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Search Results: 1 - 10 of 89736 matches for " W. Ted Brown "
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北京大学学报(医学版) , 2009,
Abstract: ?无
The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome
Hongen Wei, Carl Dobkin, Ashfaq M. Sheikh, Mazhar Malik, W. Ted Brown, Xiaohong Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036981
Abstract: Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.
IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation
Hongen Wei, Hua Zou, Ashfaq M Sheikh, Mazhar Malik, Carl Dobkin, W Ted Brown, Xiaohong Li
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-52
Abstract: Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively.In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses.Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.Autistic disorder is the most severe of a group of neurodevelopmental disorders, referred to as autism spectrum disorders (ASDs), and is characterized by problems in communication, social skills, and repetitive behavior. Susceptibility to autism is clearly attributable to genetic factors [1-4], but the etiology of the disorder is unknown. Recent studies suggest that a combination of environmental risk factors, autoimmune conditions and localized inflammation of the central nervous system may contribute to the pathogenesis of autism [5-10].Interleukin (IL)-6 was originally foun
Clinical Importance of Steps Taken per Day among Persons with Multiple Sclerosis
Robert W. Motl, Lara A. Pilutti, Yvonne C. Learmonth, Myla D. Goldman, Ted Brown
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073247
Abstract: Background The number of steps taken per day (steps/day) provides a reliable and valid outcome of free-living walking behavior in persons with multiple sclerosis (MS). Objective This study examined the clinical meaningfulness of steps/day using the minimal clinically important difference (MCID) value across stages representing the developing impact of MS. Methods This study was a secondary analysis of de-identified data from 15 investigations totaling 786 persons with MS and 157 healthy controls. All participants provided demographic information and wore an accelerometer or pedometer during the waking hours of a 7-day period. Those with MS further provided real-life, health, and clinical information and completed the Multiple Sclerosis Walking Scale-12 (MSWS-12) and Patient Determined Disease Steps (PDDS) scale. MCID estimates were based on regression analyses and analysis of variance for between group differences. Results The mean MCID from self-report scales that capture subtle changes in ambulation (1-point change in PDSS scores and 10-point change in MSWS-12 scores) was 779 steps/day (14% of mean score for MS sample); the mean MCID for clinical/health outcomes (MS type, duration, weight status) was 1,455 steps/day (26% of mean score for MS sample); real-life anchors (unemployment, divorce, assistive device use) resulted in a mean MCID of 2,580 steps/day (45% of mean score for MS sample); and the MCID for the cumulative impact of MS (MS vs. control) was 2,747 steps/day (48% of mean score for MS sample). Conclusion The change in motion sensor output of ~800 steps/day appears to represent a lower-bound estimate of clinically meaningful change in free-living walking behavior in interventions of MS.
Microarray Analysis Reveals Higher Gestational Folic Acid Alters Expression of Genes in the Cerebellum of Mice Offspring—A Pilot Study
Subit Barua,Salomon Kuizon,Kathryn K. Chadman,W. Ted Brown,Mohammed A. Junaid
Brain Sciences , 2015, DOI: 10.3390/brainsci5010014
Abstract: Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development.
NF- B Signaling in the Brain of Autistic Subjects
Mazhar Malik,Zujaja Tauqeer,Ashfaq M. Sheikh,Guang Wen,Amenah Nagori,Kun Yang,W. Ted Brown,Xiaohong Li
Mediators of Inflammation , 2011, DOI: 10.1155/2011/785265
Abstract: Autism is a neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Recent studies suggest that apoptotic and inflammatory mechanisms may contribute to the pathogenesis of this disorder. Nuclear factor- B (NF- B) is an important gene transcriptional factor involved in the mediation of inflammation and apoptosis. This study examined the activities of the NF- B signaling pathway in the brain of autistic subjects and their age-matched controls. The NF- B activation is also determined in the brain of BTBR mice, which is a promising animal model for study of pathogenic mechanisms responsible for autism. Our results showed that the level of IKK kinase, which phosphorylates the inhibitory subunit I B , is significantly increased in the cerebellum of autistic subjects. However, the expression and phosphorylation of I B are not altered. In addition, our results demonstrated that the expression of NF- B (p65), and the phosphorylation/activation of NF- B (p65) at Ser536 are not significantly changed in the cerebellum and cortex of both autistic subjects and BTBR mice. Our findings suggest that the NF- B signaling pathway is not disregulated in the brain of autistic subjects and thus may not be significantly involved in the processes of abnormal inflammatory responses suggested in autistic brain. 1. Introduction Autism is a severe neurodevelopmental disorder of childhood characterized by impairments in social interaction, deficits in verbal and nonverbal communication, and restricted, repetitive, and stereotypical patterns of behavior and interests (DSMIV criteria, American Psychiatric Association, 1994). Many areas of the brain in autism show abnormalities that include decreased Purkinje cell counts in cerebellar hemispheres and vermis [1], loss of granular cells [2], and Purkinje cell atrophy [3, 4]. Susceptibility to autism is clearly attributable to genetic factors [5, 6], but the etiology of this disorder is unknown, and no biomarkers have yet been proven to be characteristic of autism. The BTBR T+tfJ (BTBR) mice have been suggested to be a useful animal model for autism studies since they demonstrate low levels of sociability compared to the C57BL/6J (B6) mice [7–10]. The BTBR mice also exhibit an unusual pattern of ultrasonic vocalizations and high levels of self-grooming [9, 11–13] that may be homologous to the communication deficits and repetitive behaviors observed in autism. Thus, the BTBR strain of mice is currently a promising model for understanding the mechanisms that could be responsible for
北京大学学报(医学版) , 2009,
Abstract: ?无
Oligopsony, Information Technology, and Systems Integration: The Case of the Healthcare Supply Industry
Christopher Brown,Ted Lee
International Journal of Business and Management , 2009,
Abstract: This article examines the importance of oligopsony power in stimulating the diffusion of cost saving information technology throughout the healthcare supply chain. We present evidence to support the hypothesis that the optimal structure of the distribution stage of healthcare supply industry is (from the standpoint of cost minimization and reliability) highly concentrated. The hypothesis is predicated on two factors: (1) host-integrated electronic data interchange (EDI) is subject to substantial economies of scale; and (2) the oligopsony power possessed by giant distributors can be leveraged to force upstream suppliers into compliance with technical standards for EDI and automated data capture.
Increasing Maternal or Post-Weaning Folic Acid Alters Gene Expression and Moderately Changes Behavior in the Offspring
Subit Barua, Kathryn K. Chadman, Salomon Kuizon, Diego Buenaventura, Nathan W. Stapley, Felicia Ruocco, Umme Begum, Sara R. Guariglia, W. Ted Brown, Mohammed A. Junaid
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101674
Abstract: Background Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice. Methods Dams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring. Results Results from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.
Capsaicin Displays Anti-Proliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E2F Pathway
Kathleen C. Brown,Ted R. Witte,W. Elaine Hardman,Haitao Luo,Yi C. Chen,A. Betts Carpenter,Jamie K. Lau,Piyali Dasgupta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010243
Abstract: Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo.
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