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[PMID]: 24839995
[Au] Autor:Poet TS; Timchalk C; Hotchkiss JA; Bartels MJ
[Ad] Address:Summit Toxicology , Richland, WA , USA .
[Ti] Title:Chlorpyrifos PBPK/PD model for multiple routes of exposure.
[So] Source:Xenobiotica;44(10):868-81, 2014 Oct.
[Is] ISSN:1366-5928
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Abstract 1. Chlorpyrifos (CPF) is an important pesticide used to control crop insects. Human Exposures to CPF will occur primarily through oral exposure to residues on foods. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been developed that describes the relationship between oral, dermal and inhalation doses of CPF and key events in the pathway for cholinergic effects. The model was built on a prior oral model that addressed age-related changes in metabolism and physiology. This multi-route model was developed in rats and humans to validate all scenarios in a parallelogram design. 2. Critical biological effects from CPF exposure require metabolic activation to CPF oxon, and small amounts of metabolism in tissues will potentially have a great effect on pharmacokinetics and pharmacodynamic outcomes. Metabolism (bioactivation and detoxification) was therefore added in diaphragm, brain, lung and skin compartments. Pharmacokinetic data are available for controlled human exposures via the oral and dermal routes and from oral and inhalation studies in rats. The validated model was then used to determine relative dermal versus inhalation uptake from human volunteers exposed to CPF in an indoor scenario.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.3109/00498254.2014.918295

  2 / 1234778 MEDLINE  
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[PMID]: 24827375
[Au] Autor:Liu H; Li Y; Lu S; Wu Y; Sahi J
[Ad] Address:Department of Drug Metabolism and Pharmacokinetics , GlaxoSmithKline R&D China, Shanghai , People's Republic of China.
[Ti] Title:Temporal expression of transporters and receptors in a rat primary co-culture blood-brain barrier model.
[So] Source:Xenobiotica;44(10):941-51, 2014 Oct.
[Is] ISSN:1366-5928
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Abstract 1. The more relevant primary co-cultures of brain microvessel endothelial cells and astrocytes (BMEC) are less utilized for screening of potential CNS uptake when compared to intestinal and renal cell lines. 2. In this study, we characterized the temporal mRNA expression of major CNS transporters and receptors, including the transporter regulators Pxr, Ahr and Car in a rat BMEC co-cultured model. Permeability was compared with the Madin-Darby canine kidney (MDCKII)-MDR1 cell line and rat brain in situ perfusion model. 3. Our data demonstrated differential changes in expression of individual transporters and receptors over the culture period. Expression of ATP-binding cassette transporters was better retained than that of solute carrier transporters. The insulin receptor (IR) was best maintained among investigated receptors. AhR demonstrated high mRNA expression in rat brain capillaries and expression was better retained than Pxr or Car in culture. Mdr1b expression was up-regulated during primary culture, albeit Mdr1a mRNA levels were much higher. P-gp and Bcrp-1 were highly expressed and functional in this in vitro system. 4. Permeability measurements with 18 CNS marketed drugs demonstrated weak correlation between rBMEC model and rat in situ permeability and moderate correlation with MDCKII-MDR1 cells. 5. We have provided appropriate methodologies, as well as detailed and quantitative characterization data to facilitate improved understanding and rational use of this in vitro rat BBB model.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.3109/00498254.2014.919430

  3 / 1234778 MEDLINE  
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[PMID]: 24666334
[Au] Autor:Nagasaka Y; Sano T; Oda K; Kawamura A; Usui T
[Ad] Address:Analysis and Pharmacokinetics Research Labs, Astellas Pharma Inc. , Ibaraki , Japan .
[Ti] Title:Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole.
[So] Source:Xenobiotica;44(10):926-32, 2014 Oct.
[Is] ISSN:1366-5928
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Abstract 1. We investigated how deficiencies in P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) affect the pharmacokinetics of atypical antipsychotics aripiprazole and its active metabolite (dehydroaripiprazole) using normal Friend leukemia virus strain B (FVB) mice, BCRP knockout (Bcrp[-/-]) mice, and P-gp and BCRP triple knockout (Mdr1a/1b[-/-]Bcrp[-/-]) mice. 2. While plasma concentrations of aripiprazole and dehydroaripiprazole after oral administration were slightly higher in both Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice than in normal FVB mice, the difference was not marked. The increase in absolute bioavailability (F) compared with normal mice (approximately 1.3-fold increase) was comparable between Bcrp(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice. This finding suggests that BCRP may be involved in the intestinal absorption of aripiprazole in mice, albeit with minimal contribution to absorption at best. 3. In contrast, the brain-to-plasma concentration ratio (Kp,brain) for aripiprazole and dehydroaripiprazole after oral administration was significantly higher in Mdr1a/1b(-/-)/Bcrp(-/-) mice than in normal mice, whereas Bcrp(-/-) mice exhibited Kp,brain values similar to those in normal mice. In addition, the Kp,brain values in Mdr1a/1b(-/-)/Bcrp(-/-) mice were not drastically different from those previously reported in Mdr1a/1b(-/-) mice, suggesting that brain penetration of aripiprazole and dehydroaripiprazole can be affected by P-gp, but with little synergistic effect of BCRP.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.3109/00498254.2014.901585

  4 / 1234778 MEDLINE  
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[PMID]: 25196484
[Au] Autor:Lewis TB; Glasgow JN; Harms AS; Standaert DG; Curiel DT
[Ad] Address:Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. travis.lewis@uphs.upenn.edu....
[Ti] Title:Fiber-modified adenovirus for central nervous system Parkinson's disease gene therapy.
[So] Source:Viruses;6(8):3293-310, 2014.
[Is] ISSN:1999-4915
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Gene-based therapies for neurological diseases continue to develop briskly. As disease mechanisms are elucidated, flexible gene delivery platforms incorporating transcriptional regulatory elements, therapeutic genes and targeted delivery are required for the safety and efficacy of these approaches. Adenovirus serotype 5 (Ad5)-based vectors can carry large genetic payloads to provide this flexibility, but do not transduce neuronal cells efficiently. To address this, we have developed a tropism-modified Ad5 vector with neuron-selective targeting properties for evaluation in models of Parkinson disease therapy. A panel of tropism-modified Ad5 vectors was screened for enhanced gene delivery in a neuroblastoma cell line model system. We used these observations to design and construct an unbiased Ad vector platform, consisting of an unmodified Ad5 and a tropism-modified Ad5 vector containing the fiber knob domain from canine Ad serotype 2 (Ad5-CGW-CK2). Delivery to the substantia nigra or striatum showed that this vector produced a neuronally-restricted pattern of gene expression. Many of the transduced neurons were from regions with afferent projections to the injection site, implicating that the vector binds the presynaptic terminal resulting in presynaptic transduction. We show that Ad5-CGW-CK2 can selectively transduce neurons in the brain and hypothesize that this modular platform is potentially adaptable to clinical use.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.3390/v6083293

  5 / 1234778 MEDLINE  
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[PMID]: 25044505
[Au] Autor:Heo S; Spoerk S; Birner-Gruenberger R; Lubec G
[Ad] Address:Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
[Ti] Title:Gel-based mass spectrometric analysis of hippocampal transmembrane proteins using high resolution LTQ Orbitrap Velos Pro.
[So] Source:Proteomics;14(17-18):2084-8, 2014 Sep.
[Is] ISSN:1615-9861
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Membrane proteins (MPs) play diverse important roles for physical interactions, cell communication, molecular transport, and signal transduction. Membrane proteins comprise approximately 25∼35% of the genome in living organisms, but there are difficulties in the analysis at the protein chemical level, in particular due to low abundance and limited solubility. Sequence information on membrane proteins and their complexes would be beneficial to elucidate their function. Proteins were extracted from pooled whole mouse brains, enriched membrane fractions were prepared using either two commercially available kits or 6-aminocaproic acid under denaturing or native conditions followed by gel-based proteomic approaches using blue native (BN-) and SDS-PAGE with subsequent in-gel digestion with several proteases, chymotrypsin, trypsin followed by nano-LC-ESI-MS/MS analysis on LTQ Orbitrap Velos Pro. By combining three different extraction methods and two separation methods, 28.39% of proteins were identified as either "integral" or "anchored/integral" MPs based on UniProtKB database searches. MPs with more than six transmembrane domains (TMDs) were identified more efficiently from BN-PAGE separation although a higher number of proteins was identified from SDS-PAGE separation. Comparative analysis of MPs containing TMDs via gel-based LC-MS/MS using BN-PAGE and SDS-PAGE may be useful to increase the number of identified membrane proteins in brain. All MS data have been deposited in the ProteomeXchange with identifier PXD000311 (http://proteomecentral.proteomexchange.org/dataset/PXD000311).
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1002/pmic.201400077

  6 / 1234778 MEDLINE  
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[PMID]: 25194495
[Au] Autor:Steinlein OK
[Ti] Title:Preface.
[So] Source:Prog Brain Res;213:vii, 2014.
[Is] ISSN:1875-7855
[Cp] Country of publication:Netherlands
[La] Language:eng
[Pt] Publication type:EDITORIAL
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review

  7 / 1234778 MEDLINE  
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[PMID]: 25194494
[Au] Autor:Kobow K; Blümcke I
[Ad] Address:Department of Neuropathology, University Hospital Erlangen, Schwabachanlage, Erlangen, Germany.
[Ti] Title:Epigenetic mechanisms in epilepsy.
[So] Source:Prog Brain Res;213:279-316, 2014.
[Is] ISSN:1875-7855
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:In humans, genomic DNA is organized in 23 chromosome pairs coding for roughly 25,000 genes. Not all of them are active at all times. During development, a broad range of different cell types needs to be generated in a highly ordered and reproducible manner, requiring selective gene expression programs. Epigenetics can be regarded as the information management system that is able to index or bookmark distinct regions in our genome to regulate the readout of DNA. It further comprises the molecular memory of any given cell, allowing it to store information of previously experienced external (e.g., environmental) or internal (e.g., developmental) stimuli, to learn from this experience and to respond. The underlying epigenetic mechanisms can be synergistic, antagonistic, or mutually exclusive and their large variety combined with the variability and interdependence is thought to provide the molecular basis for any phenotypic variation in physiological and pathological conditions. Thus, widespread reconfiguration of the epigenome is not only a key feature of neurodevelopment, brain maturation, and adult brain function but also disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review

  8 / 1234778 MEDLINE  
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[PMID]: 25194493
[Au] Autor:Helbig I
[Ad] Address:Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, USA. Electronic address: helbigi@email.chop.edu.
[Ti] Title:New technologies in molecular genetics: the impact on epilepsy research.
[So] Source:Prog Brain Res;213:253-78, 2014.
[Is] ISSN:1875-7855
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Technical advances in the last decade have finally enabled researchers to identify epilepsy-associated genetic variants by querying virtually the entire genome. In the first decade of the twenty-first century, this technical revolution began with the advent of array comparative genomic hybridization and single nucleotide polymorphism arrays. These technologies made it possible for the first time to screen for common genetic variants and rare small deletions and duplications, referred to as microdeletions and microduplications. More recently, the repertoire of technologies has expanded to exome-wide and genome-wide sequencing approaches. These technologies led to a virtual explosion of gene identifications both in familial cases and in rare severe epilepsies, referred to as epileptic encephalopathies. This chapter aims to provide an overview of the achievements of these new technologies and the challenges that the field is currently facing.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review

  9 / 1234778 MEDLINE  
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[PMID]: 25194492
[Au] Autor:Maheshwari A; Noebels JL
[Ad] Address:Department of Neurology, Developmental Neurogenetics Laboratory, Baylor College of Medicine Houston, TX, USA. Electronic address: atul.maheshwari@bcm.edu.
[Ti] Title:Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits.
[So] Source:Prog Brain Res;213:223-52, 2014.
[Is] ISSN:1875-7855
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Absence epilepsy is a common disorder that arises in childhood and can be refractory to medical treatment. Single genetic mutations in mice, at times found in patients with absence epilepsy, provide the unique opportunity to bridge the gap between dysfunction at the genetic level and pathological oscillations within the thalamocortical circuit. Interestingly, unlike other forms of epilepsy, only genes related to ion channels have so far been linked to absence phenotypes. Here, we delineate a paradigm which attempts to unify the various monogenic models based on decades of research. While reviewing the particular impact of these individual mutations, we posit a framework involving fast feedforward disinhibition as one common mechanism that can lead to increased tonic inhibition in the cortex and/or thalamus. Enhanced tonic inhibition hyperpolarizes principal cells, deinactivates T-type calcium channels, and leads to reciprocal burst firing within the thalamocortical loop. We also review data from pharmacologic and polygenic models in light of this paradigm. Ultimately, many questions remain unanswered regarding the pathogenesis of absence epilepsy.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review

  10 / 1234778 MEDLINE  
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[PMID]: 25194491
[Au] Autor:Greenberg DA; Stewart WL
[Ad] Address:Battelle Center for Mathematical Medicine, Nationwide Children's Hospital and Pediatrics Department, Wexner Medical Center, Ohio State University, Columbus, OH, USA. Electronic address: david.greenberg@nationwidechildrens.org.
[Ti] Title:Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective on why progress on identifying genetic influences on common epilepsies has been so slow.
[So] Source:Prog Brain Res;213:199-221, 2014.
[Is] ISSN:1875-7855
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:In this chapter, we will use the concepts and perspective of population genetics and genetic analysis to discuss the trends that are currently popular in the epilepsy genetics literature. We will also show that some of the recent approaches to understanding epilepsy genetics are unlikely to lead to insight into the causes of the most common epilepsies. Much effort has been directed toward very rare influences on epilepsy expression and away from approaches that could shed light on the most heritable epilepsies. The latest genetic technology, e.g., exome sequencing and copy number variants (CNV) analysis, has been applied without proper consideration of the important principles of population genetics, inheritance, or phenotype definition that are critical in common disease studies. We will show that ignoring these issues has led to unlikely suppositions about etiology and about which genes should be pursued. We also suggest that, taken together, the existing evidence supports a neurodevelopmental origin for common epilepsies. We recommend a return to thorough phenotype definition and family studies and a more careful and thoughtful application of the new technology.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Js] Journal subset:IM
[St] Status:In-Data-Review


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