be estimated. However, this measure equally reflects home-range size and density, and is of doubtful value for population monitoring or cross-species comparisons. Plot size is ill-defined and variable in occupancy studies that detect animals at unknown distances, the commonest example being unlimited-radius point counts of song birds. We also find that plot size is ill-defined in recent treatments of "multi-scale" occupancy; the respective scales are better interpreted as temporal (instantaneous and asymptotic) rather than spatial. Occupancy is an inadequate metric for population monitoring when it is confounded with home-range size or detection distance.

  19. Occupational stressors in nursing

    Directory of Open Access Journals (Sweden)

    N. Nikpeyma

    2009-04-01

    Full Text Available Background and aimsNursing provides a wide range of potential workplace stressors as it is  a profession that requires a high level of skill, teamworking in a variety of situations and provision  of 24-hour delivery of care .Occupational stress is a major factor of Staff sickness an  absenteeism.This study investigates the main occupational stressors in nursing profession in the  hope of identification and reducing it.MethodsIn this study a questionnaire consisting of three parts:demoghraphic data,the nurses  background and questions about occupational stress from Revised index fulfilled by 140 nurses.ResultsLack of reward for work well done(48/6%, Heavy workload(46/4% ,lack of Participation in decisions (39/3% , poor Control of work place(38/4%and lack of job  development (36/4% have been the main sources of Occupational stress for nurses.chronic  diseases, Night Shift working and working hours were positively associated with occupstional  stress.Conclusion Analysis indicated that effects of work factors on occupational stress are more than demoghraphic data. The findings of this study can assist health service organisations to provide an attractive working climate in order to decrease side effects and consequences of occupational stress. Furthermore, understanding this situation can help to develop coping strategies in order to reduce work-related stress.

  20. Professional Differentiation and Occupational Earnings.

    Science.gov (United States)

    Cullen, John B.

    1985-01-01

    "Professional" and other occupational characteristics were selected as variables for predicting the earnings of occupational groups. Task complexity and education were significant predictors of occupational earnings. In support of some power theorists, the data suggested that some occupational groups derive additional earnings by influencing their…

  1. Occupational Employment Projections to 2010.

    Science.gov (United States)

    Hecker, Daniel E.

    2001-01-01

    Employment in professional and related occupations and service occupations will increase the fastest and add the most jobs from 2000 to 2010. Changes in technology or business operations will cause the largest declines in occupational demand. Occupations requiring a postsecondary award or academic degree will account for 42 percent of total job…

  2. Secondary Health Occupations Education Curriculum.

    Science.gov (United States)

    Matzen, Shelley; Muhl, V. Jane

    This color coded curriculum guide for secondary health occupations in Iowa provides units for the first phase of the curriculum, career exploration of the health occupations. The nine units cover the following topics: (1) introduction to health occupations; (2) health occupations career exploration; (3) communication skills; (4) self-care and…

  3. Review of Occupational Therapy Intervention Research in the Practice Area of Children and Youth 2009–2013

    Science.gov (United States)

    Bendixen, Roxanna M.; Huang, Yu Yun; Lim, Yoonjeong

    2014-01-01

    PURPOSE. We conducted a systematic review examining the extent to which pediatric intervention research recently published in the American Journal of Occupational Therapy reflects occupational therapy’s holistic occupation-based tenets. METHOD. We surveyed 10 systematic reviews and analyzed 38 single effectiveness studies for intervention approach, type, level of environmental targeting, level of occupational task and participation practice, and measures used. RESULTS. Of the 38 single effectiveness studies, 12 (32%) explicitly incorporated both environmental targets of intervention and practice of complex or in vivo occupational tasks, with steady increases during the 2009–2013 time frame. CONCLUSION. In the area of children and youth, occupational therapy is making steady gains in reflecting and demonstrating the effectiveness of the profession’s holistic, occupation-based tenets. Occupational therapy researchers must be mindful to ensure that despite the reductionist nature of intervention research, interventions reflect the profession’s holistic understanding of the interplay between the child, environment, and occupations. PMID:24581415

  4. Occupational therapists' perception of the concept of occupational balance.

    Science.gov (United States)

    Yazdani, Farzaneh; Harb, Alia; Rassafiani, Mehdi; Nobakht, Laya; Yazdani, Nastaran

    2017-05-10

    Occupational balance is one of the concepts used by occupational therapists with no consensus on its definition. Literature demonstrates different perspectives when this concept is applied in practice and in its link to other concepts such as health and well-being. This study aims to explore how the concept of occupational balance is perceived and practised by occupational therapy practitioners. A qualitative methodology was employed. Fourteen occupational therapists volunteered for the study. Nine occupational therapy practitioners were interviewed individually and five attended a focus group. Thematic analysis was applied to analyze the data. Six themes were identified as follows: (1) occupational balance: what it is; (2) how occupational balance is formed; (3) occupational balance and well-being (4); subjective and objective representations of occupational balance (5); what disrupts/affects occupational balance; and (6) occupational balance/imbalance and occupational therapy practice. Both objective and subjective experiences of occupational balance need to be considered in order to make an informed decision in practice. The right occupational balance for each individual should be based on his/her values but with consideration of the principal of no harm to others.

  5. Occupational health in Brazil.

    Science.gov (United States)

    Bedrikow, B; Algranti, E; Buschinelli, J T; Morrone, L C

    1997-01-01

    Brazil is a recently industrialised country with marked contrasts in social and economic development. The availability of public/private services in its different regions also varies. Health indicators follow these trends. Occupational health is a vast new field, as in other developing countries. Occupational medicine is a required subject in graduation courses for physicians. Specialisation courses for university graduated professionals have more than 700 hours of lectures and train occupational health physicians, safety engineers and nursing staff. At the technical level, there are courses with up to 1300 hours for the training of safety inspectors. Until 1986 about 19,000 occupational health physicians, 18,000 safety engineers and 51,000 safety inspectors had been officially registered. Although in its infancy, postgraduation has attracted professionals at university level, through residence programmes as well as masters and doctors degrees, whereby at least a hundred good-quality research studies have been produced so far. Occupational health activities are controlled by law. Undertakings with higher risks and larger number of employees are required to hire specialised technical staff. In 1995 the Ministry of Labour demanded programmes of medical control of occupational health (PCMSO) for every worker as well as a programme of prevention of environmental hazards (PPRA). This was considered as a positive measure for the improvement of working conditions and health at work. Physicians specialising in occupational medicine are the professionals more often hired by the enterprises. Reference centres (CRSTs) for workers' health are connected to the State or City Health Secretariat primary health care units. They exist in more populated areas and are accepted by workers as the best way to accomplish the diagnosis of occupational diseases. There is important participation by the trade unions in the management of these reference centres. For 30 years now employers

  6. Occupational Experience, Mobility, and Wages

    DEFF Research Database (Denmark)

    Groes, Fane

    In this paper we present how occupational tenure relates to wage growth and occupational mobility in Danish data. We show that the Danish data produces qualitatively similar results as found in U.S. data with respect to an increase in average wages when experience in an occupation increases. In a...... also is true for workers switching occupation and rm. After ve years of experience in an occupation the average probability of switching any type of occupation, including occupation and rm switches, has fallen from 25% to 12%....

  7. Population Health and Occupational Therapy.

    Science.gov (United States)

    Braveman, Brent

    2016-01-01

    Occupational therapy practitioners play an important role in improving the health of populations through the development of occupational therapy interventions at the population level and through advocacy to address occupational participation and the multiple determinants of health. This article defines and explores population health as a concept and describes the appropriateness of occupational therapy practice in population health. Support of population health practice as evidenced in the official documents of the American Occupational Therapy Association and the relevance of population health for occupational therapy as a profession are reviewed. Recommendations and directions for the future are included related to celebration of the achievements of occupational therapy practitioners in the area of population health, changes to the Occupational Therapy Practice Framework and educational accreditation standards, and the importance of supporting, recognizing, rewarding, and valuing occupational therapy practitioners who assume roles in which direct care is not their primary function. Copyright © 2016 by the American Occupational Therapy Association, Inc.

  8. Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor (BDNF) tohuman umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) promotescrush-injured rat sciatic nerve regeneration.

    Science.gov (United States)

    Hei, Wei-Hong; Almansoori, Akram A; Sung, Mi-Ae; Ju, Kyung-Won; Seo, Nari; Lee, Sung-Ho; Kim, Bong-Ju; Kim, Soung-Min; Jahng, Jeong Won; He, Hong; Lee, Jong-Ho

    2017-03-16

    This study was designed toinvestigate the efficacy of adenovirus vector-mediated brain-derived neurotrophic factor (BDNF) ex vivo gene transfer to human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) in a rat sciatic nerve crush injury model. BDNF protein and mRNA expression after infection was checked through an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Male Sprague-Dawley rats (200-250g, 6 weeks old) were distributed into threegroups (n=20 each): the control group, UCB-MSC group, and BDNF-adenovirus infected UCB-MSC (BDNF-Ad+UCB-MSC) group. UCB-MSCs (1×10 6 cells/10μl/rat) or BDNF-Ad+UCB-MSCs (1×10 6 cells/10μl/rat)were transplantedinto the rats at the crush site immediately after sciatic nerve injury. Cell tracking was done with PKH26-labeled UCB-MSCs and BDNF-Ad+UCB-MSCs (1×10 6 cells/10μl/rat). The rats were monitored for 4 weeks post-surgery. Results showed that expression of BDNF at both the protein and mRNA levels was higher inthe BDNF-Ad+UCB-MSC group compared to theUCB-MSC group in vitro.Moreover, BDNF mRNA expression was higher in both UCB-MSC group and BDNF-Ad+ UCB-MSC group compared tothe control group, and BDNF mRNA expression in theBDNF-Ad+UCB-MSC group was higher than inboth other groups 5days after surgeryin vivo. Labeled neurons in the dorsal root ganglia (DRG), axon counts, axon density, and sciatic function index were significantly increased in the UCB-MSC and BDNF-Ad+ UCB-MSCgroupscompared to the controlgroup four weeksaftercell transplantation. Importantly,the BDNF-Ad+UCB-MSCgroup exhibited more peripheral nerve regeneration than the other two groups.Our results indicate thatboth UCB-MSCs and BDNF-Ad+UCB-MSCscan improve rat sciatic nerve regeneration, with BDNF-Ad+UCB-MSCsshowing a greater effectthan UCB-MSCs. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Brain Basics

    Medline Plus

    Full Text Available ... Brain Research Glossary Brain Basics (PDF, 10 pages) Introduction Watch the Brain Basics video Welcome. Brain Basics provides information on how the brain works, how mental illnesses ...

  10. Brain Basics

    Science.gov (United States)

    ... Events About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  11. Brain Basics

    Medline Plus

    Full Text Available ... Events About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  12. Brain Basics

    Medline Plus

    Full Text Available ... Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... learning more about how the brain grows and works in healthy people, and how normal brain development ...

  13. Uncoupling evolutionary changes in DNA sequence, transcription factor occupancy and enhancer activity.

    Science.gov (United States)

    Khoueiry, Pierre; Girardot, Charles; Ciglar, Lucia; Peng, Pei-Chen; Gustafson, E Hilary; Sinha, Saurabh; Furlong, Eileen Em

    2017-08-09

    Sequence variation within enhancers plays a major role in both evolution and disease, yet its functional impact on transcription factor (TF) occupancy and enhancer activity remains poorly understood. Here, we assayed the binding of five essential TFs over multiple stages of embryogenesis in two distant Drosophila species (with 1.4 substitutions per neutral site), identifying thousands of orthologous enhancers with conserved or diverged combinatorial occupancy. We used these binding signatures to dissect two properties of developmental enhancers: (1) potential TF cooperativity, using signatures of co-associations and co-divergence in TF occupancy. This revealed conserved combinatorial binding despite sequence divergence, suggesting protein-protein interactions sustain conserved collective occupancy. (2) Enhancer in-vivo activity, revealing orthologous enhancers with conserved activity despite divergence in TF occupancy. Taken together, we identify enhancers with diverged motifs yet conserved occupancy and others with diverged occupancy yet conserved activity, emphasising the need to functionally measure the effect of divergence on enhancer activity.

  14. Occupancy of dopamine D{sub 2} receptors in the mouse brain measured using ultra-high-resolution single-photon emission tomography and [{sup 123}I]IBF

    Energy Technology Data Exchange (ETDEWEB)

    Acton, Paul D.; Hou, Catherine; Kung, Mei-Ping; Ploessl, Karl; Keeney, Cindy L. [Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104 (United States); Kung, Hank F. [Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104 (United States); Department of Pharmacology, University of Pennsylvania, Philadelphia (United States)

    2002-11-01

    Functional imaging of small animals, such as mice and rats, using ultra-high-resolution positron emission tomography (PET) and single-photon emission tomography (SPET) should be a valuable tool in studies of drug occupancy of cerebral binding sites. In this study we aimed to demonstrate the feasibility of using ultra-high-resolution SPET to measure the occupancy of dopamine D{sub 2} receptors by a competing drug, using the dopamine D{sub 2} receptor-specific radioligand iodine-123 5-iodo-7-N-[(1-ethyl-2-pyrrolidinyl) methyl] carboxamido-2,3-dihydrobenzofuran ([{sup 123}I]IBF). Fourteen normal male mice (CD-1) were jugular vein-cannulated and a bolus infusion protocol was used to deliver 360 MBq [{sup 123}I]IBF into the mouse (bolus-to-infusion ratio 1.8:1). The mice were scanned using an ultra-high-resolution triple-headed SPET system equipped with pinhole collimators. After sustained equilibrium had been achieved, varying doses of raclopride, a potent dopamine D{sub 2} receptor antagonist, were injected through the tail vein and the tracer was allowed to regain equilibrium. A simple equilibrium ratio of striatum to cerebellum provided a measure of D{sub 2} receptor binding both before and after injection of raclopride. Following raclopride administration, the system returned to equilibrium with lower specific binding in the striatum, while the counts in the cerebellum were unaffected. Receptor occupancy was 5.2%{+-}2.9% (control), 52.1%{+-}11.1% (0.3 mg/kg), 79.3%{+-}4.8% (1.0 mg/kg), and 94.7%{+-}2.2% (3.0 mg/kg), which gave an ED{sub 50}=0.26{+-}0.03 mg/kg using a single receptor site saturation model. This study has demonstrated clearly that ultra-high-resolution SPET of small animals is capable of measuring displacement and occupancy of dopamine D{sub 2} receptors by competing ligands. (orig.)

  15. Zoonoses as occupational diseases

    Directory of Open Access Journals (Sweden)

    Giorgio Battelli

    2008-12-01

    Full Text Available Zoonoses are discussed as occupational diseases, with special reference to animal husbandry and related activities. After quoting some historical references, occupational zoonoses are examined in relation to the evolution of the concept of occupational zoonosis, the involvement of the World Health Organization in this field, their socio-economic significance, the principal working activities, zoonoses of greatest importance (with special reference to the Mediterranean region, the evaluation of damage and risks. An outline is made of the transmission of zoonoses from farm workers to animals and the biological hazards from the environment. The present situation of occupational zoonoses and related risks in industrialised and traditional farming activities are presented and the importance of some emerging and re-emerging zoonoses for the health of workers is highlighted. The author concludes by stressing that the prevention of occupational zoonoses must be implemented jointly by both veterinary and medical services through preventive measures and epidemiological surveillance of human and animal health, risk evaluation, diagnosis of infections and prompt reporting. It is hoped that the future will offer better inter-disciplinary collaboration and that legislation will be timely and better tailored to safeguard working health and safety.

  16. Occupation-centred, occupation-based, occupation-focused: same, same or different?

    Science.gov (United States)

    Fisher, Anne G

    2013-05-01

    Since the beginning of the occupational therapy profession, engagement in occupation has been valued as the primary therapeutic agent as well as the goal of intervention. While there are few today who would not support this idea, occupational therapists continue to struggle with implementing their beliefs through "what we do" and "how we do it". Contributing to this problem is their failure to use terminology in a manner that clearly defines what and how occupational therapists do what they do in occupational therapy research, education, and practice. The author will, therefore, first discuss some key occupational therapy terms and propose that they represent an occupation-related taxonomy that can be used to more clearly define and describe for occupational therapists and others what they do and how they do what they do as occupational therapists. Then, with a goal of fostering critical self-reflection among occupational scientists and occupational therapy researchers, educators, and practitioners, the author will go through the stages of the occupational therapy process outlined in the Occupational Therapy Intervention Process Model (OTIPM) and demonstrate how a more precise use of this occupation-related taxonomy can facilitate maximizing the power of occupation in practice.

  17. Occupational skin diseases

    DEFF Research Database (Denmark)

    Mahler, Vera; Aalto-Korte, Kristiina; Alfonso, Jose Hernan

    2017-01-01

    and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation...... is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness...

  18. Brain Vascular Imaging Techniques

    Directory of Open Access Journals (Sweden)

    Bàrbara Laviña

    2016-12-01

    Full Text Available Recent major improvements in a number of imaging techniques now allow for the study of the brain in ways that could not be considered previously. Researchers today have well-developed tools to specifically examine the dynamic nature of the blood vessels in the brain during development and adulthood; as well as to observe the vascular responses in disease situations in vivo. This review offers a concise summary and brief historical reference of different imaging techniques and how these tools can be applied to study the brain vasculature and the blood-brain barrier integrity in both healthy and disease states. Moreover, it offers an overview on available transgenic animal models to study vascular biology and a description of useful online brain atlases.

  19. Modeling Structural Brain Connectivity

    DEFF Research Database (Denmark)

    Ambrosen, Karen Marie Sandø

    The human brain consists of a gigantic complex network of interconnected neurons. Together all these connections determine who we are, how we react and how we interpret the world. Knowledge about how the brain is connected can further our understanding of the brain’s structural organization, help...... improve diagnosis, and potentially allow better treatment of a wide range of neurological disorders. Tractography based on diffusion magnetic resonance imaging is a unique tool to estimate this “structural connectivity” of the brain non-invasively and in vivo. During the last decade, brain connectivity...... has increasingly been analyzed using graph theoretic measures adopted from network science and this characterization of the brain’s structural connectivity has been shown to be useful for the classification of populations, such as healthy and diseased subjects. The structural connectivity of the brain...

  20. Brain herniation

    Science.gov (United States)

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  1. MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain.

    Directory of Open Access Journals (Sweden)

    Sabine Lagger

    2017-05-01

    Full Text Available Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function.

  2. A Family Occupation

    NARCIS (Netherlands)

    Vanderwal Taylor, Jolanda

    1997-01-01

    Many of today's Dutch writers were children during World War II. Even today, the traumatic childhood experience of enemy occupation is still central to the work of many of them. This interest cuts across the traditional boundaries between fiction, autobiography and the literature of trauma and

  3. Hospitality Occupations. Curriculum Guide.

    Science.gov (United States)

    California State Dept. of Education, Sacramento. Bureau of Homemaking Education.

    This curriculum guide on the hospitality occupations was developed to help secondary and postsecondary home economics teachers prepare individuals for entry-level jobs in the hospitality industry. The content is in seven sections. The first section presents organizational charts of a medium-size hotel, food and beverage division, housekeeping and…

  4. Occupancy and Occupants’ Actions

    DEFF Research Database (Denmark)

    Schweiker, Marcel; Carlucci, Salvatore; Andersen, Rune

    2018-01-01

    into physical environmental, physiological, psychological, and social aspects. Finally, a comprehensive table of studies related to occupant behavior and the corresponding significant and non-significant predictors, based on an extensive literature review, is shown. This table highlights areas of research where...

  5. Occupational Hazards of Farming

    OpenAIRE

    White, Gill; Cessna, Allan

    1989-01-01

    A number of occupational hazards exist for the farmer and farm worker. They include the hazards of farm machinery, biologic and chemical hazards, and social and environmental stresses. Recognizing of these hazards will help the family physician care for farmers and their families.

  6. Occupational Hazards of Farming

    Science.gov (United States)

    White, Gill; Cessna, Allan

    1989-01-01

    A number of occupational hazards exist for the farmer and farm worker. They include the hazards of farm machinery, biologic and chemical hazards, and social and environmental stresses. Recognizing of these hazards will help the family physician care for farmers and their families. PMID:21248929

  7. Chef. Occupational Simulation Kit.

    Science.gov (United States)

    San Juan Basin Area Vocational-Technical School, Cortez, CO.

    This career exploration instructional booklet on the chef's occupation is one of several resulting from the rural southwestern Colorado CEPAC Project (Career Education Process of Attitude Change). Based on a job analysis and utilizing a programed instructional format, the following content is included: A brief description of a chef's job…

  8. Predicting occupational lung diseases

    NARCIS (Netherlands)

    Suarthana, E.

    2008-01-01

    This thesis aims at demonstrating the development, validation, and application of prediction models for occupational lung diseases. Prediction models are developed to estimate an individual’s probability of the presence or future likelihood of occurrence of an outcome (i.e. disease of interest or

  9. Occupational chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Omland, Oyvind; Würtz, Else Toft; Aasen, Tor Brøvig

    2014-01-01

    Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures....

  10. Mission Critical Occupation (MCO) Charts

    Data.gov (United States)

    Office of Personnel Management — Agencies report resource data and targets for government-wide mission critical occupations and agency specific mission critical and/or high risk occupations. These...

  11. Occupational Safety and Health Administration

    Science.gov (United States)

    ... Twitter Instagram RSS Subscribe Occupational Safety and Health Administration English | Spanish MENU OSHA English | Spanish Search A ... STATES DEPARTMENT OF LABOR Occupational Safety and Health Administration 200 Constitution Ave., NW, Washington, DC 20210 800- ...

  12. Occupational contact dermatitis in hairdressers

    DEFF Research Database (Denmark)

    Schwensen, Jakob F; Johansen, Jeanne D; Veien, Niels K

    2014-01-01

    BACKGROUND: Occupational contact dermatitis among hairdressers is frequent, owing to daily exposure to irritants and allergens. OBJECTIVES: To identify sensitization to the most common allergens associated with the occupation of hairdressing. METHODS: Patch test results of 399 hairdressers and 19...

  13. Occupational Therapist Assistants and Aides

    Science.gov (United States)

    ... study and include instruction in subjects such as psychology, biology, and pediatric health. In addition to taking ... Handbook , Occupational Therapy Assistants and Aides, on the Internet at https://www.bls.gov/ooh/healthcare/occupational- ...

  14. Occupational causes of male infertility

    DEFF Research Database (Denmark)

    Bonde, Jens P E

    2013-01-01

    To highlight and discuss the new evidence on occupational and environmental risk to male reproductive function.......To highlight and discuss the new evidence on occupational and environmental risk to male reproductive function....

  15. Dermatoses Ocupacionais Occupational dermatosis

    Directory of Open Access Journals (Sweden)

    Alice de Oliveira de Avelar Alchorne

    2010-04-01

    Full Text Available Dermatose ocupacional é qualquer alteração da pele, mucosa e anexos, direta ou indiretamente causada, condicionada, mantida ou agravada por agentes presentes na atividade ocupacional ou no ambiente de trabalho. Os autores referem a importância do tema, a epidemiologia e a etiopatogenia das principais dermatoses ocupacionais: dermatites de contato irritativas e alérgicas, fitodermatites, acnes (elaioconiose e cloracne, ceratoses, cânceres, granulomas de corpo estranho, infecções, oníquias e ulcerações. A clínica da dermatose ocupacional é apresentada em diferentes profissões. Analisam-se os exames laboratoriais pedidos nessas dermatoses, com especial destaque para testes de contato, que são o padrão ouro, e fornecem-se dados do tratamento e prevenção; quanto à prevenção da dermatose ocupacional, informam-se as medidas coletivas e individuais, especialmente, no que respeita ao uso adequado dos equipamentos de proteção individual.Occupational Dermatosis is described as any alteration in the skin, mucosa or annexes that is directly or indirectly caused, conditioned, maintained or aggravated by agents present in the occupational activity or work environment. The authors of the present study describe the importance of the topic and the epidemiology and etiopathogeny of the main forms of occupational dermatoses: allergic and irritative contact dermatitis, phytodermatitis, acne (elaioconioses and chloracne, keratosis, cancers, foreign body granuloma, infections, onychias, and ulcerations. Clinical findings of occupational dermatosis are presented in relation to various professions. Laboratory tests used to diagnose this condition are analysed, with special emphasis on patch testing, which is the gold standard. Information about the treatment and prevention of this disorder is provided. Collective and individual measures, especially regarding the proper use of individual protection equipment for the prevention of occupational

  16. Brain energy metabolism: development and application o